header logo image

Back to the drawing board for triple-negative breast cancer targets, researchers propose new combo approach – Endpoints News

March 18th, 2020 11:44 pm

The reason why triple-negative breast cancer is such a tough disease to treat is largely given away in its name. Such tumors cant be defined by traditional biomarkers neither estrogen receptors, progesterone receptors, nor excess HER2 protein forcing drug hunters down uncharted new pathways.

Researchers at Vanderbilt-Ingram Cancer Center explored one of them, and turned up with some new suggestions.

In a new paper, the scientists began with the observation that deregulated MYCN a member of the transcription factor family that activates expression of some oncogenes has been implicated in a subset of breast cancers with unfavorable prognostic features and clinical outcomes. They ended by putting forth a new drug regimen that could spark new hope.

Given that patients with TNBC primarily receive systemic cytotoxic chemotherapies that frequently result in unfavorable outcomes, they wrote in Science Translational Medicine, we propose the clinical development of combination BETi and MEKi for patients with advanced TNBC, with parallel evaluation of MYCN as a potential marker for patient selection.

Johanna Schafer, a graduate student working in Jennifer Pietenpols lab, is the first author, while the professor is the senior author.

The MYCN protein, sometimes dubbed N-Myc, has long been studied as a target in neuronal or neuroendocrine tumors, but its role in breast cancer is less clear. Its distinct from MYC (c-Myc), though the two are believed to affect each other.

Their intricate relationship would prove crucial in therapeutic development. But the first question is just how common they are, and according to the study, the two family members are heterogeneously expressed in separate cell nuclei within a given tumor in at least 40% of TNBC tumors. In fact, the expression of MYCN appeared to increase after neoadjuvant chemotherapy, part of the current standard of care.

The prevalence gave them enough reason to think about how to target it. When the team selected a cell line model, they had another finding that MYCN-expressing cells were essentially more prone to resistance to PI3K inhibitors, which block an alternative pathway for tumor growth.

Because the MYC family lack catalytic domains, the team resorted to epigenetic regulators, screening 158 compounds against the cell lines. BET drugs, which block the bromodomain (BRD)-containing family of transcriptional regulators, emerged as the winner.

It echoes an earlier study, done at Michigan State University, showing that the experimental class of molecules can prevent the growth of breast and lung cancers.

But thats not it and heres where the MEK inhibitors come in.

Most of the MYNC-expressing TNBCs also contain MYC-expressing cells, the researchers noted, which can still drive cancer growth. In fact, single-agent treatment with a BETi seemed to have increased MYC expression. Adding trametinib (Mekinist) to the cells, however, decreased the amount of both proteins. The results were further tested and confirmed in mouse models.

As a next step, our research team is proposing the further development and clinical trials of this combination therapy, Pietenpol, the director of Vanderbilt-Ingram and EVP for research at Vanderbilt University Medical Center, said in a statement.

Incyte, which has a pact in place to fund Vanderbilt research such as this study, has a BET inhibitor in early development.

See the original post:
Back to the drawing board for triple-negative breast cancer targets, researchers propose new combo approach - Endpoints News

Related Post

Comments are closed.


2024 © StemCell Therapy is proudly powered by WordPress
Entries (RSS) Comments (RSS) | Violinesth by Patrick