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Human Mesenchymal Stem Cells (hMSC) Market Size 2021 | Global Trends, Business Overview, Challenges, Opportunities and Forecast to 2027 The Bisouv…

Wednesday, March 3rd, 2021

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New Jersey, United States,-The Human Mesenchymal Stem Cells (hMSC) Market report provides in-depth knowledge and insights into the Human Mesenchymal Stem Cells (hMSC) market in terms of market size, market share, factors influencing growth, opportunities, and current and emerging trends. The report has the updated and latest information on the Human Mesenchymal Stem Cells (hMSC) market that has been further validated and verified by industry experts and professionals. The Human Mesenchymal Stem Cells (hMSC) market report provides historical, current, and forecast estimates of sales generation and profit for each segment and sub-segment of the Human Mesenchymal Stem Cells (hMSC) market in every key region around the world. The report also highlights the emerging growth opportunities in the business that are designed to support market growth.

The latest report is the latest study to offer 360 coverage of the Human Mesenchymal Stem Cells (hMSC) industry, which is facing the worst negative economic impact of the COVID-19 outbreak since the beginning of this year.

The report covers the following key players in the Human Mesenchymal Stem Cells (hMSC) Market:

PromoCell ThermoFisher KURABO Lifeline Cell Technology Merck

Segmentation of Human Mesenchymal Stem Cells (hMSC) Market:

The report provides an in-depth analysis of various market segments based on the product line, applications, major regions, and key companies in the industry. In addition, the report has a single section that provides a detailed analysis of the manufacturing process and includes information gathered from primary and secondary data collection sources. The main source for data collection is interviews with industry experts who provide accurate information about the future market scenario.

By the product type, the market is primarily split into:

Umbilical Cord Matrix hMSC Bone Marrow hMSC Adipose Tissue hMSC Other

By the application, this report covers the following segments:

Medical Application Research Other Applications

Human Mesenchymal Stem Cells (hMSC) Market Report Scope

Human Mesenchymal Stem Cells (hMSC) Geographic Market Analysis:

The latest business intelligence report analyzes the Human Mesenchymal Stem Cells (hMSC) market in terms of market reach and customer base in key geographic market regions. The Human Mesenchymal Stem Cells (hMSC) market can be geographically divided into North America, Asia Pacific, Europe, Latin America, the Middle East, and Africa. This section of the report provides an accurate assessment of the Human Mesenchymal Stem Cells (hMSC) market presence in the major regions. It defines the market share, market size, sales, distribution network and distribution channels for each regional segment.

Key Points of theGeographical Analysis:

** Data and information on consumption in each region** The estimated increase in consumption rate** Proposed growth in market share for each region** Geographic contribution to market income** Expected growth rates of the regional markets

Key Highlights of the Human Mesenchymal Stem Cells (hMSC)Market Report:

** Analysis of location factors** Raw material procurement strategy** Product mix matrix** Analysis to optimize the supply chain** Patent analysis** R&D analysis** Analysis of the carbon footprint** Price volatility before commodities** Benefit and cost analysis** Assessment and forecast of regional demand** Competitive analysis** Supplier management** Mergers and acquisitions** Technological advances

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[Full text] An Update on the Molecular Pathology of Metaplastic Breast Cancer | BCTT – Dove Medical Press

Wednesday, March 3rd, 2021

Introduction

Metaplastic breast cancer (MpBC) is a unique histologic subtype of breast cancer, defined by characteristic intra-tumoural heterogeneity. Although rare, MpBC accounts for significant morbidity and mortality, and has a poor prognosis. MpBC tend not to respond well to systemic chemotherapies, and together with emerging data on the genomic landscape of MpBC, there is scope for applying precision oncology in the management strategies of MpBC. We focus herein on the molecular pathology of MpBC and the current status and potential of targeted therapies to manage MpBC.

The clinical features of MpBC are similar to other high-grade cancers of no special type (NST), however, they often present at amore advanced stage. They tend to be large in size, with dimensions ranging from 1.2 to >10 cm and often present as a palpable breast mass, with ill-defined borders on mammography, ultrasonography, and magnetic resonance imaging. MpBC represents 0.21% of all breast cancers the rates vary due to the differing definitions and classification systems used over time.

MpBC do not have any distinctive macroscopic features, with the tumor varying from well-circumscribed to having an irregular border. Microscopically, they comprise a heterogenous group with differing outcomes. In the absence of sufficient molecular and outcome data, the current WHO Classification of Tumours of the Breast1,2 has maintained a descriptive morphological classification system, based on the type of the metaplastic elements present. MpBC are classified monophasic (when there is only one metaplastic component) or biphasic (with two or more metaplastic components such as squamous and spindle, or mixed metaplastic and non-metaplastic components such as spindle and invasive carcinoma NST). Further, MpBC can also be classified into epithelial-only carcinomas (with low-grade adenosquamous carcinoma or pure squamous cell carcinoma), pure (monophasic) sarcomatoid (spindle cell or matrix-producing) carcinomas, and biphasic epithelial and sarcomatoid carcinomas.

The current WHO classification includes (i) adenosquamous carcinoma mostly low grade but can be high grade rarely and (ii) pure squamous cell carcinomas (iii) pure spindle cell carcinoma (iv) fibromatosis-like metaplastic carcinoma, (iv) metaplastic carcinoma with mesenchymal differentiation that includes chondroid (myxoid/cartilaginous), osseous (bone), rhabdomyoid (muscle) and neuroglial, and (v) mixed metaplastic carcinoma where the mix may be multiple metaplastic elements or a mixture of epithelial and mesenchymal elements. Examples of the heterologous elements are shown in Figure 1. The detailed morphology of the subtypes is beyond the scope of this review and the reader is directed to the WHO Tumour Classification of the Breast 5th Ed (2019).2

Figure 1 Examples of Metaplastic breast cancer morphologies. (A) High-grade, pleomorphic de-differentiated carcinoma (IBC-NST). (B) High-grade carcinoma with focal squamous differentiation. (C) Osteoid differentiation. (D) Chondroid differentiation. (E) Spindle differentiation. Scale bar is 100 m.

MpBC are typically, though not invariably triple-negative (TN), lacking expression of estrogen and progesterone receptors (ER/PR), and HER2. Analysis of the SEER data showed that HER2 positive MpBC had an improved overall survival compared to TN, and other MpBC including ER+/PR+/HER2-cases, which accounted for 20% of the cohort.3 Conversely, HER2-positive metaplastic squamous cell carcinomas were recently demonstrated to have a poorer prognosis than the TN metaplastic squamous variants.4 MpBC fit into the claudin-low and/or basal breast cancer intrinsic subtypes,5,6 although whether or not claudin low represents an intrinsic subtype or phenotype has recently come into question.7 A recent large meta-analysis reported that approximately three quarters of all MpBC stain positively for pan-cytokeratin biomarkers (AE1/3, MNF116) and basal cytokeratin biomarkers (34E12, CK5/6, CK14 and CK17). GATA3, a common diagnostic marker used to identify tumours of breast origin, is expressed by only 21% of MpBC, while a novel breast marker, TRPS1, was shown to be highly expressed in 86% of MpBC, as well as non-metaplastic TNBC and BC more broadly.8 Frequent expression of p63 was also noted, as was an absence of staining for CD34.9 Those cases lacking cytokeratin expression were studied in more detail, and determined to be carcinomatous rather than true primary sarcomas in most cases, further evidencing the inter-tumor heterogeneity of breast cancer broadly, and MpBC specifically.10 Indeed, a pure sarcoma of the breast is rare and is a diagnosis of exclusion, requiring extensive sampling; negative stains for p63 and a range of cytokeratins; and, a morphological examination for any evidence of epithelial differentiation.

For the adenosquamous and fibromatosis-like variants of MpBC, the grade is implicitly low, and prognostic outcome is better than for the majority of MpBC which are typically classified as high grade (grade 3) tumors. Although high histologic grading is a relatively consistent finding, its prognostic value is still uncertain.11 A subset of MpBC tumors with extreme, bizarre cytologic pleomorphisms has been reported,11 with a noted enrichment in the spindle phenotype.

With respect to the TNM classification system of cancer stage, MpBC present with a larger tumor size (TNM), with reports indicating that ~60% of MpBC have tumors between 2 and 5 cm (T2;12). As for triple-negative breast cancers more broadly, lymph node (LN; the N of TNM) positivity is not a prominent feature, with LN metastasis documented in about 24% of patients. Distant metastasis (TNM) occurs with or without LN spread in MpBC, and spread to the lungs and brain has been reported.13

The innate plasticity of MpBC has led to suggestions that it is a stem-cell like breast cancer, and a wealth of data show that MpBC express classic stem cell markers. It is presently considered that there exist three categories of breast cancer stem cell (CSC): an ALDH+ epithelial-like CSC; CD44+/CD24 mesenchymal-like CSCs; and, a hybrid epithelial/mesenchymal-like ALDH+/CD44+/CD24 (reviewed in detail in14). The work of Zhang et al15 demonstrated the increased expression of classic stem cell markers ALDH1 and CD44/CD24 ratios in a series of MpBC, much like the above-noted hybrid CSC state, and also expression of characteristic epithelial to mesenchymal transition (EMT) markers (increased ZEB1 and loss of E-cadherin). This expression of stem-like markers was also supported by Gerhard et al,16 with most of their series showing positivity for CD44 and loss of CD24, as well as an enrichment for vimentin and loss of the claudins and E-cadherin. Given that cancer stem cells have well-documented chemoresistance,17 it is unsurprising that MpBC, with their enrichment of both stem-like markers and the hallmarks of EMT,5,18 also respond poorly to chemotherapeutics. Notably, MpBC have a high frequency of PIK3CA mutations (see below) and these mutations correlate with poor response to neoadjuvant chemotherapy in breast cancer subtypes broadly,19 and this holds true in the metastatic setting.20 Drugs targeting the PI3K/AKT axis are emerging in the clinic, may be appropriate for MpBC, and are discussed further below.

As shown in Table 1, the research community has yet to robustly elucidate a molecular landscape for MpBC, most likely due to the extensive sample heterogeneity. There is limited concordance between studies on the mutations present, however this is likely influenced by the sequencing platform (exome vs panel), and also the subtype composition of the cohorts.

Table 1 Genetic Alterations Identified Across MpBC Cohorts and Morphologies

PI-3 Kinase and Ras signaling pathway mutations have been shown to be early events in MpBC pathogenesis.21 Mutation frequencies reported for MpBC range from 26%-75% for TP53, and 23%-70% for PIK3CA (Table 1) and this is supported by a recent meta-analysis of 14 studies encompassing 539 cases.22 Other than TP53 and PIK3CA, the most frequently identified mutations across multiple cohorts occur in PTEN, NF1, HRAS, PIK3R1. Emerging data support that the various morphologic elements feature subtly different mutation profiles, with for example, a lack of PIK3CA mutations found in those MpBC with chondroid differentiation.23 Chondroid tumors were also shown to lack mutations in TERT promoters.21 TERT promoter mutations were enriched in the spindle and squamous type tumors, while TP53 mutations were less likely to be in spindled tumors than other MpBC types.21 An increase in mutations in Wnt pathway genes has been reported for MpBCs,23 with WISP3/CCN6 mutations more frequently seen in the epithelial components, and 3/7 CTNNB1 mutations present only in the spindle compartment of the tumor.24

In spite of the private mutations in the different morphological components as noted above, evidence supports that the different histologies have a shared origin, and following a detailed exome sequencing study, Avigdor et al postulated that methylation and/or non-coding changes may also regulate the phenotypic differentiation.25 To clarify the outstanding elements of the genomic landscape of MpBC, a concerted effort must be made to standardize sequencing approaches on an adequately powered cohort of well-annotated MpBC.

Uterine carcinosarcoma (UCS) are considered the metaplastic cancers of the gynaecological tract, and a recent study performed a comparative analysis of 57 UCS with 35 MpBC.26 Genetic differences unique to the UCS were reported, with a significant enrichment for mutations in FBXW7 and PPP2R1A, and HER2 amplifications, while shared genomic features included alterations in TP53, PIK3CA, PTEN and EMT-related Wnt and Notch signalling components. Interestingly, unlike the UCS, almost half of the profiled MpBC had a dominant homologous recombination deficiency (HRD; signature 3) signature, and these same cases showed other features of a HRD including large scale transitions, and allelic imbalance extending to the telomeres.

In the absence of indications for hormone and anti-HER2 therapies, and given their typically large size at presentation, MpBC are managed with chemotherapeutics in addition to surgery (with/without radiation). However, early studies showed that systemic therapy was less effective in MpBC12 and this data has held true over time and is supported by the overall poor outcomes of MpBC patients.27 In fact, while 90% of diagnoses of MpBC are for localized disease, half of these patients will progress to advanced BC over time.28,29 Treatment in the neoadjuvant setting appears to afford little advantage, with a 1017% pathological complete response rate reported3033 for American studies, while studies in Japan and Turkey reported no complete responders.34,35 It is clear that efficacious treatments for MpBC are an unmet clinical need, and while some clinical trials specifically for MpBC are being initiated, the potential for novel therapeutic interventions must be capitalized upon.

MpBC are characteristically triple-negative BC, thus eliminating these patients from current tailored therapeutic options of hormone therapy and anti-HER2 therapy. This triple-negativity, does however make them eligible for a multitude of trials currently recruiting, including those assessing benefit of immune checkpoint inhibitors; a non-exhaustive list of open trials is presented in Table 2.

Table 2 Active Trials Open to Metaplastic Breast Cancer Patients

MpBC show frequent alterations in the PI3K/AKT/mTOR pathway making them candidates for targeted therapies such as everolimus, temsirolimus, and alpelisib. In a Phase I intervention, a 42% rate of partial/complete remission was reported for a combination of temsirolimus and bevacizumab (HIF inhibitor).36 A 25% response rate (complete/partial response) was achieved in MpBC treated with temsirolimus/everolimus in combination with standard chemotherapy and a 21% objective response rate was also reported for the regimen of doxorubicin, bevacizumab and temsirolimus/everolimus,37 however genetic analysis showed that while PI3K pathway alterations were associated with a significant improvement in objective response rate (31% vs 0%) they were not associated with an improved clinical benefit rate (44% vs 45%). Detailed analysis of this trial data showed an improvement in overall survival for the MpBC patients, and suggests that MpBC histology is an indicator for doxorubicin with bevacizumab and everolimus/temsirolimus.38 A lone MpBC participant in the BELLE-4 Phase II/III trial responded well to a combined therapy of paclitaxel and the PI3K inhibitor buparlisib39 although toxicity was noted, and indeed buparlisib was subsequently discontinued from development, with a significantly higher burden of adverse effects noted for buparlisib than alpelisb in the B-YOND (hormone receptor positive, phase Ib) trial.40 Pre-clinical data in MpBC patient derived xenograft models suggest that a combination of PI3K and MAPK inhibitors may be a potential avenue for therapy in PIK3CA mutated MpBC patients.41

CDK4/6 inhibitors (eg, ribociclib, palbociclib, abemaciclib) are now approved as standard of care for advanced, hormone receptor positive breast cancers, however this proliferation check-point may also be a useful target in TNBC, and trials are underway to determine the efficacy of this approach (reviewed in42), including in combination with immune checkpoint inhibitors (PAveMenT: NCT04360941). A recent case report demonstrated a dramatic but short-term benefit from combined dabrafenib and trametinib in an advanced MpBC patient.43 Dabrafenib and trametinib target BRAF and MEK signalling, respectively, and their application in MpBC has not previously been reported.

Although a pre-clinical study did not support the efficacy of PARP inhibitor olaparib in an MpBC-like mouse model,44 given the recent evidence of a dominant HRD signature in almost 50% of the MpBC profiled,26 the suggestion by Tray et al45 that PARP inhibition for MpBC needs further study is certainly warranted. These studies together support further investigations into a range of targeted therapies and highlight their potential value in MpBC.

The potential benefit of therapeutic modulation of the immune system in breast cancer is becoming increasingly clear for TNBC, as well as MpBC. A case report of a remarkable, durable response to pembrolizumab (anti-PD-1) in combination with nab-Paclitaxel in advanced, pre-treated spindled MpBC was reported in 2017.46 A similar combination of durvalumab (anti-PD-L1) and paclitaxel was also shown to provide a sustained, complete response in a second case report of advanced MpBC, this time with squamous features.47 In this case, 20% of tumor cells stained with medium intensity (clone SP142), and there was an absence of staining in the TILS; while in the former case, 100% of tumor cells stained positively for PD-L1 using the 22C3 clone. Indeed, there is no standardized definition criteria for PD-L1 staining at this stage, and the characterization of expression of this and other immune checkpoint markers across TNBC and MpBC has only recently emerged. As shown in Table 3, heterogeneity in percentage positivity of PD-L1 in tumor cells is reported across TNBC, with a higher rate of positivity consistently reported for MpBC. MpBC tumor cells show a range of PD-L1 expression from 17% to 80%, recording both cytoplasmic and membranous staining, and in the immune cells from 48% to 69%. Combinations of immune-checkpoint inhibitors are also being evaluated, with the DART (Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors, Table 2) trial facilitating an MpBC specific assessment.48 Primary endpoint data confirmed clinical activity of ipilimumab combined with nivolumab and resulted in 3 cases of 17 showing a durable response, which supports further investigation. It is hoped that trials such as the Morpheus-TNBC Phase 1/1b umbrella trial (Table 2, NCT03424005), will provide insights to further our understanding of the biomarkers and patient indicators for a range of immunotherapeutic interventions.

Table 3 PD-L1 Expression in Metaplastic Breast Cancer

The morphologically diverse metaplastic breast cancers account for significant global morbidity and mortality, in spite of their relatively rare frequency, due to their aggressive clinical course. As more molecular pathology data emerges on the genomic underpinnings of this intriguing tumor type, we are increasingly better placed to consider MpBC for targeted therapies and immunotherapies.

We apologize to those authors whose work we could not include due to space restrictions.

The authors report no conflicts of interest in this work.

1. Board WCoTE. Breast Tumours. Lyon, France: Interantional Agency for Research on Cancer; 2019.

2. Reis-Filho J, Gobbi H, McCart Reed A, et al. Metaplastic Breast Cancer. Board WCoTE, editor. Breast Cancer. Lyon, France: International Agency for Research on Cancer. 2019. 135138.

3. Schroeder MC, Rastogi P, Geyer CE, Miller LD, Thomas A. Early and Locally Advanced Metaplastic Breast Cancer: presentation and Survival by Receptor Status in Surveillance, Epidemiology, and End Results (SEER) 20102014. Oncologist. 2018;23(4):481488.

4. Lei T, Pu T, Wei B, et al. Clinicopathologic characteristics of HER2-positive metaplastic squamous cell carcinoma of the breast. J Clin Pathol. 2020.

5. Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 2009;69(10):41164124.

6. Taube JH, Herschkowitz JI, Komurov K, et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci U S A. 2010;107(35):1544915454.

7. Fougner C, Bergholtz H, Norum JH, Sorlie T. Re-definition of claudin-low as a breast cancer phenotype. Nat Commun. 2020;11(1):1787.

8. Ai D, Yao J, Yang F, et al. TRPS1: a highly sensitive and specific marker for breast carcinoma, especially for triple-negative breast cancer. Mod Pathol. 2020.

9. Rakha EA, Coimbra ND, Hodi Z, Juneinah E, Ellis IO, Lee AH. Immunoprofile of metaplastic carcinomas of the breast. Histopathology. 2017;70(6):975985.

10. Rakha E, Quinn CM, Pia Foschini M, et al. Metaplastic carcinomas of the breast without evidence of epithelial differentiation: a diagnostic approach for management. Histopathology. 2020. doi:10.1111/his.14290

11. McCart Reed AE, Kalaw E, Nones K, et al. Phenotypic and molecular dissection of Metaplastic Breast Cancer and the prognostic implications. J Pathol. 2019;247(2):214227. doi:10.1002/path.5184

12. Rayson D, Adjei AA, Suman VJ, Wold LE, Ingle JN. Metaplastic breast cancer: prognosis and response to systemic therapy. Ann Oncol. 1999;10(4):413419. doi:10.1023/A:1008329910362

13. Tzanninis I-G, Kotteas EA, Ntanasis-Stathopoulos I, Kontogianni P, Fotopoulos G. Management and Outcomes in Metaplastic Breast Cancer. Clin Breast Cancer. 2016;16(6):437443. doi:10.1016/j.clbc.2016.06.002

14. Sulaiman A, McGarry S, Han X, Liu S, Wang L. CSCs in Breast CancerOne Size Does Not Fit All: therapeutic Advances in Targeting Heterogeneous Epithelial and Mesenchymal CSCs. Cancers. 2019;11(8):8. doi:10.3390/cancers11081128

15. Zhang Y, Toy KA, Kleer CG. Metaplastic breast carcinomas are enriched in markers of tumor-initiating cells and epithelial to mesenchymal transition. Mod Pathol. 2012;25(2):178184. doi:10.1038/modpathol.2011.167

16. Gerhard R, Ricardo S, Albergaria A, et al. Immunohistochemical features of claudin-low intrinsic subtype in metaplastic breast carcinomas. Breast. 2012;21(3):354360. doi:10.1016/j.breast.2012.03.001

17. May CD, Sphyris N, Evans KW, Werden SJ, Guo W, Mani SA. Epithelial-mesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression. Breast Cancer Res. 2011;13(1):202. doi:10.1186/bcr2789

18. Nunes T, Hamdan D, Leboeuf C, et al. Targeting Cancer Stem Cells to Overcome Chemoresistance. Int J Mol Sci. 2018;19(12):12. doi:10.3390/ijms19124036

19. Yuan H, Chen J, Liu Y, et al. Association of PIK3CA mutation status before and after neoadjuvant chemotherapy with response to chemotherapy in women with breast cancer. Clin Cancer Res. 2015;21(19):43654372. doi:10.1158/1078-0432.CCR-14-3354

20. Mosele F, Stefanovska B, Lusque A, et al. Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Ann Oncol. 2020;31(3):377386. doi:10.1016/j.annonc.2019.11.006

21. Krings G, Chen -Y-Y. Genomic profiling of metaplastic breast carcinomas reveals genetic heterogeneity and relationship to ductal carcinoma. Mod Pathol. 2018;31(11):16611674. doi:10.1038/s41379-018-0081-z

22. Gonzalez-Martinez S, Perez-Mies B, Carretero-Barrio I, et al. Molecular features of metaplastic breast carcinoma: an infrequent subtype of triple negative breast carcinoma. Cancers. 2020;12(7):7. doi:10.3390/cancers12071832

23. Ng CKY, Piscuoglio S, Geyer FC, et al. The landscape of somatic genetic alterations in metaplastic breast carcinomas. Clin Cancer Res. 2017;23(14):38593870. doi:10.1158/1078-0432.CCR-16-2857

24. Hayes MJ, Thomas D, Emmons A, Giordano TJ, Kleer CG. Genetic changes of Wnt pathway genes are common events in metaplastic carcinomas of the breast. Clin Cancer Res. 2008;14(13):40384044. doi:10.1158/1078-0432.CCR-07-4379

25. Avigdor BE, Beierl K, Gocke CD, et al. Whole-Exome Sequencing of Metaplastic Breast Carcinoma Indicates Monoclonality with Associated ductal carcinoma component. Clin Cancer Res. 2017;23(16):48754884. doi:10.1158/1078-0432.CCR-17-0108

26. Moukarzel L, Ferrando L, Da Cruz Paula A, et al. The genetic landscape of metaplastic breast cancers and uterine carcinosarcomas. Mol Oncol. 2020. doi:10.1002/1878-0261.12813

27. Hennessy BT, Krishnamurthy S, Giordano S, et al. Squamous cell carcinoma of the breast. J Clin Oncol. 2005;23(31):78277835. doi:10.1200/JCO.2004.00.9589

28. Abouharb S, Moulder S. Metaplastic breast cancer: clinical overview and molecular aberrations for potential targeted therapy. Curr Oncol Rep. 2015;17(3):431. doi:10.1007/s11912-014-0431-z

29. El Zein D, Hughes M, Kumar S, et al. Metaplastic carcinoma of the breast is more aggressive than triple-negative breast cancer: a study from a single institution and review ofliterature. Clin Breast Cancer. 2017;17(5):382391. doi:10.1016/j.clbc.2017.04.009

30. Han M, Salamat A, Zhu L, et al. Metaplastic breast carcinoma: a clinical-pathologic study of 97 cases with subset analysis of response to neoadjuvant chemotherapy. Mod Pathol. 2019;32(6):807816.

31. Al-Hilli Z, Choong G, Keeney MG, et al. Metaplastic breast cancer has a poor response to neoadjuvant systemic therapy. Breast Cancer Res Treat. 2019;176(3):709716.

32. Cimino-Mathews A, Verma S, Figueroa-Magalhaes MC, et al. A clinicopathologic analysis of 45 patients with metaplastic breast carcinoma. Am J Clin Pathol. 2016;145(3):365372.

33. Hennessy BT, Giordano S, Broglio K, et al. Biphasic metaplastic sarcomatoid carcinoma of the breast. Ann Oncol. 2006;17(4):605613.

34. Nagao T, Kinoshita T, Hojo T, Tsuda H, Tamura K, Fujiwara Y. The differences in the histological types of breast cancer and the response to neoadjuvant chemotherapy: the relationship between the outcome and the clinicopathological characteristics. Breast. 2012;21(3):289295.

35. Aydiner A, Sen F, Tambas M, et al. Metaplastic breast carcinoma versus triple-negative breast cancer: survival and response to treatment. Medicine. 2015;94(52):e2341.

36. Moroney J, Fu S, Moulder S, et al. Phase I study of the antiangiogenic antibody bevacizumab and the mTOR/hypoxia-inducible factor inhibitor temsirolimus combined with liposomal doxorubicin: tolerance and biological activity. Clin Cancer Res. 2012;18(20):57965805.

37. Basho RK, Gilcrease M, Murthy RK, et al. Targeting the PI3K/AKT/mTOR pathway for the treatment of mesenchymal triple-negative breast cancer: evidence from a phase 1 trial of mTOR inhibition in combination with liposomal doxorubicin and bevacizumab. JAMA Oncol. 2017;3(4):509515.

38. Basho RK, Yam C, Gilcrease M, et al. Comparative Effectiveness of an mTOR-based systemic therapy regimen in advanced, metaplastic and nonmetaplastic triple-negative breast cancer. Oncologist. 2018;23(11):13001309.

39. Yang MH, Chen IC, Lu YS. PI3K inhibitor provides durable response in metastatic metaplastic carcinoma of the breast: a hidden gem in the BELLE-4 study. J Formos Med Assoc. 2019;118(9):13331338.

40. Lu YS, Lee KS, Chao TY, et al. A phase ib study of alpelisib or buparlisib combined with tamoxifen plus goserelin in premenopausal women with hr-positive her2-negative advanced breast cancer. Clin Cancer Res. 2020.

41. Coussy F, El Botty R, Lavigne M, et al. Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancers. J Hematol Oncol. 2020;13(1):13.

42. Matutino A, Amaro C, Verma S. CDK4/6 inhibitors in breast cancer: beyond hormone receptor-positive HER2-negative disease. Ther Adv Med Oncol. 2018;10:1758835918818346.

43. Seo T, Noguchi E, Yoshida M, et al. response to dabrafenib and trametinib of a patient with metaplastic breast carcinoma harboring a braf v600e mutation. case rep oncol med. 2020;2020:2518383.

44. Henneman L, van Miltenburg MH, Michalak EM, et al. Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer. Proc Natl Acad Sci U S A. 2015;112(27):84098414.

45. Tray N, Taff J, Adams S. Therapeutic landscape of metaplastic breast cancer. Cancer Treat Rev. 2019;79:101888.

46. Adams S. Dramatic response of metaplastic breast cancer to chemo-immunotherapy. NPJ Breast Cancer. 2017;3:8.

47. Al Sayed AD, Elshenawy MA, Tulbah A, Al-Tweigeri T, Ghebeh H. Complete response of chemo-refractory metastatic metaplastic breast cancer to paclitaxel-immunotherapy combination. Am J Case Rep. 2019;20:16301635.

48. Adams S, Othus M, Patel S, et al. Dual anti-CTLA-4 and anti-PD-1 blockade in metaplastic carcinoma of the breast: dart (SWOG S1609, Cohort 36). J Clin Oncol. 2020;38.

49. Afkhami M, Schmolze D, Yost SE, et al. Mutation and immune profiling of metaplastic breast cancer: correlation with survival. PLoS One. 2019;14(11):e0224726.

50. Bataillon G, Fuhrmann L, Girard E, et al. High rate of PIK3CA mutations but no TP53 mutations in low-grade adenosquamous carcinoma of the breast. Histopathology. 2018;73(2):273283.

51. Beca F, Sebastiao APM, Pareja F, et al. Whole-exome analysis of metaplastic breast carcinomas with extensive osseous differentiation. Histopathology. 2020.

52. Edenfield J, Schammel C, Collins J, Schammel D, Edenfield WJ. Metaplastic breast cancer: molecular typing and identification of potential targeted therapies at a single institution. Clin Breast Cancer. 2017;17(1):e1e10.

53. Joneja U, Vranic S, Swensen J, et al. Comprehensive profiling of metaplastic breast carcinomas reveals frequent overexpression of programmed death-ligand 1. J Clin Pathol. 2017;70(3):255259.

54. Ross JS, Badve S, Wang K, et al. Genomic profiling of advanced-stage, metaplastic breast carcinoma by next-generation sequencing reveals frequent, targetable genomic abnormalities and potential new treatment options. Arch Pathol Lab Med. 2015;139(5):642649.

55. Tray N, Taff J, Singh B, et al. Metaplastic breast cancers: genomic profiling, mutational burden and tumor-infiltrating lymphocytes. Breast. 2018;44:2932.

56. Vranic S, Stafford P, Palazzo J, et al. Molecular profiling of the metaplastic spindle cell carcinoma of the breast reveals potentially targetable biomarkers. Clin Breast Cancer. 2020;20(4):326331.

57. Zhai J, Giannini G, Ewalt MD, et al. Molecular characterization of metaplastic breast carcinoma via next-generation sequencing. Hum Pathol. 2019;86:8592.

58. Dave B, Gonzalez DD, Liu ZB, et al. Role of RPL39 in Metaplastic Breast Cancer. J Natl Cancer Inst. 2017;109:6.

59. Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2(4):361370.

60. Beckers RK, Selinger CI, Vilain R, et al. Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome. Histopathology. 2016;69(1):2534.

61. Dogukan R, Ucak R, Dogukan FM, Tanik C, Citgez B, Kabukcuoglu F. Correlation between the Expression of PD-L1 and Clinicopathological parameters in triple negative breast cancer patients. Eur J Breast Health. 2019;15(4):235241.

62. Morgan E, Suresh A, Ganju A, et al. Assessment of outcomes and novel immune biomarkers in metaplastic breast cancer: a single institution retrospective study. World J Surg Oncol. 2020;18(1):11.

63. Lien HC, Lee YH, Chen IC, et al. Tumor-infiltrating lymphocyte abundance and programmed death-ligand 1 expression in metaplastic breast carcinoma: implications for distinct immune microenvironments in different metaplastic components. Virchows Arch. 2020;24.

64. Kalaw E, Lim M, Kutasovic JR, et al. Metaplastic breast cancers frequently express immune checkpoint markers FOXP3 and PD-L1. Br J Cancer. 2020.

65. Chao X, Liu L, Sun P, et al. Immune parameters associated with survival in metaplastic breast cancer. Breast Cancer Res. 2020;22(1):92.

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[Full text] An Update on the Molecular Pathology of Metaplastic Breast Cancer | BCTT - Dove Medical Press

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4D Pharma Appointments Paul Maier to the Board as Non-Executive Director – Business Wire

Wednesday, March 3rd, 2021

LEEDS, England--(BUSINESS WIRE)--4D pharma plc (AIM: DDDD), a pharmaceutical company leading the development of Live Biotherapeutic products (LBPs) - a novel class of drug derived from the microbiome, today announces the appointment of Paul Maier as Non-Executive Director of the Board. Mr Maier will also be a member of 4D's Audit and Risk Committee and will serve as the Companys audit committee financial expert under SEC and Nasdaq rules.

With over 25 years of extensive senior operational, international and financial management experience in the pharmaceutical and biotechnology industry, Paul will be able to provide 4D pharma with invaluable insights as we continue to execute across our business both clinically and operationally, said Duncan Peyton, Chief Executive Officer of 4D pharma. Pauls strong track record will support our Board with additional perspective and expertise.

I am excited to join 4D pharmas Board and support its goals to establish a larger global presence while working to bring its differentiated approach and pipeline of Live Biotherapeutics to patients in need, said Paul Maier, Non-Executive Director of 4D pharma. I look forward to working with 4D and offering my experiences in transactional and operational strategy as the company continues to grow, catalyzed by 4Ds upcoming NASDAQ listing.

Mr. Maier has over 25 years of investor and public relations, operational, regulatory, and finance expertise in the healthcare industry. Mr. Maier was previously the Chief Financial Officer of Sequenom Inc., where he was responsible for raising over $360 million in equity and debt financings, expanding institutional sell side research analyst coverage, as well as overseeing and establishing internal financial infrastructure. Previously, he was Senior Vice President and Chief Financial Officer of Ligand Pharmaceuticals (NASDAQ: LGND) where he helped build Ligand from a venture stage company to a commercial, integrated biopharmaceutical organization, raising over $1 billion in equity and debt financings including a successful IPO, and helped negotiate multiple R&D and commercial partnerships and transactions. He has also acted as an independent financial consultant to life sciences companies. Mr. Maier is currently a Board member of Eton Pharmaceuticals, Inc, Biological Dynamics and International Stem Cell Corporation (OTCQB: ISCO). He holds an MBA from Harvard University and a BS in Business Logistics from the Pennsylvania State University.

Additional Disclosures Required under the AIM Rules for Companies

In accordance with Schedule 2(g) of the AIM Rules, Paul Victor Maier (aged 73) currently holds the following directorships:Eton Pharmaceuticals, IncBiological Dynamics, IncInternational Stem Cell Corp.

Previous directorships held in the past five years:Ritter Pharmaceuticals, Inc (Mar 2015 May 2020)Apricus Biosciences, Inc (May 2012 Jan 2019)Mabvax, Inc (June 2014 July 2018)

Paul Maier does not currently hold any ordinary shares in the Company.

Save as set out above there are no further disclosures pursuant to Rule 17 or Schedule Two paragraph (g) of the AIM Rules for Companies in respect of the appointment of Paul Maier.

About 4D pharma

Founded in February 2014, 4D pharma is a world leader in the development of Live Biotherapeutics, a novel and emerging class of drugs, defined by the FDA as biological products that contain a live organism, such as a bacterium, that is applicable to the prevention, treatment or cure of a disease. 4D has developed a proprietary platform, MicroRx, that rationally identifies Live Biotherapeutics based on a deep understanding of function and mechanism.

4D pharma's Live Biotherapeutic products (LBPs) are orally delivered single strains of bacteria that are naturally found in the healthy human gut. The Company has six clinical programs, namely a Phase I/II study of MRx0518 in combination with KEYTRUDA (pembrolizumab) in solid tumors, a Phase I study of MRx0518 in a neoadjuvant setting for patients with solid tumors, a Phase I study of MRx0518 in patients with pancreatic cancer, a Phase I/II study of MRx-4DP0004 in asthma (NCT03851250), a Phase II study of MRx-4DP0004 in patients hospitalized with COVID-19 (NCT04363372), and Blautix in Irritable Bowel Syndrome (IBS) (NCT03721107) which has completed a successful Phase II trial. Preclinical-stage programs include candidates for CNS disease such as Parkinson's disease and other neurodegenerative conditions. The Company has a research collaboration with MSD, a tradename of Merck & Co., Inc., Kenilworth, NJ, USA, to discover and develop Live Biotherapeutics for vaccines.

For more information, refer to http://www.4dpharmaplc.com.

Forward-Looking Statements

This press release contains "forward-looking statements." All statements other than statements of historical fact contained in this announcement, including without limitation statements regarding timing of the clinical trial are forward-looking statements within the meaning of Section 27A of the United States Securities Act of 1933, as amended (the "Securities Act"), and Section 21E of the United States Securities Exchange Act of 1934, as amended (the "Exchange Act"). Forward-looking statements are often identified by the words "believe," "expect," "anticipate," "plan," "intend," "foresee," "should," "would," "could," "may," "estimate," "outlook" and similar expressions, including the negative thereof. The absence of these words, however, does not mean that the statements are not forward-looking. These forward-looking statements are based on the Company's current expectations, beliefs and assumptions concerning future developments and business conditions and their potential effect on the Company. While management believes that these forward-looking statements are reasonable as and when made, there can be no assurance that future developments affecting the Company will be those that it anticipates.

All of the Company's forward-looking statements involve known and unknown risks and uncertainties, some of which are significant or beyond its control, and assumptions that could cause actual results to differ materially from the Company's historical experience and its present expectations or projections. The foregoing factors and the other risks and uncertainties that affect the Company's business, including the risks of delays in the commencement of the clinical trial and those additional risks and uncertainties described the documents filed by the Company with the US Securities and Exchange Commission (SEC), should be carefully considered. The Company wishes to caution you not to place undue reliance on any forward-looking statements, which speak only as of the date hereof. The Company undertakes no obligation to publicly update or revise any of its forward-looking statements after the date they are made, whether as a result of new information, future events or otherwise, except to the extent required by law.

Additional Information about the Transaction and Where to Find it

This press release is being made in respect of a proposed business combination involving 4D and Longevity. Following the announcement of the proposed business combination, 4D filed a registration statement on Form F-4 (the Registration Statement) with the SEC which was declared effective on February 25, 2021. This press release does not constitute an offer to sell or the solicitation of an offer to buy or subscribe for any securities or a solicitation of any vote or approval nor shall there be any sale, issuance or transfer of securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction. The Registration Statement includes a prospectus with respect to 4Ds ordinary shares and ADSs to be issued in the proposed transaction and a proxy statement of Longevity in connection with the merger. The proxy statement/prospectus has been mailed to the Longevity shareholders on or about February 26, 2021. 4D and Longevity also plan to file other documents with the SEC regarding the proposed transaction.

This press release is not a substitute for any prospectus, proxy statement or any other document that 4D or Longevity may file with the SEC in connection with the proposed transaction. Investors and security holders are urged to read the Registration Statement and, when they become available, any other relevant documents that will be filed with the SEC carefully and in their entirety because they will contain important information about the proposed transaction.

You may obtain copies of all documents filed with the SEC regarding this transaction, free of charge, at the SECs website (www.sec.gov). In addition, investors and security holders will be able to obtain free copies of the Registration Statement and other documents filed with the SEC without charge, at the SECs website (www.sec.gov) or by calling +1-800-SEC-0330.

Participants in the Solicitation

Longevity and its directors and executive officers and other persons may be deemed to be participants in the solicitation of proxies from Longevitys shareholders with respect to the proposed transaction. Information regarding Longevitys directors and executive officers is available in its annual report on Form 10-K for the fiscal year ended February 29, 2020, filed with the SEC on April 30, 2020. Additional information regarding the participants in the proxy solicitation relating to the proposed transaction and a description of their direct and indirect interests is contained in the Registration Statement.

4D and its directors and executive officers may also be deemed to be participants in the solicitation of proxies from the shareholders of Longevity in connection with the proposed transaction. A list of the names of such directors and executive officers and information regarding their interests in the proposed transaction is included in the Registration Statement.

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4D Pharma Appointments Paul Maier to the Board as Non-Executive Director - Business Wire

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Investigative Interventions Gain Ground in GVHD – OncLive

Wednesday, March 3rd, 2021

With an increased understanding of disease biology, several approaches are under examination to optimize the management of patients with graft-versus-host disease (GVHD), Corey Cutler, MD, MPH FRCP, who added that novel combinations with steroids are gaining ground in the frontline setting, while novel agents such as JAK inhibitors are raising the bar in the steroid-refractory setting.1

When treating patients with GVHD, it is important to differentiate on a clinical level whether a patient has chronic or acute disease, as the pathobiological differences between the 2 differ greatly. Acute GVHD (aGVHD) can develop into chronic GVHD (cGVHD) and is thought to represent T-cell mediated disease that targets specific organs, such as the skin, the gastrointestinal tract, and the liver. cGVHD is a more complex disease, with several T-cell subsets, as well as involvement of the B-cell pathway and the monocyte macrophage lineage.2

[This is] particularly relevant in terminal stages of cGVHD, where we see lots of fibrosis scarring and sclerosis, Cutler, the medical director of Stem Cell Transplantation at the Dana Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School, explained during a presentation at the 25th Annual International Congress on Hematologic Malignancies.

It has become clear that the gut microbiome can play a role in the development of aGVHD, according to Cutler. Some inflammatory markers can be elucidated by the microbiome, and in the absence of conditioning-related injury, can activate the immune system; this is partially responsible for the upregulation of alloantigen presentation at the level of lamina propria, as well as the recruitment of donor T cells, added Cutler.3

Not only have we learned a lot about how to treat [patients with] GVHD, but were also learning how to prevent it through modulation of the gut microbiome, Cutler said.

Treatment goals in aGVHD are focused on improving or stabilizing organ manifestations, limiting long-term treatment-associated adverse effects, improving the functional capacity or quality of life of patients, and ultimately, improving overall survival (OS), according to Cutler.

Frontline treatment for patients with aGVHD often includes the use of corticosteroids, such as solumedrol (methylprednisolone), which is generally administered at a daily dose of 1 mg/kg to 2 mg/kg.4 Many patients will respond to this treatment but up to 20% will be steroid refractory, and another 20% to 25% will relapse, according to Cutler. Notably, until recently, no standard of care for second-line setting was available.

Several studies have been conducted to improve initial therapy for patients for aGVHD; however, many have yielded negative results, Cutler said. A significant phase 3 study (NCT01002742) evaluated the addition of mycophenolate mofetil to steroids (n = 116) vs steroids alone (n = 119) as frontline treatment in patients with aGVHD. Results showed that survival probability after 360 days with steroids plus mycophenolate mofetil was 57.8% (95% CI, 48.2%-66.3%) vs 64.7% (95% CI, 55.2%-72.6%) with steroids/placebo.5

[The addition of mycophenolate mofetil] added nothing. In fact, [the combination did] even worse than steroids alone for [patients with] aGVHD, Cutler said. We need more targets.

To this end, investigators have set out to target cytokines in aGVHD by focusing on the JAK-STAT signaling pathway, according to Cutler. Many of the inflammatory cytokines that are important in the disease, like interleukin-6 or interferon-g (INF-g), signal through JAK-STAT pathways through independent receptors.6 The assemblies of different monomers can result in varied processes, which can be targeted with agents like ruxolitinib (Jakafi), Cutler explained.

Recently, the phase 3 GRAVITAS-301 trial (NCT03139604) examined a newer JAK inhibitor itacitinib with or without steroids in the initial treatment of 436 patients with aGVHD. Participants were randomized 1:1 to receive itacitinib at a daily dose of 200 mg plus corticosteroids, or placebo plus corticosteroids. The primary end point of the trial was overall response rate (ORR) at 28 days, while the secondary end point was non-relapse mortality (NRM) at 6 months. Top-line results showed that the ORR at day 28 was slightly better in the itacitinib arm at 74.0%, compared with 66.4% in the placebo arm (P = .08); however, this was not determined to be statistically significant and so, the trial was halted.7

This was unfortunate, because the control group actually did significantly better than what we anticipated and what we had planned for, Cutler explained. This was a negative trial, although it certainly tells us that the incorporation of JAK inhibitors in the frontline might be promising.

The phase 2 BMT CTN 1501 trial (NCT02806947) enrolled a total of 127 patients with standard-risk aGVHD per the Minnesota risk criteria who were randomized 1:1 to receive either sirolimus (Rapamune; n = 58) or prednisone (n = 64). Results showed that complete response (CR) and partial response (PR) rates at day 28 were similar in the sirolimus and prednisone arms, at 64.8% (90% CI, 53.8%-75.8%) and 73.0% (90% CI, 63.6%-82.4%), respectively. Additionally, no change in OS was observed.

Subjects who had a slightly lower response rate with sirolimus ended up being salvaged very well with corticosteroids, and this did not lead to a reduction in OS, Cutler noted.

In patients with steroid-refractory aGVHD, JAK inhibition was once again examined in the phase 2 REACH-1 study (NCT02953678). To be eligible for enrollment, patients had to be at least 12 years of age with grade 2 to 4 corticosteroid-refractory aGVHD per MAGIC criteria. Here, patients were treated with ruxolitinib at a daily dose of 5 mg until treatment failure, intolerable toxicity, or death. The primary end point of the trial was ORR at day 28, while secondary end points included 6-month duration of response, NRM, malignancy relapse rate, OS, and safety.

Results indicated that the ORR with this approach was 54.9% in all patients (n = 71), while those with grade 2 disease (n = 23) experienced the highest ORR, at 82.6%. Additionally, the median time to response was 7 days. However, although response rates were high, approximately one-third of responders still experienced 1-year NRM.9

That was significantly better but still lacking in terms of a great number, in comparison with the subjects who were non-responders, of whom 85% died at 1 year, Cutlet said.

Notably, the data from this trial led to the May 2019 FDA approval of ruxolitinib for the treatment of patients with aGVHD.

This trial was followed by the phase 3 REACH-2 trial (NCT02913261), which was mostly conducted in Europe. A total of 308 patients were enrolled in this trial and they were randomized to receive either ruxolitinib at a slightly higher dose of 10 mg twice daily, or best available care per the treating physician. Several regimens were allowed in this trial, although most would not typically be considered to be standard therapy in North America, noted Cutler.

Results for this trial showed that the ORR at day 28 was 62.3% in the ruxolitinib arm (n = 154) vs 39.4% in the control arm (n = 155; P <.001). However, at day 56 of treatment, only 39.6% of patients in the ruxolitinib arm maintained their response.10

As such, we still have a long way to go in [the treatment] of [patients with] steroid-refractory aGVHD, Cutlet said.

To this end, many efforts are being made to develop other agents to treat patients with steroid-refractory aGVHD. For example, one compound under evaluation is Alpha-1 Antitrypsin; this agent prevents effector cell cytotoxic cell killing, noted Cutler. Additional agents under investigation include the CD6 T-cell inhibitor EQ001 and T-Guard, a CD3/CD7-ricin conjugated monoclonal antibody cocktail. Additionally, several efforts are being made to examine mesenchymal stromal cells and costimulation blockades, according to Cutler.

It is understood that there are 3 distinct phases of cGVHD: phase 1 is acute inflammation and tissue injury, phase 2 is chronic inflammation and dysregulated immunity, and phase 3 is aberrant tissue repair and fibrosis.11

The majority of patients will cycle through multiple lines of therapy when they are initially treated for cGVHD, noted Cutler. After 4 years, only 11% of patients have not moved on to receive second-, third-, or fourth-line therapy.12 However, several agents can now be used in the second-line setting for these patients, such as extracorporeal photopheresis, rituximab, imatinib (Gleevec), and pentostatin.

In terms of mechanistic interventions for prevention and treatment of patients with cGVHD, 2 major pathways should be focused on, according to Cutler. The first is a reduction in the alloreactive T-cell pathway, by augmenting regulatory T cells. The second pathway is one that inhibits B cells and their role in initiating cGVHD, explained Cutler.13 Several agents are able to block those individual pathways.

Ibrutinib (Imbruvica), a B-cell inhibiting compound that targets the BTK pathway, is under examination in patients with steroid-refractory cGVHD. In a phase 1/2 study (NCT02195869), investigators examined the agent in 42 patients, at a dose of 420 mg. Patients received treatment until disease progression or intolerable toxicity. Results showed that 79% of patients had responded at the time of the first assessment, and 71% had a response that extended past 5 months.14 Data from the study led to the September 2017 FDA approval of ibrutinib for patients with steroid-refractory cGVHD.

This was the first drug that was approved in cGVHD, Cutler noted. Weve now gone and tried ibrutinib as frontline therapy for [patients with] cGVHD, in conjunction with steroids, and were looking forward to seeing the results.

Ruxolitinib was also examined for patients with steroid-refractory cGVHD in the phase 3 REACH3 trial (NCT03112603), where it was compared with best available therapy (BAT). The study enrolled 300 patients and results showed that responses at week 24, which was the primary end point of the trial, were 49.7% in the ruxolitinib arm vs 25.6% in the BAT arm (odds ratio [OR], 2.99; 95% CI, 1.86-4.80; P <.0001).15 However, in terms of best overall response, rates were 76.4% in the ruxolitinib arm vs 60.4% in the BAT arm (OR, 2.17; 95% CI, 1.34-3.52), which shows that a significant number of patients who responded lost that response at 6 months, Cutler noted.

Another area of interest are agents that can block ROCK2 signaling, such as belumosudil (KD025). KD025 is an oral selective ROCK2 inhibitor which targets the immune and fibrotic pathophysiology of cGVHD, explained Cutler. When examined in the phase 1/2 KD025-208 study (NCT02841995), the agent demonstrated an ORR of 59% in patients with cGVHD who had previously received 1 to 3 lines of systemic therapy.16

The agent was also being examined in the phase 2 ROCKstar trial (KD025-213; NCT03640481). In this study, patients who had previously received 2 to 5 lines of therapy were randomized to receive 1 of 2 doses of KD025: 200 mg daily or 200 mg twice daily.17 The agent elicited clinically meaningful and statistically significant ORRs of 75% for both arms together, and the median time to response was 4 weeks. Additionally, CRs were observed in all affected organ systems, and 7 patients achieved an overall CR. In November 2020, the FDA granted a priority review designation to a new drug application for belumosudil for the treatment of patients with cGVHD; the regulatory agency is expected to make a decision on the application by May 30, 2021.

A final area of interest that Cutler noted was CSF-1dependent donor derived macrophages. A compound called axatilimab (SNDX-6352) is currently under examination in very early phase 1/2 studies, noted Cutler.

Additionally, multiple ongoing studies are examining cGVHD prevention with methods such as T-cell depletion, T-cell modulation, T-cell migration, and prophylactic B-cell depletion. However, the one garnering the most attention is post-transplant cyclophosphamide, which should kill alloreactive T-cells, Cutler concluded.

References

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Investigative Interventions Gain Ground in GVHD - OncLive

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Combination Regimens for Multiple Myeloma Show Efficacy in the Transplant-Ineligible Population, According to Dingli – Targeted Oncology

Wednesday, March 3rd, 2021

David Dingli, MD, PhD, professor of Medicine at the Mayo Clinic, reviews the combination therapies available for the treatment of multiple myeloma in a patient who is 72-years-old and transplant-ineligible.

Targeted OncologyTM: Do you believe that treating patients with multiple myeloma with multiple therapies in the maintenance setting increases their duration of response?

DINGLI: There arent much data on long-term maintenance with multiple agents. I think that it would be an unusual patient with ultrahigh-risk disease who will probably go on maintenance with a doubletfor example, lenalidomide [Revlimid] and a proteasome inhibitor at the same timewithout much data to support it.

What are the best treatment options for a patient such as this who is not eligible for transplant?

The NCCN [National Comprehensive Cancer Network] guidelines with respect to therapy in the newly diagnosed setting for non transplant-eligible patients [say] the preferred regimens are bortezomib [Velcade]/lenalidomide/dexamethasone, daratumumab [Darzalex]/lenalidomide/dexamethasone, or even a doublet with lenalidomide/dexamethasone, or CyBorD [cyclophosphamide/ bortezomib/dexamethasone].1 Other regimens are also included, although probably not many people will use them.

The NCCN guidelines include daratumumab/bortezomib/ melphalan/prednisone [D-VMP] as a regimen because it is supported by a large phase 3 trial that was done in Europe. [They also include], without data, daratumumab/cyclophosphamide/ bortezomib/ dexamethasone, where melphalan is replaced by cyclophosphamide, because of the perceived lower risk of myelotoxicity. But, as far as I know, there is no study that has looked at this in multiple myeloma. There is a study that has come out, looking at this regimen in amyloidosis, and we do know that its superior, but not in multiple myeloma at this point in time.

What factors do you consider when choosing an induction regimen for patients like these?

Age, efficacy, logistics, cost, risk status, or, with respect to disease, geography, and performance status.

[Geriatric assessment] is something that is [being] incorporated more and more into clinical trials as part of the assessment of the patient, using various tools such as the Charlson index, etc, to assess frailty of patients and how suitable they are for a specific therapy versus some other therapy.

Which trials have supported the NCCN-recommended treatment regimens in the transplant-ineligible setting?

[There are] many studies in the nontransplant-eligible population.

The MAIA study [NCT02252172] randomized patients to daratumumab/lenalidomide/dexamethasone [DRd] versus lenalidomide/dexamethasone [Rd]. The ALCYONE study [NCT02195479] looked at D-VMP versus VMP; we dont use that regimen [in the United States]. SWOG [S0777; NCT00644228], a very important, large, randomized study in this country, is looking at VRd [bortezomib/lenalidomide/dexamethasone] versus Rd. Theres the VRd Lite, which is a variation of VRd where patients get a gentler regimen, often in patients who are rather elderly. Then, there will be studies looking at Rd versus MPT [melphalan/prednisone/thalidomide (Thalomid)], and KMP [carfilzomib (Kyprolis)/melphalan/prednisone] versus VMP, which I do notthink we need to discuss in detail, because this therapy has been rather surpassed.

We can look at some data from the more relevant studies, at how we treat patients nowadays. The MAIA study showed that PFS [progression-free survival] was clearly superior for the DRd versus Rd, with a significant improvement [not reached vs 31.9 months, respectively] and reduction in the hazard ratio by 44% [HR, 0.56; 95% CI, 0.43-0.73; P <.001].2 ALCYONE showed, again, that the addition of daratumumab to a triplet regimen that includes VMP was associated with significant improvement in PFS, almost 3 times as high [36.4 vs 19.3 months with VMP alone; HR, 0.42; 95% CI, 0.34-0.51; P <.0001].3 The SWOG study that looked at VRd versus Rd showed that with a rather long follow-up period of 84 months, median PFS was 41 months in patients with the triplet versus 29 months for the Rd doublet [HR, 0.74; P =.003].4 If we look at VRd Lite, the median PFS is approximately 35 months in patients who are not transplant eligible.5

Again, there are other trials that probably are not very relevant to our practice, because most of us will not be using melphalan in patients [with a new diagnosis] or regimens that include melphalan in some form.

Can you discuss the SWOG trial and its results in more detail?

The SWOG study is an important study that probably was a benchmark for a while on how we treat patients who are not transplant eligible.6 [The trial enrolled] patients with no intention to proceed with transplant, randomized to VRd induction, with lenalidomide at 25 mg for 14 days, dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12, and bortezomib given at standard dose IV [intravenously] on days 1, 4, 8, and 11, compared with standard Rd with a 28-day cycle. So, patients received either 8 cycles of the triplet versus 6 cycles of the doublet, and then all patients received lenalidomide and dexamethasone in maintenance therapy. The main outcome was PFS, with overall response rate [ORR], overall survival [OS], and safety [as key secondary end points]. In 68% of these patients, there was a possibility of moving to transplant later, although 43% were above the age of 65. Note that follow-up is substantial, with a median follow-up of around 55 months or more.

PFS clearly favored the use of the triplet therapy, with a 41-month median PFS for the patients on the triplet versus 29 months for the doublet, with a 26% reduction in risk.4

OS was also improved in patients who received the triplet. Median OS could not be reached versus 69 months for patients who were on Rd alone [HR, 0.709; 96% CI, 0.543- 0.926; P =.0114].

As expected, there was some more toxicity in patients who were on the triplet, and the main toxicity was neuropathy with VRd. Grade 3 neuropathy was about 33%.7 This is mainly because, in my opinion, the bortezomib was given every 4 days and given intravenously.

What is different about the VRd Lite regimen?

The modified VRd, also known as VRd Lite, regimen is given with bortezomib on days 1, 8, and 15; lenalidomide is given for 21 days; and dexamethasone is given on days 1, 8, and 15. So the intensity of therapy is substantially lower, with respect to both the dexamethasone and the bortezomib. In my practice, patients who are going to go for VRd Lite will probably not get 40 mg of dexamethasone weekly; rather, Ill go with 20 mg.

[From] a retrospective chart review, the ORR [with VRD Lite was] around 87%, although the number of patients was not high. The risk of peripheral neuropathy was substantially lower, at 11.6%, although it did increase in time to about 38%, mainly grade 1 and 2.8

Can you tell us more about MAIA?

The largest study that has been done recently in nontransplant- eligible patients was the MAIA study for patients who were randomized to Rd versus DRd.2 Daratumumab was given intravenously. The daratumumab was given, as we know it, weekly for the first 4 weeks, and then every 2 weeks for 4 months, and then monthly. Lenalidomide [was given at the] standard dose, 25 mg for 21 days, and dexamethasone, PO [orally] or IV weekly. The primary end point was PFS; secondary end points were the CR [complete response], VGPR [very good partial response] rates, MRD [minimal residual disease] negativity, ORR, OS, and safety. Most of these patients were elderly, 99%...being older than 65 years of age, with a median age of 73.

The median PFS has not been reached for the triplet regimen, compared to 32 months for the doublet. At 30 months, 71% of the patients on the triplet had not progressed compared to 56% who had not progressed [on the doublet]. Its too early to look at OS. The ORRs for the triplet were 93%; [there was] stringent CR in 30% and generally higher CR, VGPR, and stringent CR [rates]. MRD negativity [rate] was 24%, and this was, I believe, at the level of 10E-5. Patients who had achieved an MRD-negative state had a lower risk of progression or death in either arm.

The primary end point, PFS, clearly showed an improvement for the triplet regimen, and were seeing that patients who achieved MRD negativity, whether on the doublet or the triplet, had a better PFS. This is an important point that keeps coming up with different studies that are looking at MRD negativityachieving MRD negativity is critical, and it seems what is important is to achieve that state, not how we get it. Now, what people have not shown is whether we can stop therapy after [achieving an] MRD-negative state, or we give limited therapy after that, whether this is true for high risk or for standard risk. I think, for the standard-risk patients, if a patient with that type of disease achieves MRD negativity, one can be fairly confident that theyre going to do very well. Im not so sure about the high-risk patients. Ive had quite a few of these, where they achieve an MRD-negative state; unfortunately, it does not seem to be maintained for that long.

[Regarding] the safety characteristics from the study, the main toxicity is hematopoietic; [theres a] somewhat high risk of neutropenia and some increased risk of infections, especially respiratory infections with pneumonia, as well as sinusitis. Infusion reactions are also common, although thesemainly occur with the first and, at the most, second dose, and after that, its not an issue. Now, with the subcutaneous availability of daratumumab, the risk of infusion reactions has virtually disappeared.

How do these standard regimens compare with each other?

[PEGASUS is] an interesting study that tries to address a question that, so far, had not been looked at in a randomized study and perhaps will never occur. So, we know that VRd is considered by many [to be the] standard of care. Now we have DRd. So can one possibly determine which regimen is superior? And because no head-to-head comparison has been done, Durie et al looked at the Flatiron [Health] database, which is a large database of patients with multiple myeloma, where the medical record is available, and they did an in silico study comparing the patients on the MAIA study versus patients who had received VRd or Vd, compared to Rd.9 From the Flatiron database they could identify 2 cohorts so that they could have an internal control, so that the Rd [patients] in the Flatiron database [would do similarly] to patients in the Rd arm of the MAIA study. The study looked at DRd versus VRd, or DRd versus Vd, and they showed that the hazard ratio for response and PFS seems to be in favor of the DRd [HR, 0.54; 95% CI, 0.42-0.71; P <.001]. This is not a randomized study.

From the PEGASUS study, they could show that, at least in this in silico analysis, the patients with DRd seemed to do better compared to even patients who were on VRd or Rd.

The ENDURANCE trial [NCT01863550] was a phase 3 study through ECOG that randomized patients with newly diagnosed disease who were not planning to go to transplant, and who did not have high-risk disease, to therapy either with VRd versus KRd.10 The VRd was given as standard therapy, except that it could be given subcutaneously; the bortezomib could be given either subcutaneously or IV at physicians discretion. Arm B was carfilzomib, initially at 20 mg/m2 and then escalated to 36 mg/m2. Then, the patients were randomized a second time to either maintenance therapy with lenalidomide for 24 cycles, and then observed, or continue with lenalidomide until progression. Primary end point was OS, with 2 different maintenance strategies of lenalidomide, either fixed duration or indefinite, as well as PFS between the different induction regimens, followed by lenalidomide maintenance. In this study, the primary end point was not met. There is no difference in either PFS or OS, so far, between these 2 regimens.

The 2 arms of the study were well balanced, with a large number of patients. The ratio distribution was similar. There were patients even with an ECOG [performance status score of] 3. The distribution of ISS [International Staging System] 1, 2, or 3 was similar. Almost all the patients had to have measurable disease, fairly standard for this type of study. Virtually all patients had normal cytogenetics, or standard-risk disease. This was a defining criterion for entering the study.

There is no difference whatsoever with respect to both PFS [HR, 1.04; 95% CI, 0.83-1.31; P =.74] or OS [HR, 0.98; 95% CI, 0.71-1.36; P =.92]. At the last data cutoff, which was earlier this year, [there was a] median PFS of about 35 months for [both] these [regimens].

There was some increased risk of cardiac, renal, or pulmonary toxicity with respect to carfilzomib; this is expected. [There also was] somewhat more risk of neuropathy in patients who received bortezomib.

How would you approach patients with multiple myeloma who are eligible for transplant?

The standard approach that we take at Mayo [Clinic] with respect to patients who are considered transplant eligible [is that] if the patient has standard-risk disease, defined by trisomiestranslocation (11;14) or (6;14)we recommend 4 cycles of VRd, collection of stem cells, and then proceed to transplant. If the patient decides not to proceed with transplant, [we recommend] 4 more cycles of VRd, followed by maintenance therapy until progression.

In patients with high-risk disease, defined as deletion 17p, t(4;14), or translation (14;16) or (14;20), [we recommend] 4 cycles of KRd or quadruplet therapy. [We recommend] at least 1 transplant. In some of these patients, we consider a second transplant in tandem, based mainly on the studies from Europe that have shown that patients with high-risk disease seem to benefit from a tandem transplant, and then a proteasome-based inhibitor maintenance.

For patients with a double- or triple-hit multiple myeloma, for example, a 17p, t(4;14), or sometimes even 1q or...MYC translocation, we prefer quadruplet therapy, an autologous stem cell transplant [possibly tandem], and then proteasome inhibitor- based maintenance therapy.

What is your perspective on the results of this poll?

Intolerance seems to be the most common reason, and patient preference. I think these are valid reasons. The risk of second malignancies appears to be somewhat lower. The initial studies from France were quite concerning, but I think over the years weve learned that the risk of second malignancies with maintenance appears to be rather low. Its not 0, but probably somewhere in the range of maybe 2% to 3%. There is some risk. Even in patients who do not receive maintenance therapy, if one looks at the natural history of the disease, some...develop second malignancies independent of maintenance therapy.

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Combination Regimens for Multiple Myeloma Show Efficacy in the Transplant-Ineligible Population, According to Dingli - Targeted Oncology

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Martin Makes Sense of the Rapidly Evolving MCL Treatment Paradigm – OncLive

Wednesday, March 3rd, 2021

As more options emerge in the mantle cell lymphoma (MCL) paradigm, choosing among the agents available has become all the more challenging, according to Peter Martin, MD, who added that treatment is shifting beyond BTK inhibitors to the utilization of novel combinations and CAR T-cell therapies.

MCL, as we understand it, is a lot more complicated than just younger vs older patients. We now have 3 BTK inhibitors to choose from and that challenges us sometimes, Martin, an associate professor of medicine and chief of the Lymphoma Program at Weill Cornell Medicine, said during a presentation delivered at the 25th Annual International Congress on Hematologic Malignancies.1 More and more [often], were looking at novel combinations. We also have CAR T cells available, and we have to decide when to use them.

The original treatment algorithm for the disease was based mostly on the agent and fitness of the patients. Specifically, younger patients receiving more intensive approaches comprised of a cytarabine-based induction, followed by autologous stem cell transplant, followed by maintenance treatment with rituximab (Rituxan), according to Martin. Older patients primarily were given bendamustine plus rituximab, potentially followed by maintenance rituximab.

This algorithm has become more complicated in the past few years. Patients with indolent MCL, defined as being asymptomatic with a low tumor burden, a low Ki-67 score, and normal lactate dehydrogenase, without TP53 aberrations, is appropriate for a watch-and-wait approach, according to Martin.

Patients who are considered to have superhigh risk MCL, defined by having blastoid morphology, a high Ki-67 level, and TP53 alterations, pose more of a challenge. No one really knows how to manage those patients, admitted Martin. Its clear that high-dose chemotherapy is not very effective, and we suspect that many of these patients should be headed toward the use of CAR T cells.

Treatment decisions for patients who fall within the middle of the spectrum can be considered based on whether they have leukemic, non-nodal disease vs nodal disease, added Martin. Although approaches will differ depending on disease proliferation, many patients should be able to receive novel agents similar to what we have been doing with chronic lymphocytic leukemia [CLL], where chemotherapy is no longer relevant.

In his presentation, Martin discussed choosing among the BTK inhibitors available for use in MCL and how to choose among them, highlighted novel combination regimens that are under exploration and are showing early promise, and shed light on setting certain patients up for CAR T-cell therapy earlier rather than later.

Weighing the 3 BTK Inhibitors Available in the Arsenal

In November 2013, the FDA granted an accelerated approval to ibrutinib (Imbruvica) for use in patients with MCLwho had received at least 1 previous therapy. The decision was based on data from the single-arm, phase 2 PCYC-1104 trial (NCT01236391), where the agent elicited an overall response rate (ORR) of 67%, with a complete response (CR) rate of 23% in the overall study population.2 Data from a combined analysis of 3 different trials with ibrutinib showed that the median progression-free survival (PFS) ranged from 10.5 months to 15.6 months.3

To me, this indicates that the efficacy of these drugs is defined less by the drug and more by the patient population taking the drug, noted Martin. That is very critical to remember when we look at all of the available agents.

Four years later, in October 2017, the second-generation BTK inhibitor acalabrutinib (Calquence) was FDA approvedfor the same indication based on data from the phase 2 ACE-LY-004 trial (NCT02213926). Here, the agent resulted in an 81% ORR per investigator assessment, with a CR rate of 40%.4 Updated data presented during the 2020 ASH Annual Meeting and Exposition showed that the median PFS with the agent was 22.0 months.5

Most recently, in November 2019, zanubrutinib (Brukinsa) was given the green light from the FDA for use in this population. The approval was based on data from 2 single-arm studies (NCT03206970 and NCT02343120) which showed that the BTK inhibitor induced an ORR of 83.7%.6 Notably, however, the agent tends to be a little less active in patients with blastoid histology and a higher Mantle Cell Lymphoma International Prognostic Index (MIPI) score, added Martin.

We have been forced to become pharmacists and pharmacologists more than we ever expected in that when were using these medications, we have to be very aware of drug-drug interactions, warned Martin. All have significant interactions with CYP3A inhibitors and inducers, although ibrutinib probably has the greatest interaction with [those drugs]. However, acalabrutinib and zanubrutinib also tend to be impacted by CYP3A inhibitors and we may need to watch out for toxicity.

Additionally, acalabrutinib appears to have a significant interaction with gastric acidreducing agents, added Martin.

Taking a Closer Look at Toxicities

When choosing among the 3 options that are available, Martin mentioned that its important to look at the safety profiles of the agents. One nice thing about adverse effects [AEs] is that theyre disease agnostic, so we can look at other clinical trials in other diseases to look at the toxicities [of these agents], said Martin. CLL is a nice one to look at because patients are typically on these agents longer, so we can get a better idea of safety profiles, overall.

In one clinical trial, investigators examined the use of acalabrutinib in patients who were intolerant to ibrutinib. Results indicated that most of the toxicities that had been reported with ibrutinib, that required patients to stop treatment with the agent, did not recur, according to Martin. Moreover, the effects that did recur, were found to be of a lower grade.7 The ORR was 75.8%, so not all of the patients who stopped ibrutinib for tolerability responded to acalabrutinib, which I thought was interesting, noted Martin.

Data from the phase 3 ELEVATE-RR trial (NCT02477696) showed that acalabrutinib demonstrated noninferior PFS to ibrutinib in previously treated patients with high-risk CLL, meeting the primary end point of the trial.8 Notably, patients who received acalabrutinib also experienced a statistically significant lower incidence of atrial fibrillation vs those who were given ibrutinib. So, [we saw] similar efficacy with less atrial fibrillation, which I think is relevant, added Martin.

Additionally, data from the phase 3 ASPEN trial (NCT03053440) showed similar efficacy with zanubrutinib vs ibrutinib in patients with Waldenstrm macroglobulinemia.9 However, investigators also noted that zanubrutinib had a lower rate of atrial fibrillation compared with ibrutinib, at 2.0% vs 15.3%, respectively. [Zanubrutinib] also had a potentially lower rate of major hemorrhage [vs ibrutinib], noted Martin, at 5.9% vs 9.2%, respectively.

Moving Beyond Single Agents: Novel Combinations Under Exploration

The phase 2 AIM trial (NCT02471391) is examining the use of ibrutinib plus the BCL-2 inhibitor venetoclax (Venclexta) in 23 patients who had relapsed/refractory MCL (n = 23) or were treatment nave but not candidates for chemotherapy (n = 1).10,11 Results demonstrated that the regimen led to a median PFS of 29 months. Sixty-seven percent of patients were minimal residual disease (MRD) negative in the bone marrow per flow cytometry (n = 19), while 38% were negative in the peripheral blood (n = 16).

What is most interesting to me is that at 16 weeks, the majority of patients were negative [for MRD], which [indicates] a very rapid response and I think that may mean something, said Martin.

Another combination under investigation is that of ibrutinib, lenalidomide (Revlimid), and rituximab. This triplet regimen is being explored as part of the phase 2 Nordic MCL6 PHILEMON trial (NCT02460276) in patients with relapsed/refractory MCL.12 Results from the trial showed that at a median follow-up of 17.8 months, the ORR with the triplet was 76% (n = 38/50), with a CR rate of 56% (n = 28).

Here, it appeared that the TP53 mutation held less sway than it does with chemotherapy, noted Martin. I think looking at TP53 one way or another is really critical in MCL and targeting those patients toward novel agents and potentially combinations of novel agents will become increasingly relevant.

In the follow-up, phase 1/2 Nordic MCL7 VALERIA trial (NCT03505944), investigators examined venetoclax, lenalidomide, plus rituximab in patients with relapsed/refractory MCL and found that a response-adapted treatment strategy, by stopping treatment in molecular remission, was feasible.13 [The combination] did not seem to be quite as effective as ibrutinib/lenalidomide and there was a small number of patients, said Martin. What I liked about this design was the continual reassessment of MRD and the potential to stop treatment. We dont have a lot of follow-up data but this approach to treatment is attractive as we move toward combinations.

Another novel combination that is under exploration in a phase 1 trial (NCT02158755) is that of ibrutinib and the CDK4/6 inhibitor palbociclib (Ibrance) in patients with relapsed/refractory MCL.13 We have significant data that suggest that palbociclib can sensitize lymphoma cells to cell killing by other drugs including ibrutinib, Martin explained. The phase 1 trial showed a [2-year] PFS [rate] of 59%. The regimen is now under exploration in a phase 2 trial (NCT03478514) led by Kami J. Maddocks, MD, of The Ohio State University Comprehensive Cancer CenterJames.

Determining When to Set Patients Up for CAR T

When we see patients with high MIPI scores, with multiple prior lines of therapy, and especially very proliferative diseases with blastoid histology, we can predict that these patients may have a response [to BTK inhibitors], but it will be a suboptimal response; it will be a very short response, noted Martin. We also know that when these patients progress, their responses are going to be very short, and well need to move very quickly. My bias in looking at these patients, before even starting a BTK inhibitor, is to say that they will likely need CAR T cells within the next few months, and Ill set them up to receive them.

Data from the phase 2 ZUMA-2 trial (NCT02601313) examining the CAR T-cell product brexucabtagene autoleucel (KTE-X19) has shown that this modality can be effective in patients who are refractory to BTK inhibitors.14 Data from 60 patients with MCL who were treated on the trial showed that the product led to an ORR of 93% with a CR rate of 67% at a median follow-up of 12.3 months. Additionally, 57% of all participants proved to have durable responses.

Its still a bit too early to say how this is going to plateaubut the key is to target these patients toward CAR T cells because once they start progressing on BTK inhibitors, were really in trouble and so we need to think about this early on, concluded Martin. We also may find that blastoid histology does respond to CAR T cells well according to CR rates, but the OS may be a little bit less than what we see with regular MCL. Getting those patients toward CAR T cells early on is probably going to be critical.

References

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Martin Makes Sense of the Rapidly Evolving MCL Treatment Paradigm - OncLive

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Hoth Therapeutics Expands License Agreement to Include Innovative Cancer and Anaphylactic Treatment – BioSpace

Wednesday, March 3rd, 2021

NEW YORK, Feb. 26, 2021 /PRNewswire/ --Hoth Therapeutics, Inc. (NASDAQ: HOTH), abiopharmaceutical company, todayannounced it has expanded its licensing agreementfrom North Carolina State University ("NC State") to include the worldwide development and commercialization of treatments targeting mast cell derived cancers and anaphylaxis.

The application of this newly licensed indication will be developed as a novel therapy ("HT-KIT") and shares the same molecular class as the Hoth's current HT-004 drug. Both treatments are being developed by Dr. Glenn Cruse, Assistant Professor at NC State. Dr. Cruse is a leading mast cell biologist in allergic and inflammatory diseases formerly from the National Institute of Health and currently a Hoth Scientific Advisory Board member. Dr. Cruse has been developing this technology with his team at NC State since 2017 and has generated initial proof-of-concept data in a neoplastic cell line supporting the novel activity of this therapeutics.

"We are delighted to expand this strategic alliance with NC State and our Scientific Advisory Board member, Dr. Glenn Cruse," saidRobb Knie, CEO of Hoth Therapeutics. "We believe that the HT-KIT pathway is a promising novel target for combating both mast cell-derived cancers and mast cell-mediated anaphylaxis. This expanded license agreement highlights the broad potential of our diverse pipeline that is aimed at meeting critical unmet patient needs and further supports Hoth's strategy to build a sustainable therapeutics company that is patient focused."

The HT-KIT drug is designed to more specifically target the receptor tyrosine kinase KIT in mast cells, which is required for the proliferation, survival and differentiation of bone marrow-derived hematopoietic stem cells. Mutations in the KIT pathway have been associated with several human cancers, such as gastrointestinal stromal tumors and mast cell-derived cancers (mast cell leukemia and mast cell sarcoma). Based on the initial proof-of-concept success, Hoth intends to initially target mast cell neoplasms for development of HT-KIT, which is a rare, aggressive cancer with poor prognosis.

The same target, KIT, also plays a key role in mast cell-mediated anaphylaxis, a serious allergic reaction that is rapid in onset and may cause death. Anaphylaxis typically occurs after exposure to an external allergen that results in an immediate and severe immune response. Hoth also intends to pursue the anaphylaxis indication for HT-KIT in parallel to cancer treatment and HT-004 development.

About Hoth Therapeutics, Inc.

Hoth Therapeutics, Inc. is a clinical-stage biopharmaceutical company focused on developing new generation therapies for unmet medical needs. Hoth's pipeline development is focused to improve the quality of life for patients suffering from indications including atopic dermatitis, skin toxicities associated with cancer therapy, chronic wounds, psoriasis, asthma, acne, and pneumonia. Hoth has also entered into two different agreements to further the development of two therapeutic prospects to prevent or treat COVID-19. To learn more, please visitwww.hoththerapeutics.com.

Forward-Looking Statement

This press release includes forward-looking statements based upon Hoth's current expectations which may constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995 and other federal securities laws, and are subject to substantial risks, uncertainties and assumptions. These statements concern Hoth's business strategies; the timing of regulatory submissions; the ability to obtain and maintain regulatory approval of existing product candidates and any other product candidates we may develop, and the labeling under any approval we may obtain; the timing and costs of clinical trials, the timing and costs of other expenses; market acceptance of our products; the ultimate impact of the current Coronavirus pandemic, or any other health epidemic, on our business, our clinical trials, our research programs, healthcare systems or the global economy as a whole; our intellectual property; our reliance on third party organizations; our competitive position; our industry environment; our anticipated financial and operating results, including anticipated sources of revenues; our assumptions regarding the size of the available market, benefits of our products, product pricing, timing of product launches; management's expectation with respect to future acquisitions; statements regarding our goals, intentions, plans and expectations, including the introduction of new products and markets; and our cash needs and financing plans. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. You should not place reliance on these forward-looking statements, which include words such as "could," "believe," "anticipate," "intend," "estimate," "expect," "may," "continue," "predict," "potential," "project" or similar terms, variations of such terms or the negative of those terms. Although the Company believes that the expectations reflected in the forward-looking statements are reasonable, the Company cannot guarantee such outcomes. Hoth may not realize its expectations, and its beliefs may not prove correct. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, market conditions and the factors described in the section entitled "Risk Factors" in Hoth's most recent Annual Report on Form 10-K and Hoth's other filings made with the U. S. Securities and Exchange Commission. All such statements speak only as of the date made. Consequently, forward-looking statements should be regarded solely as Hoth's current plans, estimates, and beliefs. Investors should not place undue reliance on forward-looking statements. Hoth cannot guarantee future results, events, levels of activity, performance or achievements. Hoth does not undertake and specifically declines any obligation to update, republish, or revise any forward-looking statements to reflect new information, future events or circumstances or to reflect the occurrences of unanticipated events, except as may be required by applicable law.

Investor Contact:LR Advisors LLCEmail:investorrelations@hoththerapeutics.comwww.hoththerapeutics.comPhone: (678) 570-6791

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SOURCE Hoth Therapeutics, Inc.

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Health Matters; Inflammation with Dr. Baumgartner [PODCAST] – WJON News

Sunday, February 14th, 2021

This week on WJON's Health Matters program I was joined by Dr. Joel Baumgartner from Rejuv Medical to talk about "Inflammation". He says inflammation doesn't always have to be bad. Dr. Baumgartner says degeneration is bad while inflammation can be good. He says if someone has a injured ankle they can see inflammation in the area signaling healing but sometimes the inflammation can be too much. Inflammation can be caused by a lack of sleep, what we eat, stress and many other triggers. Listen to our 4-part conversation below.

Dr. Baumgartner says at Rejuv Medical they can help treat inflammation in a variety of ways. He says PRP and Stem Cell replacement can be options for those looking to solve what has been chronic pain. Baumgartner says all Stem Cell replacement procedures involve PRP as part of the process to help trigger healing. Many people use anti-inflammatory pills to help with pain but he says some of those can have long-term negative effects. He warns against depending on those to get through chronic inflammation. He also suggests stretching, a proper diet, enough sleep, reduce stress and exercise meant to support the problem area.

Learn more about how Rejuv Medical can help. Health Matters airs on WJON Mondays and Saturdays from 9:10-10.

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Health Matters; Inflammation with Dr. Baumgartner [PODCAST] - WJON News

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G1 Therapeutics gains first FDA nod with myelopreservation therapy Cosela | 2021-02-12 – BioWorld Online

Sunday, February 14th, 2021

As expected, G1 Therapeutics Inc.s Cosela (trilaciclib) won FDA approval for use in extensive-stage small-cell lung cancer (SCLC) patients undergoing chemotherapy, becoming the first proactively administered myelopreservation therapy to hit the market.

The approval, conducted under the FDAs priority review, came late Feb. 12, just ahead of its Feb. 15 PDUFA date. Pricing has not yet been disclosed, but Research Triangle Park, N.C.-based G1 spent the latter half of 2020 prepping for commercial launch in the first quarter of 2021, with marketing, medical affairs and manufacturing operations fully in place and a field sales team from U.S. partner Boehringer Ingelheim GmbH trained and ready, the company reported during its presentation at the 2021 J.P. Morgan Healthcare Conference.

There are roughly 30,000 ES-SCLC patients treated annually in the U.S.

Chemotherapy remains the primary therapy for SCLC etoposide, topotecan, irinotecan and platinum-based drugs such as cisplatin or carboplatin, for example but its use results in damage to bone marrow stem cells, leading to myelosuppression. That, in turn, results in symptoms such as anemia, neutropenia or thrombocytopenia, which not only affects patients quality of life but can also disrupt treatment cycles and impact overall survival.

Some drugs are available to mitigate the damage. G-CSF drugs, for instance, are designed to prevent febrile neutropenia resulting from chemotherapy and erythropoiesis-stimulating agents are used to keep anemia in check. But those usually have their own treatment-limiting side effects.

Preserving immune function

Trilaciclib, a CDK4/6 inhibitor that received an FDA breakthrough therapy designation, is designed to preserve bone marrow and immune system function during chemotherapy treatment. Approval was based on data pooled from three pivotal studies that read out over 2018 and 2019.

In December 2018, G1 reported top-line data from its randomized, double-blind, placebo-controlled phase II trial evaluating combination of the therapy with topotecan as a treatment for second- and third-line SCLC, showing trilaciclib reduced clinically relevant consequences of myelosuppression vs. placebo. The trilaciclib arm demonstrated statistically significant reductions in both the duration of grade 4 neutropenia in cycle one (mean eight days vs. two days; adjusted one-sided p<0.0001) and occurrence of grade 4 neutropenia (75.9% vs. 40.6%; adjusted one-sided p=0.0160) as compared to the placebo arm.

Data from a phase II study testing trilaciclib with the combination of etoposide/carboplatin for the treatment of first-line SCLC demonstrated clinically meaningful improvements for neutrophil, red blood cell and lymphocyte measures in patients vs. placebo. In regard to lymphocytes, in particular, trilaciclib preserved or improved B-cell and T-cell subset counts, including activated CD8-positive cells, and increased CD8-positive/regulatory T-cell and activated CD8-positive/regulatory T-cell ratios in peripheral blood compared to placebo.

It also showed benefit in another phase II study in combination with chemotherapy and Tecentriq (atezolizumab), the PD-L1 inhibitor from Roche Holding AG. Data showed statistically significant improvements in both primary endpoints of occurrence of grade 4 neutropenia and duration of grade 4 neutropenia in cycle one, as well as a statistically significant reduction in grade 4 thrombocytopenia and clinically meaningful reduction in red blood cell transfusions. Trilaciclib reduced clinically relevant consequences of myelosuppression vs. placebo when administered in combination with chemotherapy (etoposide and carboplatin) and Tecentriq across neutrophils, red blood cells and platelets.

An established sales team

G1s three-year, SCLC-focused co-promotion deal with Boehringer, inked in June 2020, calls for G1 to lead marketing, market access and medical engagement initiatives, which are expected to extend to a focus on updating NCCN clinical practice guidelines to include trilaciclib. Boehringer brings to the table the established lung cancer sales team. Under the terms, G1 will book revenue and retain development and commercialization rights, paying Boehringer a promotion fee determined by net sales.

H.C. Wainwright analyst Edward White in Nov. 5, 2020, note, said he estimates trilaciclib sales of $21.4 million in 2021.

G1 also is looking to expand use of the drug beyond SCLC. In December, the company reported phase II data at the San Antonio Breast Cancer Symposium showing significantly improved overall survival in patients with triple-negative breast cancer (TNBC) treated with trilaciclib in combination with gemcitabine/carboplatin (GC) vs. GC alone. G1 plans to launch a registrational study this year to test trilaciclib plus GC in first-line patients with metastatic TNBC who have not received a PD-1/PD-L1 inhibitor and in second-line patients with metastatic TNBC who have received prior PD-1/PD-L1 therapy.

Trilaciclib also is included in the ongoing pivotal I-SPY 2 study in neoadjuvant breast cancer.

In August 2020, G1 licensed greater China rights for trilaciclib to Simcere Pharmaceutical Co. Ltd. in a $170 million deal.

Shares of G1 (NASDAQ:GTHX) were trading up 12% in after-hours trading Feb. 12.

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G1 Therapeutics gains first FDA nod with myelopreservation therapy Cosela | 2021-02-12 - BioWorld Online

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Kris Gopalakrishnan on innovation – Fortune India

Sunday, February 14th, 2021

Your familys philanthropic foundation, Pratiksha Trust, has also invested in brain research. In 2014, it donated 225 crore to set up the Centre for Brain Research (CBR), at IISc. How is that going?

There are two interesting projects the CBR is pursuing. The first one is a longitudinal study. It is studying 10,000 people over a period of 10 years in Kolar [district, in Karnataka] to see how the brain ages. These people are healthy individuals without dementia, aged 45 years and above.

There have been some hiccups in conducting the study and collecting data due to the pandemic. But it will restart soon. Till now, they have covered more than 2,000 people. It will be the first comprehensive database of Indian subjects on how they age. Theres a similar study done by CBR on urban subjects in Bengaluru which is funded by the Tata Trusts. The studies show interesting insights and the contrasting lifestyle between people in urban and rural areas.

The second programme is the Genome India Project (GIP) which is supported by the Department of Biotechnology [under the ministry of science and technology]. CBR at IISc is one of the over 20 labs involved in the project across the country. [The project aims to collect over 10,000 genetic samples from people across India to build a reference genome.] We dont have a comprehensive database of DNA sequences of Indian subjects. Besides my grant of 225 crore, there are other research programmes that I support. Overall, my support for research work alone is approximately 400 crore, currently spanning across brain, brain sciences, stem cell research, and others.

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Change is coming, and at an ever-accelerating pace – Al Jazeera English

Tuesday, January 12th, 2021

One of the great science and technology stories of 2020 is the development of COVID-19 vaccines, from start, through testing, to delivery, at a rate never seen before. Not just one vaccine. Three. (With more on the way and not counting the vaccines already in use in China and Russia.) All able to pass rigorous tests and examinations.

Two of them came from Big Pharma.

They threw lots of money and lots of researchers at the problem. We have been taught to expect that that is what they do for us. One of the reasons we think that maybe the primary one is that Big Pharma has thrown lots of money and employed lots of experts to tell us how very useful they are.

The throwing the money part seems to be true of Pfizer. But not for the others.

The US government put between $10bn and $18bn into Operation Warp Speed. Several of the programmes main recipients Johnson & Johnson, Novavax, Sanofi with GlaxoSmithKline have yet to deliver a successful vaccine. Moderna, which has, got about $2.5bn.

A headline from Scientific American stated cogently and concisely: For Billion-Dollar COVID Vaccines, Basic Government-Funded Science Laid the Groundwork. The subhead pointed out: Much of the pioneering work on mRNA vaccines was done with government money, though drugmakers could walk away with big profits.

The third vaccine came from Oxford University (In association with AstraZeneca which is Big Pharma and which received substantial sums from Operation Warp Speed). It appears to be much easier to use. It is going to market at about $6-8 for two doses. Compared with $40 for Pfizer and $50-74 for Moderna, per pair. (A fun fact is that these prices are about 25 percent higher in the US than in the European Union). This should remind us that much of the most important work in medicine has come out of universities and that contributing to health and making money are two separate things.

A far more obscure science and technology story appeared on the front page of the business section of the New York Times on December 29, 2019. It is about a guy named Mike Strizki.

Strizkis story is a throwback to the days of individual tinkerer-inventors. People like that telegraph operator, Thomas Edison, those bicycle mechanics, the Wright Brothers, and a daughter of American aristocracy, Mary Phelps Jacob who was later scandalously famous for her wild parties, drug use, open marriage, her whippet named Clytoris, and being the co-founder of the Black Sun Press, making her the literary godmother to the Lost Generation of expatriate writers in Paris who invented the modern brassiere when she was nineteen.

Strizki is the only guy on the East Coast who drives a hydrogen car.

There are more on the West Coast, nearly 9,000, plus 48 buses. They have 42 stations where they can refuel. There are none on the East Coast. Therefore, Mike makes his own hydrogen fuel in his back yard using solar power. The only byproduct from the process is one atom of oxygen for every two atoms of hydrogen. When the hydrogen is put through fuel cells creating the electricity that drives the car, it recombines with oxygen and the only byproduct is water.Such cars routinely go about 484 kilometres (300 miles) on a full tank. Hyperion claims they have a car that gets a bit over 1,609km (1,000 miles) on a single tank. Refilling them is quicker than refilling the gas tank on the old fashioned internal combustion vehicles most of us drive. They do not have to drag about 453 kilogrammes (1,000 pounds) of batteries like full electric vehicles. Yet, Elon Musk of Tesla, who is hugely invested in battery power cars, calls hydrogen fuel cell cars staggeringly dumb.

Mike has also made the first house in the United States to be powered entirely by hydrogen produced on-site using solar power. Keep in mind that Steve Jobs of Apple, Bill Gates of Microsoft and Mark Zuckerberg of Facebook all could be in that category of tinkerer-inventor, at least at their start.

Right now, Elon Musk and his Teslas seem way out ahead of Strizki and his single hydrogen vehicle. But that contest is far from over. Watch for the HTWO, Hyundais new brand dedicated to hydrogen fuel cell power. Daimler Truck, Iveco, OMV, Shell and the Volvo Group are in an alliance named H2Accelerate to promote hydrogen powered trucks.

The point of both of these stories the one about Big Pharma, Big Money, Big University and the other one about the home tinkerer is that science and technology are moving faster and faster.

We are moving closer to actual fusion power. The best research for it seems to be coming out of South Korea. Water cell batteries may soon replace lithium-ion batteries. Check your phone, youve got a computer in your pocket. Quantum computing is on the way. The exponential increase in the amount of material travelling over the internet means we need much greater communication capacity. It is happening. We have gone from megahertz, one million cycles per second, to gigahertz, a billion, and we are on the way to terahertz frequencies, a trillion cycles per second. 3D metal printing is here. Babel earbuds which translate as you go are ready though I must say if its translations are like the ones I get online, it may be like an illiterate babbling in your ear. An Alzheimers blood test may soon be on the market. We can now make artificial structures that mimic early embryos using only stem cells no egg or sperm necessary.

Human history, for the most part, has been a long, flat line of subsistence economies. There were brilliant moments with small brilliant elites but they always rested on the agricultural labour of peons, serfs, slaves, or peasants and fell back again. It was such from the beginning of time until about 1800 with the First Industrial Revolution. Since then, the curve of productivity has been on an upward climb. The 19th and early 20th century is often called the Second Industrial Revolution. We are now in the third, or fourth, or even the fifth industrial revolution or maybe it is the Post-Industrial Revolution or the Digital Age depending on whose book you are reading. Whatever name you prefer to give to this current period, its defining feature remains the same: The changes are coming faster and faster. They are reaching more and more people. They are coming from more and more people.

Yes, of course, we know from the machine guns of WWI, the bombers and then the nuclear weapons of WWII, that technology can be used for destruction. The speed and almost zero cost of internet communication have freed us from the grip of media barons and governments, but then opened the way for exploitation and the spread of disinformation, the existence of alternative facts and tribal truths. Even the changes that would be rated as positive for the general good, are often negative for specific individuals.

We may have anti-science governments. Like the Trump administration has so obviously and obnoxiously been. Yet while they muddled the airwaves with disinformation about the pandemic, they were also the ones who threw billions to science to come up with a vaccine. Big Oil ran campaigns denying climate change, modelled on Big Tobaccos past campaigns claiming cigarettes do not cause cancer,. Yet most of the major oil companies are investing in alternative energy technology.

Big Money invested in established business resists change. Speculative Money and theres lots of it wants to bet on the next big thing which usually has to be, by definition, based on new science and new technology.

This election cycle weve seen that the Internet and social media can do black magic, spreading disinformation, misinformation, and lots of outright lies. They also mean that real information from grammar school to graduate school and beyond is getting to be within reach of the whole world. Its a two-way street. Information, ideas, and research can zip in an instant from a mountain village, a yurt in the desert, public housing, to Harvard, Tohoku, and Oxford.

It would be wonderful if politicians, public intellectuals (if they still exist), sociologists, and economists (should they wish to deal with realities rather than models), turned their thinking and their efforts into figuring out how we as societies and as individuals can best deal with all this change.

Whether they do or they do not, the changes will come, are coming, are here, at that ever-accelerating rate.

The views expressed in this article are the authors own and do not necessarily reflect Al Jazeeras editorial stance.

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MCL Landscape Adapts to Changes After CAR T-Cell Therapy Approval – OncLive

Saturday, January 9th, 2021

Despite the introduction of CAR T-cell therapy to the mantle cell lymphoma (MCL) armamentarium, induction therapy followed by stem cell transplant has maintained a role, said James Gerson, MD, who added that he continues to recommend transplant for patients, since they are still eligible for CAR T-cell therapy upon relapse on transplant.

I tell patients that we have very long-term data that a consolidative transplant for those who are eligible leads to a prolonged remission, Gerson explained. If a patient can be in remission for 10 years, maybe 10 years from now we will have something that is even better and more tolerable than CAR T-cell therapy.

In July 2020, the FDA approved brexucabtagene autoleucel (Tecartus) for the treatment of adult patients with relapsed/refractory MCL. The indication was based on findings from the phase 2 ZUMA-2 trial where brexucabtagene autoleucel, given as a single infusion, induced an 87% objective response rate and a 62% complete response rate in this patient population.

Unlike in diffuse large B-cell lymphoma where more restrictions [with CAR T-cell therapy] exist, any patient with MCL who had 1 prior therapy and relapsed can go straight to CAR T-cell therapy, Gerson said. We can use BTK inhibitors to bridge them, but we dont have to. There are a lot of possibilities.

Though not yet planned, further studies evaluating CAR T-cell therapy in the frontline setting for patients with high-risk MCL may be worth exploring, said Gerson.

In an interview with OncLive during a 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Gerson, an assistant professor of clinical medicine at Penn Medicine, discussed navigating treatment selection amid the approval of CAR T-cell therapy in MCL and the role of transplant after induction therapy.

OncLive:What induction regimens do you consider for your patients with MCL and how do you select between possible options?

Gerson: For young, fit patients, there is really no right answer for induction therapy because [treatment selection] is based on phase 2, nonrandomized data. Typically, induction therapy involves high-dose chemotherapy. Im actually very intrigued by a recent publication from the French group that looked at obinutuzumab [Gazyva] with DHAP [dexamethasone, cytarabine, and cisplatin; O-DHAP] as frontline therapy for young patients prior to consolidative transplant.

Ive used a lot of R-DHAP [rituximab (Rituxan) plus DHAP], but I havent used this O-DHAP. I think there is rationale to be excited about that option. Even though it is a phase 2 trial, it should [yield] reasonable data to take to insurance and get approval for. Again, it is not something Ive given, but Im very compelled by it and it is something I will try in the coming months.

Then, [we] usually follow [induction therapy] with a stem cell transplant for patients who are eligible.

In the relapsed setting, second-line BTK inhibition is pretty much the standard of care now. There is no right answer between [ibrutinib (Imbruvica) and acalabrutinib (Calquence)]. Anecdotally and by some limited published data, ibrutinib seems to have a higher occurrence of adverse effects [AEs]. Acalabrutinib is a little bit different but seems to be more tolerable in the long run. I tend to tell patients that and then they tend to want the medication that probably has fewer AEs. A lot of us end up choosing acalabrutinib, but from an efficacy standpoint, we have no comparative data. The curves are pretty similar when we look between the 2 trials.

In the era of cellular therapy, what is the role of transplant in MCL?

The challenge, of course, is that with the FDA approval of brexucabtagene autoleucel and CAR T-cell therapy coming into MCL, it is hard to know if we should still be transplanting patients. No one knows the answer because it is obviously not something that has been explored. The only thing that is known is that patients who have been transplanted can still go forward with [CAR T-cell] therapy and respond quite well. Therefore, it is not that getting a transplant means a patient cannot get CAR T-cell therapy in the future.

[With that], I usually tell my patients not to skip transplant because of the approval of brexucabtagene autoleucel in the relapsed/refractory setting. That said, it is an individualized choice. Certainly, some patients might make that choice not to undergo a transplant now that CAR T-cell therapy is available to them should they relapse. Still, in my practice, I will still offer transplant to a patient who is young and fit as a consolidative measure after induction therapy.

Do you see CAR T-cell therapy gaining a more significant role in MCL? Will it eventually moveinto the frontline setting?

Right now, the label given to brexucabtagene autoleucel was very open, [encompassing] any relapsed/refractory patient [with MCL]. That is great not only for patients but for practicing physicians.

[Bringing CAR T-cell therapy to] the frontline setting will likely be investigated in the future, especially for high-risk patients with high MIPI [Mantle Cell Lymphoma International Prognostic Index] scores,TP53mutations, blastoid variant MCL, or pleomorphic variant MCL. [These features] tend to [confer] worse outcomes. There are areas where using [CAR T-cell therapy] in the frontline setting is worth looking into.

It is completely up to the company whether they want to pursue it. Otherwise, it is going to be left to investigator-initiated trials, which are going to be difficult because of the cost associated with CAR T-cell therapy. Some centers may pursue using homegrown CAR T-cell therapy where the cost is much lower for some of these high-risk patients, but I hope the company will pursue such trials in the frontline setting.

What other regimens are potentially on the horizon in MCL and how could they best fit into the paradigm?

There are a lot of similarities between chronic lymphocytic leukemia [CLL] and MCL. A similar triplet strategy to ibrutinib, obinutuzumab, and venetoclax [(Venclexta) in CLL] is being looked at in frontline and relapsed/refractory MCL. That is incredibly exciting and could very well supplant typical [cytarabine]-based induction and transplant. We will need long-term follow-up, so we probably wont know for many years.

Thankfully, with minimal residual disease [MRD], we will possibly be able to know much sooner, because if we can get a large percentage of patients into an MRD-negative state, that is a proxy for outcome. Again, we wont know for probably about 10 years before we get that long-term follow-up, but we will have a good enough idea if we [should] use MRD as a surrogate end point.

Reference

Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Eng J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347

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5 questions facing gene therapy in 2021 – BioPharma Dive

Saturday, January 9th, 2021

Three years ago, the Food and Drug Administration granted a landmark approval to the first gene therapy for an inherited disease, clearing a blindness treatment called Luxturna.

Since then, the regulator has approved one more gene therapy,the spinal muscular atrophy treatment Zolgensma, and given a green light for dozens of biotech and pharmaceutical companies to start clinical testing on others. Genetic medicines for a range of diseases, including hemophilia, sickle cell and several muscular dystrophies, appear in reach, and new science is galvanizing research.

But, entering 2021, the gene therapy field faces major questions after a series of regulatory and clinical setbacks have shaded optimism. "The ups and downs of adolescence are on full display" analysts at Piper Sandler wrote in September, summing up the state of gene therapy research.

Here are five questions facing scientists, drugmakers and investors this year. How they're answered will matter greatly to the patients and families holding out hope for one-time disease treatments.

The FDA was widely expected last year to approve a closely watched gene therapy for hemophilia A, the more common type of the blood disease. Instead, the agency in August surprisingly rejected the treatment, called Roctavian, and asked its developer, BioMarin Pharmaceutical, to gather more data.

The next day, Audentes Therapeutics reported news came a third clinical trial participant had died after receiving the biotech's experimental gene therapy for a rare neuromuscular disease. The tragedy brought flashbacks to past safety scares in gene therapy, although the current wave of treatments being tested have generally appeared safe.

A little less than five months later, the gene therapy field is grappling with two more setbacks. UniQure is exploring whether a study volunteer's liver cancer was caused by its gene therapy for hemophilia B. And Sarepta, one of the sector's top developers, faces significant doubts about its top treatment for Duchenne muscular dystrophy after disclosing a key study missed one of its main goals.

In each case, the drugmakers involved offered explanations and reasons for optimism. BioMarin still expects to obtain an approval; Audentes' trial is now cleared by the FDA to resume testing; UniQure thinks it's unlikely the cancer case is linked to treatment; and Sarepta argued its negative data were the product of unlucky study design.

But taken together, the developments are powerful reminders of both the stakes and uncertainty still facing gene therapy.

All four events also highlighted lingering worries about one-time genetic treatment. In rejecting Roctavian, for example, the FDA seemed to be concerned the impressive benefit hemophilia patients initially experienced may wane over time. The deaths in Audentes' study, meanwhile,renewed warnings about extremely high doses of gene therapy. Researchers have long watched for evidence that replacing or altering genes may cause cancer to develop in rare instances, particularly after four infants developed leukemia in a gene therapy study in the early 2000s.And Sarepta's negative findings were surprising because early signs of dramatic biological benefit that didn't seem to translate into clear-cut functional gains for all patients.

Experts are still confident gene therapy can deliver on its promise. Bu recent events suggest getting there may take a bit longer than some expected.

"The process is the product," is an often-used cliche about gene therapy, which are complex treatments with exacting manufacturing standards.

Most of the roughly 60,000 pages in Spark Therapeutics' application for approval of Luxturna, for instance, involved what's known in the industry as "chemistry, manufacturing and controls."

The therapeutic basis for gene therapy, by contrast, is much clearer for many of the rare, monogenic diseases that developers are targeting. If mutations in a single gene lead to disease, replacing or otherwise fixing that gene should have a large benefit.

"Genetic medicine is not industrialized serendipity," said Gbola Amusa, an analyst at Chardan, contrasting gene therapy with chemical-based drugs."It often is an engineering question."

In 2020, the FDA gave ample notice that it's watching gene (and cell) therapy manufacturing closely.Sarepta,Voyager Therapeutics,Iovance Biotherapeuticsand Bluebird biowere all forced to revise their development timelines after the agency asked for new details about production processes.

"The FDA is saying to companies that you've got to up your standards," Amusa added.

For their part, FDA officials have indicated the spate of data requests are a product of the sharply higher numbers of companies advancing through clinical testing.

While setbacks have piled up for therapies that seek to replace genes, 2020 was a "transformative year" for therapies designed to edit them, according to Geulah Livshits, an analyst at Chardan.

CRISPR gene editing, already widely recognized as a scientific breakthrough, gained further prestige with the awarding of the Nobel Prize in Chemistry to two early pioneers, Jennifer Doudna and Emmanuelle Charpentier.

But the year also brought important progress from early biotech adopters.Editas Medicine and Intellia Therapeutics, for example, notched CRISPR firsts with use of the editing technology inside the human body.

And CRISPR Therapeutics and partner Vertex showed their experimental therapy, which uses CRISPR to edit stem cells, worked exceptionally well in the first 10 patients with either sickle cell disease or beta thalassemia treated in two early studies.

The data are the most concrete sign yet that CRISPR's clinical use can live up to its laboratory promise. While all three companies' therapies are still in early stages, their advances have ginned up substantial investor enthusiasm.

Together, the market value of CRISPR Therapeutics, Editas and Intellia totals nearly $25 billion. Beam Therapeutics, a startup that uses a more precise form of gene editing, is worth nearly $6 billion.

"Gene therapy will have a big role to play," said John Evans, Beam's CEO. "But I do think in the last year or so there's a growing realization that, when possible, you'd probably rather edit than add an extra gene."

Clinical tests will prove that out but, until then, the large upswing in share price for gene editing companies may not be sustainable as valuations creep higher and higher. Some of the recent run-up, for instance,appears driven by money flowing from generalist investors through exchange-trade funds, rather than from investors experienced in handicapping preclinical- or early clinical-stage companies.

"They're overdue for some type of rationalization," predicted Brad Loncar, CEO of Loncar Investments, adding that many companies are targeting similar diseases, most commonly sickle cell and beta thalassemia.

Tasked with replacing faulty genes with functional ones, scientists for the most part have turned to two types of viruses to safely shuttle genetic instructions into cells. Adeno-associated viruses, or AAVs,are typically used for infused treatments, while researchers working on cells extracted from patients generally opt for lentiviruses.

Each virus class has advantages, but also notable drawbacks. AAVs, for instance, can trigger pre-existing immune defenses in some people, making those individuals ineligible or poor candidates for gene therapy. Lentiviruses, by contrast, are known to integrate their DNA directly into the genomes of cells they infect a useful attribute in some regards but limiting in others.

Over decades of gene therapy research, scientists have found ways to tweak and modify these viral vectors to better suit their needs, but the basic tools are the same. Jim Wilson, a gene therapy pioneer who ran the study that led to the death of teenager Jesse Gelsinger in 1999, told attendees at a STAT conference last fall that he's "somewhat disappointed" by slow progress in viral vector research.

And as more and more gene therapies enter clinical testing, the limitations of current viral vectors have become more apparent.

The pace of research might be picking up, however. Recently, a number of companies aiming to build better delivery tools have launched, including Harvard University spinout Dyno Therapeutics and 4D Molecular Therapeutics, which recently raised $222 million in an initial public offering.

Larger companies are interested, too. Roche, Sarepta and Novartis have all partnered with Dyno, for example.

In gene editing, meanwhile, researchers are developing new ways to cut DNA, while Beam and others are advancing different editing approaches altogether.

Billions of dollars have flowed from pharmaceutical companies into gene therapy over the past few years, leaving few large multinational drugmakers without a research presence.

2020 was no different, with sizable acquisitions inked by Bayer and Eli Lilly, as well as an array of smaller investments from Pfizer, Novartis, Johnson & Johnson, Biogen,and UCB. And CSL Behring, best known for its blood plasma products, spent nearly half a billion dollars to buy UniQure's most advanced gene therapy, a treatment for hemophilia B.

Over the past three years, there's been at least $30 billion spent on biotechs involved in gene or cell therapy. (Four deals account for the majority of that value.)

All of that dealmaking, while following promising and compelling science, is ultimately a bet that one-time genetic treatments can be scaled up and commercialized into a lucrative business.

Many of the acquired companies are working on therapies for very rare disorders affecting hundreds or thousands of people. A handful, however, are taking aim at more prevalent conditions, starting with still relatively uncommon diseases like hemophilia to ones affecting millions of people like Parkinson's.

"For gene therapy to meet our lofty expectations not just for investors, but for society it has to make the leap from these ultra-rare diseases," said Loncar.

Commercially, the track record for the few therapies on the market in the U.S. is mixed.Luxturna, now owned by Roche, is a niche product.Zolgensma has broader use and earned Novartis about $1 billion in the year and a half it's been commercially available.

Two cell therapies from Novartis and Gilead, meanwhile, have struggled to gain traction.

Gene therapy's biggest commercial test yet was supposed to come this year, with the expected approval of BioMarin's Roctavian in hemophilia A. The FDA's surprise rejection could mean a yearslong delay in the U.S., but the challenges of pricing, reimbursement and patient access in gene therapy remain dauntingly large.

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RNA molecules are masters of their own destiny – MIT News

Saturday, January 9th, 2021

At any given moment in the human body, in about 30 trillion cells, DNA is being read into molecules of messenger RNA, the intermediary step between DNA and proteins, in a process called transcription.

Scientists have a pretty good idea of how transcription gets started: Proteins called RNA polymerases are recruited to specific regions of the DNA molecules and begin skimming their way down the strand, synthesizing mRNA molecules as they go. But part of this process is less-well understood: How does the cell know when to stop transcribing?

Now, new work from the labs of Richard Young, Whitehead Institute for Biomedical Research member and MIT professor of biology, and Arup K. Chakraborty, professor of chemical engineering, physics, and chemistry at MIT, suggests that RNA molecules themselves are responsible for regulating their formation through a feedback loop. Too few RNA molecules, and the cell initiates transcription to create more. Then, at a certain threshold, too many RNA molecules cause transcription to draw to a halt.

The research, published in Cell on Dec. 16, 2020, represents a collaboration between biologists and physicists, and provides some insight into the potential roles of the thousands of RNAs that are not translated into any proteins, called noncoding RNAs, which are common in mammals and have mystified scientists for decades.

A question of condensates

Previous work in Youngs lab has focused on transcriptional condensates, small cellular droplets that bring together the molecules needed to transcribe DNA to RNA. Scientists in the lab discovered the transcriptional droplets in 2018, noticing that they typically formed when transcription began and dissolved a few seconds or minutes later, when the process was finished.

The researchers wondered if the force that governed the dissolution of the transcriptional condensates could be related to the chemical properties of the RNA they produced specifically, its highly negative charge. If this were the case, it would be the latest example of cellular processes being regulated via a feedback mechanism an elegant, efficient system used in the cell to control biological functions such as red blood cell production and DNA repair.

As an initial test, the researchers used an in vitro experiment to test whether the amount of RNA had an effect on condensate formation. They found that within the range of physiological levels observed in cells, low levels of RNA encouraged droplet formation and high levels of RNA discouraged it.

Thinking outside the biology box

With these results in mind, Young lab postdocs and co-first authors Ozgur Oksuz and Jon Henninger teamed up with physicist and co-first author Krishna Shrinivas, a graduate student in Arup Chakrabortys lab, to investigate what physical forces were at play.

Shrinivas proposed that the team build a computational model to study the physical and chemical interactions between actively transcribed RNA and condensates formed by transcriptional proteins. The goal of the model was not to simply reproduce existing results, but to create a platform with which to test a variety of situations.

The way most people study these kinds of problems is to take mixtures of molecules in a test tube, shake it and see what happens, Shrinivas says. That is as far away from what happens in a cell as one can imagine. Our thought was, Can we try to study this problem in its biological context, which is this out-of-equilibrium, complex process?

Studying the problem from a physics perspective allowed the researchers to take a step back from traditional biology methods. As a biologist, it's difficult to come up with new hypotheses, new approaches to understanding how things work from available data, Henninger says. You can do screens, you can identify new players, new proteins, new RNAs that may be involved in a process, but you're still limited by our classical understanding of how all these things interact. Whereas when talking with a physicist, you're in this theoretical space extending beyond what the data can currently give you. Physicists love to think about how something would behave, given certain parameters.

Once the model was complete, the researchers could ask it questions about situations that may arise in cells for instance, what happens to condensates when RNAs of different lengths are produced at different rates as time ensues? and then follow it up with an experiment at the lab bench. We ended up with a very nice convergence of model and experiment, Henninger says. To me, it's like the model helps distill the simplest features of this type of system, and then you can do more predictive experiments in cells to see if it fits that model.

The charge is in charge

Through a series of modeling and experiments at the lab bench, the researchers were able to confirm their hypothesis that the effect of RNA on transcription is due to RNAs molecules highly negative charge. Furthermore, it was predicted that initial low levels of RNA enhance and subsequent higher levels dissolve condensates formed by transcriptional proteins. Because the charge is carried by the RNAs phosphate backbone, the effective charge of a given RNA molecule is directly proportional to its length.

In order to test this finding in a living cell, the researchers engineered mouse embryonic stem cells to have glowing condensates, then treated them with a chemical to disrupt the elongation phase of transcription. Consistent with the models predictions, the resulting dearth of condensate-dissolving RNA molecules increased the size and lifetime of condensates in the cell. Conversely, when the researchers engineered cells to induce the production of extra RNAs, transcriptional condensates at these sites dissolved. These results highlight the importance of understanding how non-equilibrium feedback mechanisms regulate the functions of the biomolecular condensates present in cells, says Chakraborty.

Confirmation of this feedback mechanism might help answer a longstanding mystery of the mammalian genome: the purpose of non-coding RNAs, which make up a large portion of genetic material. While we know a lot about how proteins work, there are tens of thousands of noncoding RNA species, and we dont know the functions of most of these molecules, says Young. The finding that RNA molecules can regulate transcriptional condensates makes us wonder if many of the noncoding species just function locally to tune gene expression throughout the genome. Then this giant mystery of what all these RNAs do has a potential solution.

The researchers are optimistic that understanding this new role for RNA in the cell could inform therapies for a wide range of diseases. Some diseases are actually caused by increased or decreased expression of a single gene, says Oksuz, a co-first author. We now know that if you modulate the levels of RNA, you have a predictable effect on condensates. So you could hypothetically tune up or down the expression of a disease gene to restore the expression and possibly restore the phenotype that you want, in order to treat a disease.

Young adds that a deeper understanding of RNA behavior could inform therapeutics more generally. In the past 10 years, a variety of drugs have been developed that directly target RNA successfully. RNA is an important target, Young says. Understanding mechanistically how RNA molecules regulate gene expression bridges the gap between gene dysregulation in disease and new therapeutic approaches that target RNA.

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Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market: Industry Analysis and Forecast (2019-2026): By indication type, treatment type,…

Saturday, January 9th, 2021

The Platelet Rich Plasma and Stem Cell Alopecia Treatment market is expected to grow from US$ XXBn in 2018 to USD XX Bn by 2026, at a CAGR of 6.1% during the forecast period.

Platelet Rich Plasma and Stem Cell Alopecia Treatment marketThe report study has analyzed revenue impact of COVID -19 pandemic on the sales revenue of market leaders, market followers and market disrupters in the report and same is reflected in our analysis.Platelet-rich plasma (PRP) a new biotechnology, is the product of a heightened interest in cell-based therapy and tissue engineering. This therapy is defined as an autologous preparation of plasma with concentrated platelets.

Global Atomic Force Microscopes Market Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Drivers and RestrainsFactors contributing to the growth of this market include rise in disease awareness, treatment rate, and growing adoption of novel treatment therapies providing positive patient outcome. Moreover, lower incidences of negative side effects of this therapy are anticipated to fuel demand for platelet rich plasma (PRP) and stem cell therapy.

Treatment options for androgenic alopecia are limited and include topical minoxidil and oral finasteride (FDA approved) alone or in combination. Several reported side effects such as headache and increase in body hair are there for minoxidil whereas loss of libido has been reported with oral finasteride are considered to be major restraint to the global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market.

Hair loss is one of the significant factors that will foster the global hair transplant market growth over the projection period. Increasing patient pool in developing countries significant success rate and hair transplant procedures coupled with innovative technologies also help hair transplant market to grow seamlessly in the near future.

Advance treatments for alopecia are enhanced by dermatologists and patients over regular medications, for example, corticosteroids. More prominent inclination for these treatments emerges from proficient and quicker hair regrowth when contrasted with other corticosteroid medications. Furthermore, simplicity of organization of these novel treatments is anticipated to boost the global market.

Request For View Sample Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Report Pagehttps://www.maximizemarketresearch.com/request-sample/36142/

Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market by key segments

The stem cell therapy segment has been further classified into bone marrow treatment and adipose treatment. The dermatology clinics segment accounted for 88% of the total market revenue in 2018, owing to its lower therapy cost as compared to hospitals.

About 45% men and 35% women develop androgenic alopecia by 60, which is the highest among all the types of alopecia in the year 2018. A study published in the International Journal of Womens Dermatology in 2019 revealed that the use of PRP to treat androgenic alopecia is promising due to its autologous nature, minimal invasiveness, lack of major side effects, and low cost compared to hair restoration surgery.

Global Systemic Inflammatory Response Syndrome Treatment Market Regional AnalysisNorth America is anticipated to held leading position for global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market . In 2018, XX% of women suffer from androgenetic alopecia in North America. This has led the country to dominate the platelet rich plasma & stem cell alopecia treatment market in North America. The market in Asia Pacific is projected to expand at a significantly high CAGR during the forecast period, owing to the emergence of strong local manufacturers offering various technological advancements for platelet rich plasma & stem cell alopecia treatment at lower prices and increase in awareness among people about these treatment methods. Additionally, highest application of PRP for the treatment of alopecia has been observed in the past few years. This is likely to fuel the market in the region. Furthermore, technological advances and huge numbers of investments in Platelet Rich Plasma Therapies by key players are likely to fuel the global market in the emerging regions such as in china and India.

The objective of the report is to present comprehensive analysis of Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market including all the stakeholders of the industry. The past and current status of the industry with forecasted market size and trends are presented in the report with the analysis of complicated data in simple language. The report covers the all the aspects of industry with dedicated study of key players that includes market leaders, followers and new entrants by region. PORTER, SVOR, PESTEL analysis with the potential impact of micro-economic factors by region on the market have been presented in the report. External as well as internal factors that are supposed to affect the business positively or negatively have been analyzed, which will give clear futuristic view of the industry to the decision makers.

Do Inquiry Before Purchasing Market Platelet Rich Plasma and Stem Cell Alopecia Treatment Report Here:@https://www.maximizemarketresearch.com/inquiry-before-buying/36142/

The report also helps in understanding Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market dynamics, structure by analyzing the market segments, and project the Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market size. Clear representation of competitive analysis of key players by Type, price, financial position, product portfolio, growth strategies, and regional presence in the Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market make the report investors guide.Global Platelet Rich Plasma & Stem Cell Alopecia Treatment Market, by Treatment

Platelet Rich Plasma Therapies Stem Cell TherapyGlobal Platelet Rich Plasma & Stem Cell Alopecia Treatment Market, by Indication

Androgenic Alopecia Congenital Alopecia Cicatricial or Scarring AlopeciaGlobal Platelet Rich Plasma & Stem Cell Alopecia Treatment Market, by Type

Men womenKey players operating on Global Platelet Rich Plasma & Stem Cell Alopecia Treatment Market

Kerastem Eclipse Regen Lab SA Restore Hair Replicel LifeScience Histogen Inc. Glofinn Oy Orange County Hair Restoration Center, Hair Sciences Center of Colorado, Anderson Center for Hair, Evolution Hair Loss Institute, Savola Aesthetic Dermatology Center, Virginia Surgical Center, Hair Transplant Institute of Miami, Colorado Surgical Center & Hair Institute.

Major Table Platelet Rich Plasma and Stem Cell Alopecia Treatment Market of Contents Report

Chapter One: Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Overview

Chapter Two: Manufacturers Profiles

Chapter Three: Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Competition, by Players

Chapter Four: Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Size by Regions

Chapter Five: North America Platelet Rich Plasma and Stem Cell Alopecia Treatment Revenue by Countries

Chapter Six: Europe Platelet Rich Plasma and Stem Cell Alopecia Treatment Revenue by Countries

Chapter Seven: Asia-Pacific Platelet Rich Plasma and Stem Cell Alopecia Treatment Revenue by Countries

Chapter Eight: South America Platelet Rich Plasma and Stem Cell Alopecia Treatment Revenue by Countries

Chapter Nine: Middle East and Africa Revenue Platelet Rich Plasma and Stem Cell Alopecia Treatment by Countries

Chapter Ten: Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Segment by Type

Chapter Eleven: Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Segment by Application

Browse Full Report with Facts and Figures of Platelet Rich Plasma and Stem Cell Alopecia Treatment Market Report at:https://www.maximizemarketresearch.com/market-report/global-platelet-rich-plasma-and-stem-cell-alopecia-treatment-market/36142/

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Global Platelet Rich Plasma and Stem Cell Alopecia Treatment Market: Industry Analysis and Forecast (2019-2026): By indication type, treatment type,...

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Harpoon Therapeutics : Clin Cancer Res 2021; OnlineFirst version Jan 6, 2021 – Marketscreener.com

Saturday, January 9th, 2021

Published OnlineFirst December 1, 2020; DOI: 10.1158/1078-0432.CCR-20-3392

CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY

Preclinical Characterization of HPN536, a Trispecic, T-Cell-Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors A C

Mary Ellen Molloy1, Richard J. Austin1, Bryan D. Lemon1, Wade H. Aaron1, Vaishnavi Ganti1, Adrie Jones1,

Susan D. Jones1, Kathryn L. Strobel1, Purbasa Patnaik1, Kenneth Sexton1, Laurie Tatalick1, Timothy Z. Yu1, Patrick A. Baeuerle1,2,3, Che-Leung Law1, and Holger Wesche1

ABSTRACT

Purpose: Mesothelin (MSLN) is a glycophosphatidylinositol- linked tumor antigen overexpressed in a variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast can- cer. Early signs of clinical efcacy with MSLN-targeting agents have validated MSLN as a promising target for therapeutic inter- vention, but therapies with improved efcacy are still needed to address the signicant unmet medical need posed by MSLN- expressing cancers.

Experimental Design: We designed HPN536, a 53-kDa, tri- specic, T-cell-activatingprotein-based construct, which binds to MSLN-expressing tumor cells, CD3e on T cells, and to serum albumin. Experiments were conducted to assess the potency, activ-

Introduction

Redirection of cytotoxic T cells with bispecic antibody constructs for cancer therapy has been validated in the clinic (1-6). Blinatumo- mab is the rst and thus far the only bispecic T-cell engager (BiTE) approved by the FDA (7). T-cell-engaging biologics function by forming an immunologic cytolytic synapse between cancer target cells and T cells, which leads to target cell lysis independent of T-cell receptor (TCR) specicity, peptide antigen presentation by HLA, and T-cell costimulation. Despite the clinical success of blinatumomab for treating relapsed and refractory acute lymphoblastic leukemia, other molecules, including BiTE antibodies, showed only limited activity in the treatment of solid tumors (8, 9). Their short plasma half-life required continuous intravenous infusion limiting their utility for most solid tumor indications. Novel designs for T-cell-engaging antibodies aim at overcoming limitations of the rst generation and are already being tested in clinical trials (10).

The Trispecic T-cell-Activating Construct (TriTAC) design has been specically developed to treat solid tumors (11). TriTACs consist of a single polypeptide chain aligning three humanized, antibody- derived binding domains: a single-domain antibody (sdAb) specic for

1Harpoon Therapeutics, South San Francisco, California. 2MPM Capital, Cam- bridge, Massachusetts. 3Institute for Immunology, Ludwig-Maximilians University Munich, Planegg- Martinsried, Munich, Germany.

Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

Corresponding Author: Mary Ellen Molloy, Harpoon Therapeutics, 131 Oyster

Point Boulevard, 300, South San Francisco, CA 94080. Phone: 773-318-0796;

E-mail: mmolloy@harpoontx.com

Clin Cancer Res 2020;XX:XX-XX

doi: 10.1158/1078-0432.CCR-20-3392

2020 American Association for Cancer Research.

ity, and half-life of HPN536 in in vitro assays, rodent models, and in nonhuman primates (NHP).

Results: HPN536 binds to MSLN-expressing tumor cells and to CD3e on T cells, leading to T-cell activation and potent redirected target cell lysis. A third domain of HPN536 binds to serum albumin for extension of plasma half-life. In cynomolgus monkeys, HPN536 at doses ranging from 0.1 to 10 mg/kg demonstrated MSLN- dependent pharmacologic activity, was well tolerated, and showed pharmacokinetics in support of weekly dosing in humans.

Conclusions: HPN536 is potent, is well tolerated, and exhibits extended half-life in NHPs. It is currently in phase I clinical testing in patients with MSLN-expressing malignancies (NCT03872206).

a tumor antigen, a sdAb specic for serum albumin for half-life extension, and a single-chain fragment variable (scFv) specic for the CD3e subunit of the TCR complex (11). Their molecular size of 53 kDa is about one-third of that of an IgG. Binding of TriTACs to tumor antigen and CD3e is monovalent, which minimizes off-target CD3e clustering that can potentially lead to nonspecic T-cell activation. The absence of an Fc-gamma domain for half-life extension is functionally compensated by an albumin-binding domain. HPN424 (11) and HPN536, the rst two TriTACs are in phase I clinical testing in hormone refractory prostate cancer and mesothelin (MSLN)-over- expressing solid tumors, respectively.

Human MSLN is produced as a 71-kDa precursor of 628 amino acids, which is expressed as a glycophosphatidylinositol-linked cell surface glycoprotein. Its 31-kDaN-terminal domain is released as a soluble protein, termed as the megakaryocyte potentiating factor (MPF), while the 40-kDaC-terminal domain remains attached to the plasma membrane as mature MSLN (12-14). MSLN expression on normal tissue is conned to the single-cell mesothelial layer covering the surface of tissues and organs of the pleural, pericardial, and peritoneal cavities (13, 15). MUC16/CA125 is a binding partner for MSLN, implicating a role for MSLN in cell adhesion (16, 17). However, the precise physiologic functions of MSLN have not been dened, and MSLN-knockout mice exhibit no detectable phenotype or developmental abnormality (18).

MSLN is overexpressed in many malignancies, including ovarian cancer (13, 15, 19), pancreatic cancer (20, 21), non-small cell lung cancer (22-26),triple-negative breast cancer (26, 27), and mesothe- lioma (28, 29). In triple-negative breast cancer (25) and in lung and pancreatic adenocarcinomas (22, 23, 30), overexpression of MSLN correlates with poor prognosis. Differential expression of MSLN in cancer versus normal tissue has made it an attractive target for MSLN- directed imaging agents and therapeutics (10, 31-33). A challenge in developing MSLN-directed therapeutics is the expression of MSLN on normal mesothelial cells, potentially leading to dose-limiting toxicities.

Published OnlineFirst December 1, 2020; DOI: 10.1158/1078-0432.CCR-20-3392

Molloy et al.

Translational Relevance

Patients with mesothelin (MSLN)-overexpressing tumors, including ovarian, pancreatic, lung, and triple-negative breast cancer, have a high unmet clinical need. A number of MSLN- targeted therapeutics have been developed that show limited efcacy and safety in clinical trials. HPN536 is a novel, MSLN- targeted, trispecic, T-cell-activating protein construct that can potently redirect T cells to lyse tumor cells and was remarkably well tolerated in nonhuman primates at single doses up to 10 mg/kg, which is far above the expected therapeutic dose level. Our ndings suggest that HPN536 has the potential for high clinical activity and a wide therapeutic window. Its long serum half-life supports once-weekly dosing in humans. Currently, HPN536 is the only MSLN-targeting,T-cell-engaging biologic in clinical testing.

HPN536 specically redirects T cells for potent redirected lysis of MSLN-expressing cancer cells with concomitant T-cell activation. In three different mouse xenograft models, HPN536 induced durable antitumor activity at very low doses. In cynomolgus monkeys, HPN536 was well tolerated, showed a long serum half-life, and elicited signs of target engagement on mesothelial structures.

Materials and Methods

Protein production

Sequences of TriTACs, sdAbs, and extracellular domains of target proteins fused to an Fc domain or a hexahistidine tag were cloned into mammalian expression vector, pcDNA 3.4 (Invitrogen), preceded by a leader sequence. Expi293 Cells (Life Technologies) were maintained in suspension in Optimum Growth Flasks (Thomson) between 0.2 and

8 106 cells/mL in Expi293 media. Puried plasmid DNA was transfected into Expi293 cells in accordance with Expi293 Expression System Kit (Life Technologies) protocols and cultured for 4-6 days after transfection. Alternatively, HPN536 was produced in CHO- DG44 DHFR-decient cells (34). The amount of expressed proteins in conditioned media was quantitated using an Octet RED96 instru- ment with Protein A Tips (ForteBio/Pall) using appropriate puried control proteins for a standard curve. Conditioned media from either host cell were ltered and puried by protein A afnity and desalted or subjected to preparative size exclusion chromatography (SEC) using an AKTA Pure Chromatography System (GE Healthcare). Protein A puried TriTAC proteins were further puried by ion exchange and

formulated in a buffered solution containing excipients. Final purity was assessed by SDS-PAGE by resolving 2.5 mg/lane on TRIS-Glycine

gels and visualized with Simply Blue Stain (Life Technologies). Native purity was also assessed by analytic SEC using a Yarra SEC150 3 mm

4.6 150 mm Column (Phenomenex) resolved in an aqueous/organic mobile phase buffered at neutral pH on a 1290 LC system and peaks were integrated with OpenLab ChemStation Software (Agilent Technologies).

In vitro afnity measurements

Afnities of HPN536 analyte for albumin, CD3e, and MSLN ligands were measured by biolayer interferometry using an Octet RED96 instrument with Streptavidin Tips (ForteBio/Pall). Experiments were performed at 27 C in PBS plus casein in the absence or presence of 15 mg/mL has, as described in Results section and gure legends. Binding sensograms generated from empirically determined ligand

loads, appropriate serial dilutions of known analyte concentrations, and association and dissociation times were then t globally to a one- to-one binding model using Octet DataAnalysis 9.0 software.

In vitro T-cell-dependent cell cytotoxicity and T-cell activation assays

T cells from healthy donors were puried from leukopaks (leuka- pheresis samples, StemCell Technologies) using EasySep Human T Cell Isolation Kits (StemCell Technologies, 17951) following the manufacturer's instructions. All cancer cell lines were obtained from the ATCC, with the exception of OVCAR8 cells, which were obtained from the NCI (Bethesda, MD). Cell lines were passaged a maximum of 36 times after being received from the ATCC. Cell line authentication and Mycoplasma testing were not performed. T-cell-dependent cell cytotoxicity (TDCC) assays were performed as described previously (35). Briey, luciferase-expressing target cells and puried human T cells were seeded per well of a 384-well plate at a 10:1 T cell-to-target cell ratio. Target cell killing was assessed following incubation for 48 hours at 37oC and 5% CO2. Target cell viability was assessed by incubation with the SteadyGlo Reagent (Promega). Luminescence was measured using a PerkinElmer EnVision Detection System. Activated T cells were identied by CD69 and CD25 surface expression (BD Biosciences). Samples were analyzed on a FACSCelesta Flow Cyt- ometer (BD Biosciences). Flow cytometry data were processed using FlowJo v10 Software (FlowJo, LLC).

Binding of HPN536 on MSLN-expressing OVCAR and T cells Cultured cells were incubated with 1 mg/mL HPN536 or anti-GFP

TriTAC (control) for 1 hour. Binding was detected using Alexa647- anti-TriTAC antibody using a FACSCelesta Flow Cytometer (BD Biosciences). The QIFIKIT (Dako) was used according to the man- ufacturer's instructions to estimate the number of MSLN molecules expressed per cell.

Cytokines in the presence of T cells

To measure the cytokines, AlphaLISA Kits were used (PerkinElmer) per the manufacturer's instructions, except that the assays were performed in 384-well plates instead 96-well plates. Plates containing conditioned media from TDCC assays were used for analysis. Plates were read on a PerkinElmer EnVision Plate Reader equipped with an AlphaLISA module.

In vivo mouse efcacy studies

All mouse studies were performed in accordance with the policies of the Institutional Animal Care and Use Committee (IACUC) at

Harpoon Therapeutics and Charles River Laboratories. For TOV21G and HPAFII experiments, NCG (NOD-Prkdcem26Cd52Il2rgem26Cd22/

NjuCrl) mice received subcutaneous coimplants of human cancer cells (5 106) and human T cells (5 106) in 50% Matrigel (BD Biosciences) on day 0. Human T cells were expanded before implantation using Human T Cell Activation/Expansion Kit (Miltenyi Biotec) according to the manufacturer's instructions. Mice were dosed on days 1-15 (HPAFII, Fig. 4A and TOV21G, Fig. 4C) or days 7-16 (HPAFII, Fig. 4B) via intraperitoneal injection. For NCI-H292 experi- ments, NCG mice received subcutaneous coimplants of human cancer cells (1 107) and human peripheral blood mononuclear cells (PBMC;

1 107). Mice were administered HPN536 daily for 10 days starting on

day 6 via intravenous injection. Tumor size was measured twice weekly and calculated using the following formula: tumor volume (mm3)

(w2 l)/2. Percent tumor growth inhibition (%TGI) was dened as the difference between the mean tumor volume (MTV) of the control

OF2 Clin Cancer Res; 2021

CLINICAL CANCER RESEARCH

Rela

HPN536

An

group and the MTV of the treated group, expressed as a percentage of the MTV of the control group.

Exploratory cynomolgus monkey dose range-ndingstudy The pharmacology, pharmacokinetics, and toxicity of HPN536

were evaluated after a single intravenous bolus dose of 0.1, 1.0, or 10 mg/kg HPN536 in one male and one female cynomolgus monkey per group followed by either a 1- or 3-weekpostdose recovery period. The study followed the protocol and standard operating procedures of the testing facility (Charles River Labo- ratories) and was approved by their IACUC. Pharmacologic activ- ity was evaluated by clinical observations, cytokine assessments, ow cytometry, and evidence of target engagement by histology. Two research electrochemiluminescence assays, a functional assay and an anti-idiotypeassay, were used for measuring HPN536 levels in serum. For the functional assay, HPN536 was captured with biotinylated CD3e and was detected with a sulfo-taggedMSLN. For the anti-idiotypeassay, HPN536 was captured with an anti- idiotype antibody recognizing the anti-albumindomain and was detected with a sulfo-taggedCD3e. Toxicokinetic parameters were estimated using Phoenix WinNonlin pharmacokinetic software. A noncompartmental approach, consistent with the intravenous bolus route of administration, was used for parameter estimation.

Published OnlineFirst December 1, 2020; DOI: 10.1158/1078-0432.CCR-20-3392

HPN536 an Anti-MSLN/Anti-CD3T-Cell Engager for Solid Tumors

Toxicity endpoints included daily morbidity and mortality, daily clinical observations, weekly body weights, daily food consump- tion, clinical pathology (hematology, clinical chemistry, and coag- ulation), and anatomic pathology (gross necropsy, organ weights, and histopathology).

Results

Production, structure, and biochemical characteristics of

HPN536

Recombinant HPN536 has a molecular weight of approximately

53 kDa. A humanized llama sdAb specic for human MSLN is placed at its N-terminus (Fig. 1A). A humanized llama sdAb specic for human serum albumin (HSA) is placed in the middle of the molecule. The C-terminal end contains a humanized scFv specic for the human CD3e subunit of the TCR complex. GGGGSGGGS linkers connect the three binding domains.

HPN536 is produced by eukaryotic cell culture and secreted as a single, nonglycosylated polypeptide. Stability studies subjecting HPN536 to various stress conditions, including multiple freeze thaw cycles and storage at 4 C and 40 C for 2 weeks, suggest the protein is stable and stress resistant (Supplementary Fig. S1). The high stability of HPN536 ensures limited aggregation, which would otherwise lead to

huMSLN

huCD3e

huALB

A

B

MSLN

ALB

MSLN

CD3

ALB

CD3

In vitro anity

Human KD (nmol/L)

0.21

6.6

6.3

measurements

CynoK D (nmol/L)

1.1

6.2

5.6

Mouse (nmol/L)

210

NB

170

HPN536 binding to MSLN-

HPN536 binding to

expressing OVCAR8 cells

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Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity – Science Advances

Tuesday, January 5th, 2021

Abstract

Various characteristics of cancers exhibit tissue specificity, including lifetime cancer risk, onset age, and cancer driver genes. Previously, the large variation in cancer risk across human tissues was found to strongly correlate with the number of stem cell divisions and abnormal DNA methylation levels. Here, we study the role of synthetic lethality in cancer risk. Analyzing normal tissue transcriptomics data in the Genotype-Tissue Expression project, we quantify the extent of co-inactivation of cancer synthetic lethal (cSL) gene pairs and find that normal tissues with more down-regulated cSL gene pairs have lower and delayed cancer risk. Consistently, more cSL gene pairs become up-regulated in cells treated by carcinogens and throughout premalignant stages in vivo. We also show that the tissue specificity of numerous tumor suppressor genes is associated with the expression of their cSL partner genes across normal tissues. Overall, our findings support the possible role of synthetic lethality in tumorigenesis.

Cancers of different human tissues have markedly different molecular, phenotypic, and epidemiological characteristics, known as the tissue specificity in cancer. Various aspects of this intriguing phenomenon include a considerable variation in lifetime cancer risk, cancer onset age, and the genes driving the cancer across tissue types. The variation in lifetime cancer risk is known to span several orders of magnitude (1, 2). Such variation cannot be fully explained by the difference in exposure to carcinogens or hereditary factors and has been shown to strongly correlate with differences in the number of lifetime stem cell divisions (NSCD) estimated across tissues (2, 3). As claimed by Tomasetti and Vogelstein (2), these findings are consistent with the notion that tissue stem cell divisions can propagate mutations caused either by environmental carcinogens or random replication error (4). In addition, the importance of epigenetic factors in carcinogenesis has long been recognized (5), and Klutstein et al. (6) have recently reported that the levels of abnormal CpG island DNA methylation (LADM) across tissues are highly correlated with their cancer risk. Although both global (e.g., smoking and obesity) and various cancer typespecific (e.g., HCV infection for liver cancer) risk factors are well known (7), no factors other than NSCD and LADM have been reported to date to explain the across-tissue variance in lifetime cancer risk.

Besides lifetime cancer risk, cancer onset age, as measured by the median age at diagnosis, also varies among adult cancers (1). Although most cancers typically manifest later in life [more than 40 years old (1, 8)], some such as testicular cancer often have earlier onset (1). Many tumor suppressor genes (TSGs) and oncogenes are also tissue specific (911). For example, mutations in the TSG BRCA1 are predominantly known to drive the development of breast and ovarian cancer but rarely other cancer types (12). In general, factors explaining the overall tissue specificity in cancer could be tissue intrinsic (10, 13), and their elucidation can further advance our understanding of the forces driving carcinogenesis.

Synthetic lethality/sickness (SL) is a well-known type of genetic interaction, conceptualized as cell death or reduced cell viability that occurs under the combined inactivation of two genes but not under the inactivation of either gene alone. The phenomenon of SL interactions was first recorded in Drosophila (14) and then in Saccharomyces cerevisiae (15). In recent years, much effort has been made to identify SL interactions specifically in cancer, since targeting these cancer SLs (cSLs) has been recognized as a highly valuable approach for cancer treatment (1619). The effect of cSL on cancer cell viability has led us to investigate whether it plays an additional role even before tumors manifest, i.e., during carcinogenesis. In this study, we quantify the level of cSL gene pair co-inactivation in normal (noncancerous) human tissue as a measure of resistance to cancer development (termed cSL load, explained in detail below). We show that cSL load can explain a considerable level of the variation in cancer risk and cancer onset age across human tissues, as well as the tissue specificity of some TSGs. Together, these correlative findings support the effect of SL in impeding tumorigenesis across human tissues.

To study the potential effects of cSL in normal, noncancerous tissues, we define a measure called cSL load, which quantifies the level of cSL gene pair co-inactivation based on gene expression of normal human tissues from the Genotype-Tissue Expression (GTEx) dataset (20). Specifically, we used a recently published reference set of genome-wide cSLs that are common to many cancer types, identified from both in vitro and The Cancer Genome Atlas (TCGA) cancer patient data (21) via the identification of clinically relevant synthetic lethality (ISLE) (table S1A) (22, 23). For each GTEx normal tissue sample, we computed the cSL load as the fraction of cSL gene pairs (among all the genome-wide cSLs) that have both genes lowly expressed in that sample (Methods; illustrated in Fig. 1). We further defined tissue cSL load (TCL) as the median cSL load value across all samples of each tissue type in GTEx (Methods and table S2A). We then proceed to test our hypothesis that TCL can be a measure of the level of resistance to cancer development intrinsic to each human tissue (outlined in Fig. 1).

This diagram illustrates the computation of cSL load for each sample and each tissue type (i.e., TCL) and depicts the outline of this study, where we attempted to explain the tissue-specific lifetime cancer risk, cancer onset age, and TSGs using TCL. See main text and Methods for details.

SL is widely known to be context specific across species, tissue types, and cellular conditions (24). In theory, a cancer-specific cSL gene pair can be co-inactivated in the normal tissue without reducing normal cell fitness, while conferring resistance to the emergence of malignantly transformed cells due to the lethal effect specifically on the cancer cells. Different normal tissues can have varied TCLs (representing the levels of cSL gene pair co-inactivation) as a result of their specific gene expression profiles, and we hypothesized that normal tissues with higher TCLs should have lower cancer risk, as transforming cancerous cells in these tissues will face higher cSL-mediated vulnerability and lethality. To test this hypothesis, we obtained data on the tissue-specific lifetime cancer risk in humans (Methods) and correlated that with the TCL values computed for the different tissue types. We find a strong negative correlation between the TCL (computed from older-aged GTEx samples, age 50 years) and lifetime cancer risk across normal tissues (Spearmans = 0.664, P = 1.59 104; Fig. 2A and table S2A). This correlation is robust, as comparable results are obtained when this analysis is carried out in various ways (e.g., different cutoffs for low expression of genes, different cSL network sizes, and different cancer typenormal tissue mappings; fig. S1 and note S3). We also showed that this correlation is not confounded by the number of poised genes associated with bivalent chromatin, variation in cancer driver gene expression, and immune cell or fibroblast abundance (notes S11 to S13 and figs. S12 to S14). Notably, the cSL load varies with age due to age-related gene expression changes, and the correlation with lifetime cancer risk is not found when the TCL is computed on samples from the young population (20 age < 50 years, Spearmans = 0.0251, P = 0.901; fig. S2A); this is consistent with the observation that lifetime cancer risk is mostly contributed by cancers occurring in older populations (1). We still see a marked negative correlation between TCL and lifetime cancer risk when analyzing samples from all age groups together (Spearmans = 0.49, P = 0.01; fig. S2B). Repeating these analyses using different control gene pairs including (i) random gene pairs, (ii) shuffled cSL gene pairs, and (iii) degree-preserving randomized cSL network (same size as the actual cSL network; note S4) results in significantly weaker correlations (empirical P < 0.001; fig. S3, A to C, and note S4), confirming that the associations found with cancer risk results from a cSL-specific effect.

(A) Scatterplot showing Spearmans correlations between lifetime cancer risk and TCL computed for the older population (age 50 years) (ranked values are used as lifetime cancer risk spans several orders of magnitude.) (B) Lifetime cancer risks across tissues were predicted using linear models (under cross-validation) containing different sets of explanatory variables: (i) TCL only, (ii) the number of stem cell divisions (NCSD) only, and (iii) TCL and NSCD (27 data points). The prediction accuracy is measured by Spearmans , shown by the bar plots. The result of a likelihood ratio test between models (ii) and (iii) is also displayed. (C) A similar bar plot as in (B) comparing the predictive models for cancer risk involving the following variables: (i) TCL only, (ii) the LADM only, and (iii) TCL and LADM combined (21 data points only due to the smaller set of LADM data). A model containing all the three variables does not increase the prediction power (Spearmans = 0.77 under cross-validation) and is not shown. (D) Bar plot showing the correlations between lifetime cancer risk with TCLs computed (age 50 years) using subsets of cSLs: hcSLs, lcSLs, and all cSLs. Spearmans and P values are shown. The hcSLs and lcSLs are identified using data of matched TCGA cancer types and GTEx normal tissues (Methods), which correspond to only a subset of tissue types. To facilitate comparison, here, the correlation for all cSLs was also computed for the same subset of tissues, and therefore, the resulting correlation coefficient is different from that in (A).

While the randomized cSL networks used in the control tests described above provide significantly weaker correlations with cancer risk than those observed with cSLs, many of these correlations are still significant by themselves (fig. S3, B and C). This suggests that there may be a possible association between the expression of single genes in the cSL network (cSL genes) and cancer risk. To investigate this, we computed the tissue cSL single-gene load (SGL; the fraction of lowly expressed cSL genes) for each tissue (Methods). We do find a significant negative correlation between tissue SGL levels and cancer risk (Spearmans = 0.49, P = 0.01; fig. S3D and note S5). This correlation vanishes when we use random sets of single genes (fig. S3F). However, after controlling for the single-gene effect, the partial correlation between TCL and cancer risk is still highly significant (Spearmans = 0.69, P = 6.10 105; fig. S3G), pointing to the dominant role of the SL genetic interaction effect (note S5).

We next compared the predictive power of TCL to those obtained with the previously reported measures of NSCD (2, 3) and LADM (6), using the set of GTEx tissue types investigated here (Methods). We first confirmed the strong correlations of NSCD and LADM with tissue lifetime cancer risk in our specific dataset (Spearmans = 0.72 and 0.74, P = 2.6 105 and 1.3 104, respectively; fig. S4). These correlations are stronger than the one we reported above between TCL and cancer risk. However, adding TCL to either NSCD or LADM in linear regression models leads to enhanced predictive models of cancer risk compared to those obtained with NSCD or LADM alone [log-likelihood ratio (LLR) = 2.18 and 2.39, P = 0.037 and 0.029, respectively]. Furthermore, adding TCL to each of these factors increases their prediction accuracy under cross-validation (Spearmans s from 0.67 and 0.69 with NSCD and LADM alone to 0.71 and 0.77, respectively; Fig. 2, B and C). LADM and NSCD are significantly correlated (Spearmans = 0.66, P = 0.02), while the TCL correlates only in a borderline significant manner with either NSCD (Spearmans = 0.57, P = 0.06) or LADM (Spearmans = 0.52, P = 0.08). Together, these observations support the hypothesis that TCL is associated with tissue cancer risk, with a partially independent role from either NSCD or LADM.

We have shown results that support the role of TCL in impeding cancer development, and we reason that such an effect is dependent on the notion that many of the cSLs are specific to cancer while having weaker or no lethal effects in normal tissues. We tested and found that the co-inactivation of cSL gene pairs is under much weaker negative selection in GTEx normal tissues versus matched TCGA cancers [Wilcoxon rank sum test P = 2.93 106 (fig. S5A), also shown using cross-validation (note S7)]. Moreover, we hypothesize that those cSLs with the highest specificity to cancer (i.e., with the strongest SL effect in cancer and no or the weakest effect on normal cells) should have the strongest effect on cancer development. To test this, we identified the subset of such cSLs (termed highly specific cSLs or hcSLs) and those with the lowest specificity to cancer (termed lowly specific cSLs or lcSLs; Methods) and recomputed the TCLs of all normal GTEx tissues using these two cSL subsets, respectively. The TCLs computed from the hcSLs correlate much stronger with cancer lifetime risk than those computed from the lcSLs (Spearmans = 0.593 versus 0.319; Fig. 2D), testifying that these cSLs with high functional specificity to cancer are more relevant to carcinogenesis. These hcSLs are enriched for cell cycle, DNA damage response, and immune-related genes [false discovery rate (FDR) < 0.05; table S5 and Methods], which are known to play key roles in tumorigenesis.

We have thus established that TCL in the older population is inversely correlated with lifetime cancer risk across tissues. We next hypothesized that higher cSL load in a given normal tissue in the young population may delay cancer onset, which typically occurs later (age >40 years) (1). To test this, we use the median age at cancer diagnosis (1) of a certain tissue as its cancer onset age (table S3 and Methods). We find that the TCL values (for age 40 years) are markedly correlated with cancer onset age (Spearmans = 0.502, P = 0.011; Fig. 3A). This result is again robust to variations in our methods to compute TCL and cancer onset age (fig. S6, table S3, and note S3). We note that the cancer onset age is not significantly correlated with lifetime cancer risk (Spearmans = 0.279, P = 0.28).

(A) Scatterplot showing Spearmans correlations between cancer onset age and TCL (age 40 years). (B) Bar plot showing the correlations between cancer onset age with TCLs computed (age 40 years) using subsets of cSLs: hcSLs, lcSL, and all cSLs. Spearmans and P values are shown. As in Fig. 2D, this analysis was done for a subset of GTEx normal tissues for which we had matched TCGA cancer types to identify the hcSLs and lcSLs (Methods); therefore, the correlation result for all cSLs is also different from that in (A).

Similar to our earlier analysis, we see that the TCLs computed from the hcSLs correlate much stronger with onset age than those from the lcSLs or all cSLs (Spearmans = 0.603 versus 0.157; Fig. 3B and fig. S7A) and also stronger than those obtained from control tests performed as before (empirical P < 0.001; fig. S7, B to D). As with the case of cancer risk, the observed correlation is dominated by the SL genetic interaction effects rather than the single-gene effects (fig. S7, E to G, and note S5).

To further corroborate the relevance of cSL load to carcinogenesis, we next investigated whether carcinogen treatment in normal (noncancer) cell lines and primary cells in vitro can lead to cSL load decrease. First, we analyzed gene expression data from a recent study where human primary hepatocytes, renal tube epithelial cells, and cardiomyocytes were treated with the carcinogen and hepatotoxin thioacetamide-S-oxide (25). We computed the cSL load in each cell type after treatment versus control and found a significant decrease of cSL load only in the hepatocytes (Wilcoxon rank sum test P = 0.014; Fig. 4A), which is consistent with thioacetamide-S-oxides role as a hepatotoxin and a carcinogen primarily in the liver. Second, we collected the gene expression signatures of chemotherapy drug treatments in a total of four primary cells and normal cell lines from the Connectivity Map (CMAP) (26). We quantified the drug-induced cSL load changes indirectly from the gene signatures (Methods), comparing the strongly mutagenic DNA-targeting drugs (n = 6) including alkylating agents and DNA topoisomerase inhibitors to the weak/nonmutagenic taxanes and vinca alkaloids (n = 5), which act on the cytoskeleton and not directly on DNA (27). We find that the strong mutagenic chemotherapy drugs lead to a significantly larger decrease in cSL load (Fig. 4B, P = 0.03 from a linear model controlling for cell type; Methods). The strong mutagenicity of alkylating agents and DNA topoisomerase inhibitors is consistent with their mechanisms of actions; they are also World Health Organization class I carcinogens (28), supported by incidence of secondary cancers in patients treated by these drugs for their primary cancers (29). In contrast, taxanes and vinca alkaloids have shown negative or weak/inconclusive results in mutagenic tests (27, 30). These results are not likely affected by cell death, as the cSL decreased specifically only for the two classes among all tested chemotherapy drugs. Although the CMAP dataset used for this analysis does not include cell viability information, the gene expression of the cells does not show an apoptotic signature after the drug treatment.

(A) Box plots showing the cSL loads in control versus thioacetamide-S-oxidetreated samples in human primary hepatocytes (liver), renal tube epithelial cells (kidney), and cardiomyocytes (heart), using the data from (25). One-sided Wilcoxon rank-sum test P values are shown. (B) Box plots showing the cSL load changes after treatment by different classes of chemotherapy drugs in four cell types, using the CMAP data (26). Asterisk indicates that the cSL load change is estimated indirectly from the CMAP drug treatment gene expression signatures (Methods). Strongly mutagenic drugs (n = 6), including alkylating agents (green points) and DNA topoisomerase inhibitors (purple points), lead to a significantly larger cSL load decrease compared to weak or nonmutagenic drugs (n = 5), including taxanes (red points) and vinca alkaloids (blue points); P = 0.03 from a linear model controlling for cell type. HA1E is an immortalized kidney cell line; PHH, primary human hepatocyte; ASC, adipose-derived stem cell; SKB, human skeletal myoblast. (C) Box plots showing the cSL load in samples of different stages of premalignant lesions in the lung (including normal tissue and lung squamous cell carcinoma) (28). The cSL load shows an overall decreasing trend from normal to different pre-cancer stages to cancer (one-sided Wilcoxon rank sum test of normal versus cancer P = 4.47 105; ordinal logistic regression has negative coefficient 28.7, P = 5.89 107).

Further beyond these in vitro findings, analyzing a recently published lung cancer dataset (31), we find that cSL load decreases progressively as cancers develop from normal tissues throughout the multiple stages of premalignant lesions in vivo (normal versus cancer Wilcoxon rank sum test P = 4.47 105, ordinal logistic regression P = 5.89 107 with negative coefficient 28.7; Fig. 4C). These results provide further evidence supporting cSL as a factor that may be involved in cancer development.

Given the role of cSLs in cancer development, we turned to ask whether cSL may also contribute to the tissue/cancer-type specificity of TSGs (10, 32). Specifically, we reasoned that the loss of function of a gene is unlikely to have cancer-driving effects in tissues where its cSL partner genes are lowly expressed, due to the synthetic lethal effect of such co-inactivation on the emerging cancer cells. In other words, this gene is unlikely to be a TSG in such tissues. To study this hypothesis, we obtained a list of TSGs together with the tissues in which their loss is annotated to have a tumor-driving function from the COSMIC database (table S6A) (11). We further identified the cSL partner genes of each such TSG using ISLE (Methods and table S6B) (22). In total, there are 23 TSGs for which we were able to identify more than one cSL partner gene. Consistent with our hypothesis, we find that in most of the cases, the cSL partner genes of TSGs have higher expression levels in the tissues where the TSGs are known drivers compared to the tissues where they are not established drivers (binomial test for the direction of the effect P = 0.023; Fig. 5A). We identified 10 TSGs whose individual effects are significant (FDR < 0.05) and cSL specific (as shown by the random control test), and all these 10 cases exhibit the expected direction of effect (labeled in Fig. 5A and table S6C; two example TSGs, FAS and BRCA1, are shown in Fig. 5B, details are in fig. S8 and Methods). Reassuringly, these findings disappear under randomized control tests involving random partner genes of the TSGs and shuffled TSGtissue type mappings (note S9), further consolidating the role of cancer-specific cSLs of normal tissues in cancer risk and development.

(A) For each tissue-specific TSG gene Gi, the expression levels of its cSL partner genes in the tissue type(s) where gene Gi is a TSG were compared to those where gene Gi is not an established TSG, using GTEx normal tissue expression data. The volcano plot summarizes the result of comparison with linear models. Positive linear model coefficients (x axis) mean that the expression levels of the cSL partner genes are, on average, higher in the tissue(s) where gene Gi is a TSG. Many cases have near-zero P values and are represented by points (half-dots) on the top border line of the plot. Overall, there is a dominant effect of the cSL partner genes of TSGs having higher expression levels in the tissues where the TSGs are known drivers (binomial test P = 0.023). All TSGs with FDR < 0.05 that also passed the random control tests are labeled. (B) Examples of two well-known TSGs, FAS and BRCA1, are given. The heatmaps display the normalized expression levels of their cSL partner genes (rows) in tissues of where these two genes are known to be TSGs [according to the annotation from the COSMIC database (11)] and in tissues where they are not established TSGs (columns), respectively. High and low expressions are represented by red and blue, respectively. For clarity, one typical tissue type where the TSG is a known driver (e.g., testis for FAS) and three other tissue types where the TSG is not an established driver (and the least frequently mutated) are shown.

In this work, we show that the cSL load in normal tissues is a strong predictor of tissue-specific lifetime cancer risk and is much stronger than the pertaining predictive power observed on the individual gene level. Consistently, we find that higher cSL load in the normal tissues from young people is associated with later onset of the cancers of that tissue. As far as we know, no other factor has been previously reported to be predictive of cancer onset age across tissues. Furthermore, cSL load decreases upon carcinogen treatment in vitro and during cancer development through stages of precancerous lesions in vivo. Last, we show that the activity status of cSL partners of TSGs can explain their tissue-specific inactivation.

We have shown that the correlation between cSL and cancer risk in normal tissues may be explained by the fact that many of the cSLs are specific to cancer and have weak or no functional lethal effect in the normal tissues (Figs. 2D and 3B and fig. S5); therefore, normal tissues can bear relatively high cSL loads without being detrimentally affectedquite to the contrary, they become more resistant to cancer due to the latent effect of these cSLs on potentially emerging cancer cells. We emphasize that while we quantified the cSL loads using the normal tissue data from GTEx, the set of cSLs we used was derived exclusively in cancer from completely independent cancer datasets (and without using any information regarding lifetime cancer risk, onset, or tumor suppressor tissue specificity), so there is no circularity involved. The cSL load in normal tissues was computed to reflect the summed effects of individual cSL gene pairs. The underlying assumption is that the low expression of each cSL gene pair is synthetic sick (i.e., reducing cell fitness to some extent) and that the effects from different cSL gene pairs are additive, consistent with the ISLE method of cSL identification (22). Many experimental screenings of SL interactions also rely on techniques such as RNA interference that inhibits gene expression rather than completely knocks out a gene (33), and it is evident that most of the resulting SL gene pairs have milder than lethal effects. While these cSLs likely act via a diverse range of biological pathways and thus do not provide pathway-specific mechanisms, the additive cancer-specific lethal effect of such cSL gene pairs, however, could form a negative force impeding cancer development from normal tissues.

Obviously, as we are studying the across-tissue association between cSL load and cancer risk, it is essential to focus on cSLs that are common to many cancer types (i.e., pan-cancer). Therefore, we focused on cSLs identified computationally by ISLE via the analysis of the pan-cancer TCGA patient data (22). In contrast, most experimentally identified cSLs are obtained in specific cancer cell lines and are thus less likely to be pan-cancer [and possibly, less clinically relevant (22)]. However, for completeness, we also compiled a set of experimentally identified cSLs from published studies (22, 34) (note S1 and table S1B). The corresponding TCL values computed using this set of cSLs correlate significantly with lifetime cancer risk but not with cancer onset age; the correlation with cancer risk is also markedly weaker than that obtained from ISLE-derived cSLs [Spearmans = 0.433, P = 0.024 (fig. S9A), control tests and detailed analysis are explained in note S4]. These experimentally identified cSLs can explain some cases of tissue-specific TSGs including BRCA1 and BRCA2 (fig. S9E) but do not result in overall significant accountability for a large proportion of TSGs present in the analysis (like in Fig. 5A). This corroborates the importance of pan-cancer cSLs and their relevance to cancer risk.

TCL is not likely to be a corollary of NSCD and LADM [while LADM was thought to be closely related to NSCD (6)], as the cSL load is computed by analyzing expression data of bulk tissues, where stem cells occupy only a minor proportion. We have shown that TCL significantly adds to either NSCD or LADM in predicting lifetime cancer risk (Fig. 2, B and C), which also suggests that cSL load is an independent factor correlated with cancer risk with unique underlying mechanisms. Furthermore, NSCD is measured as the product of the rate of tissue stem cell division and the number of stem cells residing in a tissue (2), and we confirmed that TCL is correlated with lifetime cancer risk independent of both of these components (partial Spearmans = 0.510 and 0.567, P = 0.007 and 0.002, respectively; fig. S10, A and B). We additionally tested and verified that proliferation indices computed for the bulk normal tissues do not correlate with lifetime cancer risk across tissues (Spearmans = 0.062, P = 0.77; fig. S10C and note S10). Furthermore, we verified that our observed correlations are not confounded by the number of samples from each cancer or tissue type (fig. S11).

Since cSL load can vary with age, one may wonder whether cSL load could be extended to correlate with age-specific cancer risk within a tissue (as opposed to across tissues). However, variations in cancer risk across tissues and across ages can be driven by different factors. We did not find a consistent correlation between cSL load computed by age range and age-specific cancer risk in all tissue types (note S14 and fig. S15). Another extension to our current research question is studying the effect of higher-order genetic interactions on cancer risk, which is plausible but challenging to study due to the limited knowledge available on such complex interactions.

While revealing cSL as a previously unknown factor associated with cancer development, our study has several limitations. First, because of the importance of using pan-cancer cSLs as discussed above, we mainly relied on the cSLs computationally inferred by ISLE (22) as one of the most comprehensive pan-cancer cSL datasets. However, current cSL prediction algorithms are far from perfect and should not be regarded as the gold standard for general cSL identification. Only a minor fraction of the large number of predicted cSLs have been experimentally validated only in specific cell types. The cSLs inferred by ISLE should be best viewed as a set of candidate cSL pairs that emerge from genetic screen data in vitro but with further support from patient and phylogenetic data. Future studies that provide experimentally validated pan-cancer cSLs are needed to consolidate our current findings. Second, we have relied on analyzing the gene expression data of bulk tissues from GTEx and not the expression data of the specific cells of origin of the corresponding cancers. More refined future analysis is desirable using single-cell data across normal human tissues as such data becomes more widely available. Last, our study does not establish a causal relationship between the cSL load and the risk of cancer, as it is challenging to experimentally perturb a large number of cSLs simultaneously. The results shown are descriptive and association based, and the causal role of SLs in carcinogenesis remains to be studied mechanistically.

Together, our findings demonstrate strong associations between SL and cancer risk, onset time, and context specificity of tumor suppressors across human tissues. This suggests that beyond the effect on cancer after it has developed, cSL could also play an important role during the entire course of carcinogenesis, although further studies are needed to establish causality. While SL has been attracting tremendous attention as a way to identify cancer vulnerabilities and target them, this is the first time that its potential role in mediating cancer development is uncovered.

The cSL gene pairs computationally identified by the ISLE (identification of clinically relevant SL) pipeline were obtained from (22). We used the cSL network identified with FDR < 0.2 for the main text results, containing 21,534 cSL gene pairs, which is a reasonable size representing only about one cSL partner per gene on average. This also allows us to capture the effects of many weak genetic interactions. Nevertheless, we also used the cSL network with FDR < 0.1 (only 2326 cSLs) to demonstrate the robustness of the results to this parameter (notes S1 and S3). Each gene pair is assigned a significance score [the SL-pair score defined in (22)], that a higher score indicates that there is stronger evidence that the gene pair is SL in cancer. Out of these, we used 20,171 cSL gene pairs whose genes are present in the GTEx data (table S1A). The experimentally identified cSL gene pairs were collected from 18 studies [obtained from the supplementary data 1 of Lee et al. (22) except for those from Horlbeck et al. (34)]. Horlbeck et al. (34) provided a gene interaction (GI) score for each gene pair in two leukemia cell lines. Gene pairs with GI scores of <1 in either cell line were selected as cSLs. A total of 27,975 experimentally identified cSLs were obtained, out of which 27,538 have both their genes present in the GTEx data (table S1B).

The V6 release of GTEx (20) RNA sequencing (RNA-seq) data [gene-level reads per kilobase of transcript, per million mapped reads (RPKM) values] was obtained from the GTEx Portal (https://gtexportal.org/home/). The associated sample phenotypic data were downloaded from dbGaP (35) (accession number phs000424.vN.pN). For comparing the level of negative selection to co-inactivation of cSL gene pairs between normal and cancer tissues, the RNA-seq data of TCGA and GTEx as RNA-seq by expectation-maximization (RSEM) values that have been processed together with a consistent pipeline that helps to remove batch effects were downloaded from UCSC Xena (36). The expression data for each tissue type (normal or cancer) was normalized separately (inverse normal transformation across samples and genes) before being used for the downstream analyses. We mapped the GTEx tissue types to the corresponding TCGA cancer types (table S2B), resulting in one-on-many mappings, e.g., the normal lung tissue was mapped to both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).

Lifetime cancer risk denotes the chance a person has of being diagnosed with cancer during his or her lifetime. Lifetime cancer risk data (table S2A) are from Tomasetti and Vogelstein (2), which are based on the U.S. statistics from the SEER (Surveillance, Epidemiology, and End Results) database (1). We derived the cancer onset age based on the age-specific cancer incidence data from the SEER database with the standard formula (37). Specifically, for each cancer type, SEER provides the incidence rates for 5-year age intervals from birth to 85+ years old. The cumulative incidence (CI) for a specific age range S is computed from the corresponding age-specific incidence rates (IRi, i S) as CI = 5i S IRi, and the corresponding risk is computed as risk = 1 exp(CI). The onset age for each cancer type (table S3) was computed as the age when the CI from birth is 50% of the lifetime CI (i.e., birth to 85+ years old). Usually, the onset age defined as such is between two ages where the actual CI data are available, so the exact onset age was obtained by linear interpolation. Alternative parameters were used to define onset age (note S3) to show the robustness of the correlation between TCL and cancer onset age based on different definitions.

For each sample, we computed the number of cancer-derived SL gene pairs that have both genes lowly expressed and divided it by the total number of cSLs available to get the cSL load per sample. In the ISLE method described in (22), low expression was defined as having expression levels below the 33 percentile in each tissue or cell type. Thus, the ISLE-derived cSL gene pairs were shown to exhibit synthetic sickness effects when both genes in the gene pair are expressed at levels below the 33 percentile in each tissue, even though this appears to be a very tolerant cutoff (22). We therefore adopted the same criterion for low expression for the main results, although we also explored other low expression cutoffs to demonstrate the robustness of the results (note S3).

TCL of each tissue type is the median value of the cSL loads of all the samples (or a subpopulation of samples) in that tissue, with the cSL load of a sample computed as above. For example, TCL for the older population (age 50 years) is the median cSL load for the samples of age 50 years in each tissue type. For analyzing the correlation between the TCLs computed from GTEx normal tissues and cancer risk, we mapped the GTEx tissue types to the corresponding cancer types for which lifetime risk data are available from Tomasetti and Vogelstein (2), resulting in 16 GTEx types mapped to 27 cancer types (table S2A). Gallbladder nonpapillary adenocarcinoma and osteosarcoma of arms, head, legs, and pelvis are not mapped to GTEx tissues and excluded from our analysis. Similarly for the correlation between TCLs and cancer onset age, we mapped GTEx tissue types to the tissue sites from the SEER database (as given in the data slot site recode ICD-O-3/WHO 2008) by their names (table S3).

To investigate the effect on the single-gene level, we computed the cSL SGL in a paralleling way to the computation of the cSL load. Among all the unique genes constituting the cSL network (i.e., cSL genes), we computed the fraction of lowly expressed cSL genes for each sample as the cSL SGL, where low expression was defined in the same way as the computation of cSL load as elaborated above. Similarly, tissue cSL SGL is the median value of the cSL SGLs of all the samples in a tissue.

The lifetime cancer risks across tissue types were predicted with linear models containing three different sets of explanatory variables: (i) the number of total stem cell divisions (NSCD) alone, (ii) TCL alone, and (iii) NSCD together with TCL. LLR test was used to determine whether model (iii) (the full model) is significantly better than model (i) (the null model) in predicting lifetime cancer risks. The three models were also used to predict the lifetime cancer risks with a leave-one-out cross-validation procedure, and the prediction performances were measured by Spearman correlation coefficient. A similar analysis was performed to predict lifetime cancer risks across tissue types with three linear models involving the level of abnormal DNA methylation levels of the tissues (6): (i) the number of LADM alone, (ii) TCL alone, and (iii) LADM together with TCL.

For each pair of GTEx normalTCGA cancer of the same tissue type (table S2B), we computed the fraction of samples where a cSL gene pair i has both genes lowly expressed (defined above) among the normal samples (fni) and cancer samples (fci) and computed a specific score as rsi = fni fci. We selected the hcSLs as those whose specific scores are greater than the 75% percentile of all scores and lcSLs as those with a score below the 25% percentile (table S4, A and B). We compared SL significance scores between the hcSLs and lcSLs in each tissue using a Wilcoxon rank sum test. For each type of the GTEx normal tissues used in this analysis (i.e., those that can be mapped to TCGA cancer types), we also computed the TCL as above but using the hcSLs, lcSLs, or all cSLs, respectively, and analyzed their correlation with lifetime cancer risk or cancer onset age across the tissues.

We designed an empirical enrichment test as below to account for the fact that each cSL consists of two genes. For the hcSLs in each tissue type and each given pathway from the Reactome database (38), we computed the odds ratio (OR) for the overlap between the genes in hcSLs and the genes within the pathway based on the Fishers exact test procedure, with the background being all the genes in the ISLE-inferred cSLs. A greater than 1 OR indicates that the hcSLs are positively enriched for the genes of the pathway. To determine the significance of the enrichment, we repeatedly and randomly sampled the same number of cSLs as that of the hcSLs, computed the ORs similarly, and computed the empirical P value as the fraction of cases where the OR from the random cSLs is greater than that from the hcSLs. We corrected for multiple testing across pathways with the Benjamini-Hochberg method.

The phase I CMAP (26) data were downloaded from the Gene Expression Omnibus database (GSE92742). Level 5 data that represent the consensus perturbation-induced differential expression signature were used. We focused on CMAP data that involve treatment by specific classes of chemotherapy drugs (mutagenic: alkylating agents and DNA topoisomerase inhibitors; nonmutagenic: taxanes and vinca alkaloids) in normal cell lines or primary cells. We identified a total of 11 drugs tested in four cell types. Given the signature (z score) of a drug treatment in a cell, we estimated the drug-induced cSL load change as follows1|S|((i,j)SI(zi<0.5zj<0.5)(i,j)SI(zi>0.5zj<0.5))where S is the set of cSLs, and |S| is the total number of cSL gene pairs. A gene pair is denoted by (i, j), and zi and zj are the z scores of gene i and gene j, respectively. I() is the indicator function. Intuitively, the above formula quantifies the number of cSL gene pairs where both genes are down-regulated with a z score cutoff of 0.5 (i.e., contributing to cSL load increase), minus the number of cSL gene pairs where either gene is up-regulated with a z score cutoff of 0.5 (i.e., contributing to cSL load decrease), normalized by the total number of cSL gene pairs. We then tested whether the mutagenic drugs lead to a larger decrease in cSL load compared to nonmutagenic drugs with a linear model that controls for both cell type and drug.

We obtained the list of TSGs and their associated tissue types from the COSMIC database (11) (https://cancer.sanger.ac.uk/cosmic/download, the Cancer Gene Census data; table S6A). For each TSG, their cSL partner genes were identified using the ISLE pipeline (22) with an FDR cutoff of 0.1 (table S6B). Here, the FDR cutoff is more stringent than that used for the pan-cancer genome-wide cSL network (FDR < 0.2 for the main results) since, here, FDR correction was performed for each TSG, corresponding to a much lower number of multiple hypotheses. As a result, the FDR correction has more power, and a relatively more stringent cutoff can give rise to a more reasonable number of cSL partner genes per TSG. We focused our analysis on 23 TSGs for which more than one cSL partner genes were identified (no cSL partner was identified for most of the other TSGs). The expression levels of the cSL partner genes were then compared between tissue type(s) where the TSG is a known driver and the rest of the tissues where the TSG is not an established driver with linear models. Specifically, the expression levels of the cSL partners were modeled with two explanatory variables: (i) driver status of the TSG in the tissue (binary) and (ii) cSL partner gene (categorical, indicating each of the cSL partner genes of a TSG). The coefficient and P value associated with variable (i) were used to analyze the general trend of differential expression among the cSL partner genes. Positive coefficients of variable (i) means that the expression levels of the cSL partner genes are, on average, higher in the tissue(s) where the TSG is a known driver compared to those in the tissues where the TSG is not an established cancer driver.

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Versiti Blood Centers and Noodles & Company Serve Up Thanks to Blood Donors – PRNewswire

Tuesday, January 5th, 2021

MILWAUKEE, Dec. 30, 2020 /PRNewswire/ -- Versiti Blood Centers and premier partner Noodles & Company are dishing out discounts for life-saving donations during National Blood Donor Month this January.

Since 2016, Noodles & Company has supported Versiti's mission by aligning as a community partner and donating over $1.3 million in discounts and coupons to blood donors. Throughout January 2020, all attempting blood donors will receive a coupon redeemable for $4 off their order when they donate at a Versiti donor center or select community blood drive.

January is National Blood Donor Month, which highlights the critical need for blood during winter when donations often decline. Donors of all blood types are needed, but especially O negative blood donors who carry the universal blood type given to people in emergency situations.

To schedule an appointment, visit versiti.org.

About Versiti Blood Centers Versiti is a not-for-profit organization headquartered in Milwaukee that specializes in blood services, esoteric diagnostic testing, organ, tissue and stem cell donation, medical services and leading-edge research. Founded in 1947, Versiti is the primary provider of blood products and services for more than 250 hospitals in five midwestern states: Illinois, Indiana, Michigan, Ohio and Wisconsin. Versiti collects more than 602,000 units of blood each year at 35 permanent donation sites and more than 12,000 community blood drives. For more, visit versiti.org.

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Versiti Blood Centers and Noodles & Company Serve Up Thanks to Blood Donors - PRNewswire

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January 2021: 2020 Papers of the Year – Environmental Factor Newsletter

Tuesday, January 5th, 2021

Research funded by grantsPFAS linked with liver injury in children

Exposure to per- and polyfluoroalkyl substances (PFAS) in the womb may increase liver injury risk in children, according to NIEHS-funded researchers. This study is the first to examine the impact of early life exposures to a PFAS mixture on child liver injury. PFAS, a large group of synthetic chemicals found in a variety of consumer products, have been linked to immune dysfunction, altered metabolism, brain development, and certain cancers.

The study used data from 1,105 mothers and their children enrolled in the Human Early-Life Exposome, or HELIX, study in Europe. Using computational modeling, the scientists found that higher exposures to PFAS during pregnancy were associated with higher levels of liver enzymes in children. High liver enzyme levels may point to nonalcoholic fatty liver disease (NAFLD). The researchers also identified a profile for children at high risk for liver injury, characterized by high prenatal PFAS exposures.

Citation: Stratakis N, Conti DV, Jin R, Margetaki K, Valvi D, Siskos AP, Maitre L, Garcia E, Varo N, Zhao Y, Roumeliotaki T, Vafeiadi M, Urquiza J, Fernandez-Barres S, Heude B, Basagana X, Casas M, Fossati S, Grazuleviciene R, Andrusaityte S, Uppal K, McEachan RRC, Papadopoulou E, Robinson O, Haug LS, Wright J, Vos MB, Keun HC, Vrijheid M, Berhane KT, McConnell R, Chatzi L. 2020. Prenatal exposure to perfluoroalkyl substances associated with increased susceptibility to liver injury in children. Hepatology 72(5):17581770. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dert/index.htm#a1))

In an NIEHS-funded study, researchers uncovered a previously unknown way that genes code for proteins. Rather than directions going one way from DNA through messenger RNA (mRNA) to proteins, the study showed that RNA can modify how DNA is transcribed into mRNA and translated to produce proteins.

Using mouse stem cells, the scientists found that mRNA modifies how DNA is transcribed using a reversible chemical reaction called methylation, which can change the activity of a DNA segment without changing the sequence. The researchers identified and characterized several proteins that recognized the methylated mRNA. They also discovered a group of RNAs called chromosome-associated regulatory RNAs (carRNAs) that used the same methylation process and controlled how DNA was stored and transcribed. The team found that a specific methylation modification, N6-methyladenosine, served as a switch to control carRNA levels, which regulated DNA transcription.

Citation: Liu J, Dou X, Chen C, Chen C, Liu C, Xu MM, Zhao S, Shen B, Gao Y, Han D, He C. 2020. N 6-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription. Science 367(6477):580586. (Synopsis(https://factor.niehs.nih.gov/2020/4/papers/dert/index.htm#a1))

Loss of the enzyme topoisomerase 1 (TOP1) leads to DNA damage in neurons and neurodegeneration, according to an NIEHS-funded study. TOP1 plays an important role in facilitating the expression of long genes that are important for neuronal function. The data suggest that TOP1 maintains proper gene function in the central nervous system.

The researchers deleted TOP1 in mouse neurons and examined behavior, development, and underlying indicators of neurodegeneration, such as inflammation. Mice lacking TOP1 showed signs of early neurodegeneration, with brains 3.5-times smaller at postnatal day 15 compared with controls. Although neurons developed normally, mice without TOP1 showed motor deficits, exhibited lower levels of nicotinamide adenine dinucleotide (NAD-plus) a compound critical in energy metabolism and died prematurely. However, when these mice received supplemental NAD-plus, they lived 30% longer, had less inflammation, and showed improved neuronal survival.

Citation: Fragola G, Mabb AM, Taylor-Blake B, Niehaus JK, Chronister WD, Mao H, Simon JM, Yuan H, Li Z, McConnell MJ, Zylka MJ. 2020. Deletion of topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration. Nat Commun 11(1):1962. (Synopsis(https://factor.niehs.nih.gov/2020/6/papers/dert/index.htm#a4))

NIEHS grantees found that a protein known as XPA bends DNA and pauses in response to DNA damage, revealing the location of damaged DNA and potentially promoting the recruitment of DNA repair proteins. Using single molecule experiments and imaging techniques, the researchers observed the biochemistry of a living cell.

The researchers used a new method to calculate the molecular weight of small proteins bound to DNA and tracked proteins involved in DNA repair in 3D using real-time single molecule imaging. XPA cycled through three distinct states on DNA: rapidly hopping over long distances of the DNA strand; slowly sliding over short ranges of DNA while bending local DNA regions; and pausing and forming complexes with bent DNA. XPA paused more frequently in the presence of more DNA damage. The work provided insight into a new damage sensor role for XPA.

Citation: Beckwitt EC, Jang S, Detweiler IC, Kuper J, Sauer F, Simon N, Bretzler J, Watkins SC, Carell T, Kisker C, Van Houten B. 2020. Single molecule analysis reveals monomeric XPA bends DNA and undergoes episodic linear diffusion during damage search. Nat Commun 11(1):1356. (Synopsis(https://factor.niehs.nih.gov/2020/5/papers/dert/index.htm#a2))

NIEHS grantees found that individual cells in a population respond differently to estrogen stimulation at both the level of single cells and alleles, which are other possible forms of a gene. These differences were not explained by estrogen receptor levels in the cells or receptor activation status.

The researchers treated human breast cancer cells with estrogen and examined two genes, GREB1 and MYC, whose activities are regulated by estrogen. Unexpectedly, individual cells exhibited large differences in the level of gene activation, even between alleles within the same cell. The scientists used automated high-throughput technologies to test small molecule inhibitors of the estrogen receptor regulators. One inhibitor, called MS049, markedly increased the response of individual alleles to estrogen. The researchers altered estrogenic response by inhibiting estrogen receptor regulators, establishing a previously unrecognized regulation path for estrogen to activate genes at the single cell level.

Citation: Stossi F, Dandekar RD, Mancini MG, Gu G, Fuqua SAW, Nardone A, De Angelis C, Fu X, Schiff R, Bedford MT, Xu W, Johansson HE, Stephan CC, Mancini MA. 2020. Estrogen-induced transcription at individual alleles is independent of receptor level and active conformation but can be modulated by coactivators activity. Nucleic Acids Res 48(4):18001810. (Synopsis(https://factor.niehs.nih.gov/2020/4/papers/dert/index.htm#a3))

NIEHS grantees showed that mice exposed to e-cigarette smoke (ECS) were more likely to develop lung adenocarcinomas, a type of lung cancer. They also found that exposed mice had higher levels of bladder urothelial hyperplasia, an abnormal increase in epithelial cells that can precede development of bladder tumors.

The researchers exposed one group of mice to ECS aerosols generated from e-juice containing nicotine and compared them to a second group of mice exposed to a control aerosol without ECS. A third group of mice was exposed only to filtered air. Of the ECS mice, 22.5% developed lung adenocarcinomas and 57.5% developed urothelial hyperplasia. Mice with ECS-induced lung adenocarcinomas were not more prone to developing urothelial hyperplasia, which suggested that the two outcomes were divergent events and might involve different mechanisms.

Citation: Tang MS, Wu XR, Lee HW, Xia Y, Deng FM, Moreira AL, Chen LC, Huang WC, Lepor H. 2019. 2019. Electronic-cigarette smoke induces lung adenocarcinoma and bladder urothelial hyperplasia in mice. Proc Natl Acad Sci U S A 116(43):2172721731. (Synopsis(https://factor.niehs.nih.gov/2020/1/papers/dert/index.htm#a1))

NIEHS grantees identified a novel pathway that controls the metabolic response of astrocytes, which are brain and spinal cord cells essential to maintaining central nervous system (CNS) health. Although astrocytes perform various functions, such as providing nerve cells with nutrients, they have been linked to CNS inflammation and multiple sclerosis (MS).

Using a mouse model of MS, researchers found that during the progressive phase of the disease, brain astrocytes switched on metabolic pathways that activated a protein called the mitochondrial antiviral signaling (MAVS) protein. It led to activation of several proinflammatory genes, triggering inflammation in the brain and spinal cord. If the scientists gave the mice the drug miglustat before the onset of MS, they were able to suppress MAVS activation and subsequent inflammation. The findings suggest a new role for MAVS in CNS inflammation and a potential therapeutic target for MS.

Citation: Chao CC, Gutierrez-Vazquez C, Rothhammer V, Mayo L, Wheeler MA, Tjon EC, Zandee SEJ, Blain M, de Lima KA, Takenaka MC, Avila-Pacheco J, Hewson P, Liu L, Sanmarco LM, Borucki DM, Lipof GZ, Trauger SA, Clish CB, Antel JP, Prat A, Quintana FJ. 2019. Metabolic control of astrocyte pathogenic activity via cPLA2-MAVS. Cell 179(7):14831498.e22. (Synopsis(https://factor.niehs.nih.gov/2020/2/papers/dert/index.htm#a3))

NIEHS-funded researchers found that a mutation in the ultraviolet irradiation resistanceassociated gene (UVRAG), which is involved in cell regulation, can disrupt autophagy in mice. Autophagy is the process of removing damaged cells so the body can regenerate newer cells. The scientists say the UVRAG mutation causes increased inflammatory response and tumor development. The study provides the first genetic evidence connecting UVRAG suppression to autophagy regulation, inflammation, and cancer predisposition.

The researchers generated mice that expressed UVRAG with a frameshift mutation, which is a deletion or insertion in DNA that shifts the way the sequence is read. After inducing sepsis or intestinal colitis, they found that mice with the UVRAG mutation displayed increased inflammatory responses in both conditions and increased spontaneous tumor development compared with wild-type mice. The results indicate UVRAG could be one reason people are more susceptible to cancers as they age.

Citation: Quach C, Song Y, Guo H, Li S, Maazi H, Fung M, Sands N, O'Connell D, Restrepo-Vassalli S, Chai B, Nemecio D, Punj V, Akbari O, Idos GE, Mumenthaler SM, Wu N, Martin SE, Hagiya A, Hicks J, Cui H, Liang C. 2019. A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice. Nat Commun 10(1):5681. (Synopsis(https://factor.niehs.nih.gov/2020/2/papers/dert/index.htm#a4))

Exposure to polybrominated biphenyl (PBB) 153, a type of brominated flame retardant, alters DNA methylation in sperm, according to NIEHS grantees. DNA methylation refers to heritable changes in gene expression that occur with no alteration in the DNA sequence. Because PBB153 is toxic to living organisms following direct exposure, the study suggests it may also harm future generations.

The results of a Michigan PBB study showed that PBB153 was associated with gene methylation events in mens sperm. Based on this information, the research team conducted sperm studies and determined that exposure to PBB153 decreased methylation at regions of DNA that control imprinted genes, which are essential for fetal growth and play an important role in other aspects of development. These effects could explain some of the endocrine-related health effects that have been observed among children of PBB-exposed parents.

Citation: Greeson KW, Fowler KL, Estave PM, Thompson SK, Wagner C, Edenfield RC, Symosko KM, Steves AN, Marder EM, Terrell ML, Barton H, Koval M, Marcus M, Easley CA 4th. 2020. Detrimental effects of flame retardant, PBB153, exposure on sperm and future generations. Sci Rep 10(1):8567. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dert/index.htm#a4))

NIEHS grantees determined that in mice, air pollution may play a role in the development of cardiometabolic diseases, such as diabetes, with effects comparable to eating a high-fat diet (HFD). They also established that effects were reversed when exposure to air pollution stopped.

The scientists divided male mice into three categories: those that received clean filtered air; those exposed to concentrated particulate matter 2.5 air pollution; and those that received clean filtered air and were fed an HFD. After 14 weeks, team members measured insulin resistance and glucose levels and assessed epigenetic changes, or chemical tags, that attach to DNA and affect gene expression.

Air pollution exposure was comparable to eating an HFD. Mice in the air pollution and HFD groups had impaired insulin resistance, high glucose, and reduced metabolism. After removing air pollution from the environment, health and epigenetic changes reversed within eight weeks.

Citation: Rajagopalan S, Park B, Palanivel R, Vinayachandran V, Deiuliis JA, Gangwar RS, Das LM, Yin J, Choi Y, Al-Kindi S, Jain MK, Hansen KD, Biswal S. 2020. Metabolic effects of air pollution exposure and reversibility. J Clin Invest 130(11):60346040. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dert/index.htm#a3))

NIEHS researchers learned that mineralocorticoid receptors (MRs) control the gene profiles of neurons within the CA2 brain region, which is associated with learning and memory. MRs are a type of steroid receptor activated by corticosteroid hormones. The findings revealed the essential roles of MRs in the development and maintenance of CA2 neurons, as well as CA2-related behaviors.

In response to environmental stress, the body secretes corticosteroids that bind to MRs or glucocorticoid receptors and that induce gene expression changes in the brain. The CA2 region of the mouse and human hippocampus is enriched with MRs. Neuronal deletion of MRs at embryonic, early postnatal development, or adulthood stages in mice led to significantly reduced expression of CA2 molecular markers. Mice with CA2-targeted deletion of MRs showed disrupted social behavior and altered responses to novel objects. Therefore, MRs control both the identity and function of CA2 neurons.

Citation: McCann KE, Lustberg DJ, Shaughnessy EK, Carstens KE, Farris S, Alexander GM, Radzicki D, Zhao M, Dudek SM. 2019. Novel role for mineralocorticoid receptors in control of a neuronal phenotype. Mol Psychiatry; doi: 10.1038/s41380-019-0598-7 [Online 19 November 2019]. (Synopsis(https://factor.niehs.nih.gov/2020/1/papers/dir/index.htm#a2))

NIEHS researchers discovered a novel symbiotic interaction between mammalian cells and bacteria that boosts nicotinamide adenine dinucleotide biosynthesis in host cells. NAD is a cofactor that exists in all cell types and is necessary for life. Decreased levels of NAD are associated with aging, and elevated levels of its biosynthesis are important to sustain the higher metabolic needs of tumors.

The researchers showed that cancer cell lines infected with Mycoplasma hyorhinis were protected against toxicity by nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, which halt NAD biosynthesis. This same effect was observed in vivo, when infected versus noninfected cancer cells were injected in mice. Using a variety of screens and techniques, they showed that this resistance was the result of bacteria providing alternative NAD precursors to mammalian cells through the bacterial nicotinamidase PncA, bypassing the NAMPT-dependent pathway.

Citation: Shats I, Williams JG, Liu J, Makarov MV, Wu X, Lih FB, Deterding LJ, Lim C, Xu X, Randall TA, Lee E, Li W, Fan W, Li J-L, Sokolsky M, Kabanov AV, Li L, Migaud ME, Locasale JW, Li X. 2020. Bacteria boost mammalian host NAD metabolism by engaging the deamidated biosynthesis pathway. Cell Metab 31(3):564579.e7. (Synopsis(https://factor.niehs.nih.gov/2020/5/papers/dir/index.htm#a3)) (Story)

New insights into how the liver adapts to an HFD may lead to novel treatments for obesity-related diseases such as NAFLD, according to a study by NIEHS researchers. They found that long-term consumption of a diet high in saturated fat led to dramatic reprogramming of gene regulation in the mouse liver.

NAFLD involves the buildup of excessive fat in the liver of an individual who is not a heavy user of alcohol, increasing the risk of liver damage. When the scientists fed mice an HFD, the mice became obese and showed other changes similar to metabolic syndrome in humans. Moreover, their livers became fatty and showed wide-ranging abnormalities at both molecular and cellular levels. The livers adaptation to the fat-rich diet was mediated by a protein called hepatocyte nuclear factor 4 alpha.

Citation: Qin Y, Grimm SA, Roberts JD, Chrysovergis K, Wade PA. 2020. Alterations in promoter interaction landscape and transcriptional network underlying metabolic adaptation to diet. Nat Commun 11(1):962. (Synopsis(https://factor.niehs.nih.gov/2020/4/papers/dir/index.htm#a3)) (Story)

An NIEHS study reported a concerning rise in the prevalence of antinuclear antibodies (ANAs), which are commonly used biomarkers for autoimmunity. ANAs, which are produced by a persons own immune system, bind to and sometimes attack healthy cells. This study is the first to evaluate ANA changes over time in a representative sampling of the U.S. population. The findings may indicate an increase in autoimmune diseases.

Team members used the National Health and Nutrition Examination Survey to analyze serum ANAs in 14,211 participants aged 12 years and older from three time periods. ANA prevalence increased as follows.

The researchers found the largest ANA increases in adolescents, males, non-Hispanic whites, and adults older than 50 years compared with other subgroups.

Citation: Dinse GE, Parks CG, Weinberg CR, Co CA, Wilkerson J, Zeldin DC, Chan EKL, Miller FW. 2020. Increasing prevalence of antinuclear antibodies in the United States. Arthritis Rheumatol 72(6):10261035. (Synopsis(https://factor.niehs.nih.gov/2020/6/papers/dir/index.htm#a4)) (Story)

Ubiquitin (Ub) stimulates the removal of topoisomerase 2 DNA-protein crosslinks (TOP2-DPCs) by tyrosyl-DNA phosphodiesterase 2 (TDP2) according to NIEHS researchers and their collaborators in Spain. The team also reported that TDP2 single nucleotide polymorphisms can disrupt the TDP2-Ub interface. Because TDP2 works with a protein called ZATT to remove dangerous DNA-protein crosslinks, the work is important for understanding how cells handle this type of DNA damage.

Using X-ray crystallography and small angle X-ray scattering analysis, the scientists examined how Ub-dependent links and TDP2 function as they relate to DNA repair and other cellular pathways. Previous studies hypothesized that TDP2 interacts with K48-Ub chains to promote recruitment to TOP2-DPCs that are repaired using a proteasome-mediated TOP2 degradation pathway. However, the authors showed that TDP2 preferentially binds to K63-linked Ub3 and associates with K27 and K63 poly-Ub chains.

Citation: Schellenberg MJ, Appel CD, Riccio AA, Butler LR, Krahn JM, Liebermann JA, Cortes-Ledesma F, Williams RS. 2020. Ubiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2. Nucleic Acids Res 48(11):63106325. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dir/index.htm#a4))

NIEHS researchers and their collaborators concluded that a protein called tankyrase serves a critical role in mammalian embryonic genome activation (EGA). Using an in vitro culture system, the researchers identified and characterized tankyrase, a factor that allows EGA to occur. The characterization of tankyrase during the oocyte-to-embryo transition fills a gap in knowledge about how factors are activated in mammalian oocytes and early embryos and may lead to improved strategies for treating infertility.

Using a mouse model, the scientists depleted tankyrase from the embryos and observed that they could not perform EGA and stopped developing. They also found that tankyrase is necessary for gene transcription, protein translation, DNA damage repair, and modulation of beta-catenin in the early embryo. This study found a new role for tankyrase during normal development, revealing an essential function of this protein during the oocyte-to-embryo transition.

Citation: Gambini A, Stein P, Savy V, Grow EJ, Papas BN, Zhang Y, Kenan AC, Padilla-Banks E, Cairns BR, Williams CJ. 2020. Developmentally programmed tankyrase activity upregulates beta-catenin and licenses progression of embryonic genome activation. Dev Cell 53(5):545560.e7. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dir/index.htm#a3)) (Story)

NIEHS researchers showed that an enzyme called CLP1 plays an important role in transfer RNA (tRNA) processing by regulating the ligation of tRNAs. They also demonstrated that mature, functional tRNAs are generated from pre-tRNAs through a process called TSEN, or (tRNA splicing endonuclease)mediated splicing of introns. Mutations in CLP1 and the TSEN complex often lead to severe neurological disorders.

Using a technique that allowed Escherichia coli to produce several proteins at once, the scientists expressed and reconstituted the TSEN protein complex, which cleaved tRNA. TSEN complex alone was sufficient for removing tRNA introns, but CLP1, a binding partner for TSEN, was needed to correctly regulate the ligation step that generates mature tRNAs and tRNA intronic circular RNAs (tricRNAs). Genetic knockdown of CLP1 led to increases in mature tRNAs and tricRNAs, which suggested that CLP1 acts as a negative modulator of tRNA processing.

Citation: Hayne CK, Schmidt CA, Haque MI, Matera AG, Stanley RE. 2020. Reconstitution of the human tRNA splicing endonuclease complex: insight into the regulation of pre-tRNA cleavage. Nucleic Acids Res 48(14):76097622. (Synopsis(https://factor.niehs.nih.gov/2020/8/papers/dir/index.htm#a2))

Researchers at NIEHS and the National Toxicology Program developed the Tox21BodyMap to predict which organs in the human body may be affected by a chemical. The tool will help scientists generate novel hypotheses to test, prioritize chemicals for toxicity testing, and identify knowledge gaps.

To identify organs that could potentially be affected by a chemical, Tox21BodyMap used data from 971 high-throughput screening assays that evaluated approximately 10,000 unique chemicals. Specifically, it combined information about which gene an assay targets, how highly expressed that gene is in a human organ, and at what tested concentrations a chemical generated a positive assay result. The result was an overall picture of chemical bioactivity. The Tox21BodyMap provided multiple visualizations of the data, highlighting target organs on a map of the body, as well as showing a web of network connections and providing downloadable data.

Citation: Borrel A, Auerbach SS, Houck KA, Kleinstreuer NC. 2020. Tox21BodyMap: a webtool to map chemical effects on the human body. Nucleic Acids Res 48(W1):W472W476. (Synopsis(https://factor.niehs.nih.gov/2020/8/papers/dir/index.htm#a4))

In pregnant women, polyunsaturated fatty acids and their metabolic derivatives called eicosanoids are associated with infant size at delivery, according to NIEHS scientists and their collaborators. This work also provides novel longitudinal characterization of eicosanoids in blood plasma during different gestational ages of pregnancy. The results link inflammatory eicosanoids with adverse fetal growth outcomes.

The blood plasma concentration of polyunsaturated fatty acids, including omega-3 and omega-6, in study participants was found to be higher in cases of low birth weight and lower in cases of higher birth weight. Lower and higher birth weights were defined as equal to or less than the 10th percentile and equal to or greater than the 90th percentile for gestational age, respectively. In addition, certain eicosanoids, which are known to derive from inflammatory processes from these fatty acids, were found to be exclusively higher in pregnancy cases, which resulted in low birth weight.

Citation: Welch BM, Keil AP, van't Erve TJ, Deterding LJ, Williams JG, Lih FB, Cantonwine DE, McElrath TF, Ferguson KK. 2020. Longitudinal profiles of plasma eicosanoids during pregnancy and size for gestational age at delivery: a nested case-control study. PLoS Med 17(8):e1003271. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dir/index.htm#a2))

Researchers at NIEHS and collaborators at the National Institute of Diabetes and Digestive and Kidney Diseases uncovered the neural basis behind the drive to select calorie-rich foods over nutritionally balanced diets. The findings partly explain the difficulty of dieting.

One group of mice received a standard diet (SD) consisting of regular chow, and another group ate an HFD. When the HFD mice were switched to a SD, they refused to eat. Even after fasting to stimulate their appetites, HFD mice preferred fatty food, rather than regular chow.

However, whenHFD mice were switched to a SD, regular chow no longer fully alleviated the response. The authors also saw that dopamine signaling, which is responsible for the pleasurable feelings from eating, were significantly diminished in the SD mice following HFD exposure.

Citation: Mazzone CM, Liang-Guallpa J, Li C, Wolcott NS, Boone MH, Southern M, Kobzar NP, Salgado IA, Reddy DM, Sun F, Zhang Y, Li Y, Cui G, Krashes MJ. 2020. High-fat food biases hypothalamic and mesolimbic expression of consummatory drives. Nat Neurosci 23(10):12531266. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dir/index.htm#a4))

To uncover novel deletion patterns in mitochondrial DNA (mtDNA), NIEHS researchers and their collaborators developed LostArc, an ultrasensitive method for quantifying deletions in circular mtDNA molecules. The team used the technique to reveal links between mitochondrial DNA replication, aging, and mitochondrial disease.

A mutation in POLG, a nuclear gene responsible for maintaining the mitochondrial genome, is known to be the most common cause of mitochondrial disease, a condition in which the mitochondria fail to produce enough energy for the body to function properly.

The scientists analyzed mtDNA from skeletal muscle biopsies of 41 patients with mitochondrial disease with wild-type and mutated POLG. They used LostArc to detect loss of mtDNA segments by mapping split-reads in the samples to a normal mtDNA reference. Thirty-five million deletion segments were detected in the biopsies. They spanned more than 470,000 unique segments, 99% of which were novel.

Citation: Lujan SA, Longley MJ, Humble MH, Lavender CA, Burkholder A, Blakely EL, Alston CL, Gorman GS, Turnbull DM, McFarland R, Taylor RW, Kunkel TA, Copeland WC. 2020. Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging. Genome Biol 21(1):248. (Synopsis(https://factor.niehs.nih.gov/2020/11/papers/dir/index.htm#a3))

Individual heterogeneity, or genetic variability among samples, can substantially affect reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), according to NIEHS scientists and their collaborators. iPSCs are stem cells that are derived from differentiated cells, such as fibroblasts, and they can both self-renew and are pluripotent, meaning they can be differentiated into other cell types. In a previous publication, the research team obtained fibroblasts from healthy diverse donors and observed that each persons fibroblasts had consistent differences in the ability to be reprogrammed to iPSCs. Ancestry was identified as a large contributing factor.

Using 72 dermal fibroblast-iPSCs from self-identified African Americans and White Americans, the researchers found ancestry-dependent and ancestry-independent genes associated with reprogramming efficiency. They also added 36 new genomic profiles of African American fibroblast-iPSCs pairs to publicly available databases, which will help address the underrepresentation of genomic data from non-European groups.

Citation: Bisogno LS, Yang J, Bennett BD, Ward JM, Mackey LC, Annab LA, Bushel PR, Singhal S, Schurman SH, Byun JS, Napoles AM, Perez-Stable EJ, Fargo DC, Gardner K, Archer TK. 2020. Ancestry-dependent gene expression correlates with reprogramming to pluripotency and multiple dynamic biological processes. Sci Adv 6(47):eabc3851. (Synopsis(https://factor.niehs.nih.gov/2021/1/papers/dir/index.htm#a2))

Researchers in the Division of the National Toxicology Program (DNTP) at NIEHS successfully compiled a rich resource to explore data on polycyclic aromatic compound (PACs) toxicity. This data-driven approach to contextualizing PAC hazard characterization allows researchers to predict eight different toxicity profiles of various PACs and other classes of compounds.

PACs are a structurally diverse class of human-made toxicants found widely in the environment. Unfortunately, information about human exposure and health effects of PACs is limited. To facilitate greater understanding of PAC toxicity in a cost-effective manner, DNTP researchers created an automated approach to identify PAC structures using computer workflows, algorithms, and clusters. Using existing data on similar compounds, the scientists categorized PACs based on structure and hazard characterization. The analysis results are available and searchable through an interactive web application.

Citation: Hsieh JH, Sedykh A, Mutlu E, Germolec DR, Auerbach SS, Rider CV. 2020. Harnessing in silico, in vitro, and in vivo data to understand the toxicity landscape of polycyclic aromatic compounds (PACs). Chem Res Toxicol; doi:10.1021/acs.chemrestox.0c00213 [Online 16 October 2020]. (Synopsis(https://factor.niehs.nih.gov/2020/12/papers/dir/index.htm#a1))

DNTP scientists and their collaborators used computational modeling to probe databases and to identify existing drugs that could be repurposed to fight SARS-CoV-2, the virus that causes COVID-19.

Proteases are enzymes that break down proteins. An essential step in the formation of infectious viral particles is the breakdown of precursor viral proteins by viral proteases. A class of antiviral drugs called protease inhibitors block the activity of viral proteases. The main protease (Mpro) of SARS-CoV-2 is a proposed target for COVID-19 drugs. The structure and activity of Mpro is highly conserved across the coronavirus family. In this study, previous data on drug interactions with SARS-CoV Mpro were used to develop quantitative structure-activity relationship models, which the team used to virtually screen all drugs in the DrugBank database. They identified 42 drugs that could be repurposed against SARS-CoV-2 Mpro.

Citation: Alves VM, Bobrowski T, Melo-Filho CC, Korn D, Auerbach S, Schmitt C, Muratov EN, Tropsha A. 2020. QSAR modeling of SARS-CoV Mpro inhibitors identifies sufugolix, cenicriviroc, proglumetacin, and other drugs as candidates for repurposing against SARS-CoV-2. Mol Inform; doi:10.1002/minf.202000113 [Online 28 July 2020]. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dir/index.htm#a1))

DNTP scientists evaluated a high-throughput transcriptomics approach using liver and kidney tissue from 5-day assays in male rats to estimate the toxicological potency of chemicals.

Toxicity and carcinogenicity are typically assessed by the resource intensive two-year cancer bioassay. In the 5-day assays, the authors determined toxicological potency based on the most sensitive sets of genes active in the liver and kidney. For most chemicals, the results approximated the toxicological potency derived from the most sensitive histopathological effects independent of target tissue or organ observed in male rats in long-term assays. Notably, these approximations were similar in female rats, as well as in male and female mice. The findings suggest that estimates of transcriptomics-based potency from short-term in vivo assays can, in the absence of other data, provide a rapid and effective estimate of toxicological potency.

Citation: Gwinn WM, Auerbach SS, Parham F, Stout MD, Waidyanatha S, Mutlu E, Collins B, Paules RS, Merrick BA, Ferguson S, Ramaiahgari S, Bucher JR, Sparrow B, Toy H, Gorospe J, Machesky N, Shah RR, Balik-Meisner MR, Mav D, Phadke DP, Roberts G, DeVito MJ. 2020. Evaluation of 5-day in vivo rat liver and kidney with high-throughput transcriptomics for estimating benchmark doses of apical outcomes. Toxicol Sci 176(2):343354. (Synopsis(https://factor.niehs.nih.gov/2020/8/papers/dir/index.htm#a1))

Researchers from DNTP studied the effects of gestational and postnatal boron exposure on developing rat pups. The team was the first to show that pups exposed to boric acid, an oxidized form of boron commonly found in the environment, gained significantly less weight during postnatal development.

Pregnant rats were exposed to varying concentrations of boric acid once daily by oral gavage dosing, a technique that administered it directly to the stomach. Food intake, body weight, boron blood plasma levels, and any signs of morbidity were evaluated during gestation. After birth, the pups received boric acid at the same concentration as their mothers, and the scientists monitored the same parameters in the pups for the next 28 days. The team observed that the pups that received the highest dose of boric acid had a 23% reduction in weight gain.

Citation: Watson ATD, Sutherland VL, Cunny H, Miller-Pinsler L, Furr J, Hebert C, Collins B, Waidyanatha S, Smith L, Vinke T, Aillon K, Xie G, Shockley KR, McIntyre BS. 2020. Postnatal effects of gestational and lactational gavage exposure to boric acid in the developing Sprague Dawley rat. Toxicol Sci 176(1):6573. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dir/index.htm#a1))

When scientists from DNTP analyzed the entire genetic code of tumors in rodent cancer studies, they determined that most rodent tumors whether arising spontaneously or induced by chemicals had DNA mutation signatures resembling those seen in human cancers.

Tumors can form as a result of DNA damage or they can arise spontaneously when physiological processes do not function properly. To understand the mechanism of cancer formation, members of the research team sequenced lung and liver tumor DNA from mice exposed to 20 carcinogens. They compared the sequences to those from tumors that formed spontaneously and from normal tissue. DNA signatures from exposure to 17 of the chemicals were similar to those from spontaneous tumors in mice. The finding suggests chemicals promote tumor formation through mechanisms that build on existing cancer processes.

Citation: Riva L, Pandiri AR, Li YR, Droop A, Hewinson J, Quail MA, Iyer V, Shepherd R, Herbert RA, Campbell PJ, Sills RC, Alexandrov LB, Balmain A, Adams DJ. 2020.The mutational signature profile of known and suspected human carcinogens in mice. Nat Genet 52(11):11891197. (Story)

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January 2021: 2020 Papers of the Year - Environmental Factor Newsletter

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Ozone in the air is bad for birds – Massive Science

Tuesday, January 5th, 2021

In 2007, scientists developed a method to determine the sexes of Atlantic walruses using only their jaws' size and shape. Researchers have now put that sexing (identification of an organism's sex) method to the test with Pacific walruses.

There was some doubt about whether this technique would work for one, Pacific walruses are significantly larger than their Atlantic counterparts. This size difference shows even in individual body parts, including the mandibles.

Yet, the team, led by Nathan Taylor at the University of Alaska, Fairbanks, persisted in applying the sex identification strategy since, if successful, it would significantly reduce the time and financial commitment needed for researching preserved, unidentified walrus specimens. To distinguish between male and female Pacific walruses, they measured the length and height of the jawbone, the minimum jawbone depth (from about the middle point of the jaw to the back), and jaw thickness.

A female Pacific walrus and a calf

USFWS via Wikimedia

The scientists had to be mindful of whether the jawbones were "not fully fused" (not fully developed, unique to juvenile walruses) or "fused" (fully developed, the sign of a mature walrus). Walruses with partially fused mandibles were likely to yield misleading results.

For example, jaws from male walruses that had not yet fully fused were similar in dimensions to mature females' jaws. To ensure the results were accurate, they could only include fully matured, fused specimens.

After measuring 67 modern specimens (33 of which were male, 24 belonging to females, and ten unknown) and 11 archaeological samples, the researchers concluded that jaw size is indeed a reliable body part to distinguish between male and female walruses. The most significant differences were jaw length and thickness, with females notably smaller in both categories.

A male Pacific walrus

Joel Garlich-Miller, USFWS, via Wikimedia

With the original sexing method now confirmed to work for Pacific walruses, scientists will be better prepared to perform several types of analyses, including measuring stable isotopes, trace elements, and hormones in study animals, with greater confidence and less risk of misidentification.

This is a crucial finding, given the insufficient data on Pacific walrus populations, and will hopefully push conservation efforts for this species forward.

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Ozone in the air is bad for birds - Massive Science

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