Researchers from Boston University School of Medicine, Johns Hopkins University, Università di Pavia, Harvard Medical School, and the University of Leicester have announced development of a compound that successfully inhibits the growth of melanoma cells by targeting specific epigenetic-modifying proteins.
Findings from the new study—published in Nature Communications in an article entitled “Targeting the CoREST Complex with Dual Histone Deacetylase and Demethylase Inhibitors”—describes how the novel compound, dubbed corin, specifically targets these epigenetic changes in cells and could, therefore, provide significant improvements in patients without unwanted side effects.
"It is anticipated that this novel compound will have significant efficacy in human melanomas and other cancers either as a stand-alone therapy or in combination with other targeted or immune-based therapies," explained co-senior study investigator Rhoda Alani, M.D., chair of dermatology at Boston University School of Medicine (BUSM).
Currently, there are few epigenetic drugs in clinical use, including histone deacetylase (HDAC 1) inhibitors, which are used to treat some lymphomas, and histone demethylase inhibitors (LSD1), which are used to treat some leukemias. These reagents have not been more broadly useful in cancers due to their limited therapeutic window and untoward side effects.
However, in the current study, the investigators found that corin specifically acts to inhibit both demethylase and deacetylase activity in cells. Corin is particularly attractive as an inhibitor of epigenetic modifications because it has dual-target specificity, which allows for more selective targeting of epigenetic complexes in treated cells.
To evaluate the efficacy of the new compound, the researchers first tested it using a cell culture system to evaluate melanoma cell biology in vitro and found a variety of cancer-associated processes were affected, including cellular growth, differentiation, and migration. The compound then was tested in an experimental model for melanoma and found to significantly inhibit tumor cell growth without appreciable toxicities.
“Enzymologic analysis reveals that corin potently targets the CoREST complex and shows more sustained inhibition of CoREST complex HDAC activity compared with entinostat [an HDAC inhibitor currently in clinical trials],” the authors wrote. “Cell-based experiments demonstrate that corin exhibits a superior anti-proliferative profile against several melanoma lines and cutaneous squamous cell carcinoma lines compared to its parent monofunctional inhibitors but is less toxic to melanocytes and keratinocytes.”
The research team is optimistic about the findings from their current study and believe there are other disease entities, aside from cancers, that may be significantly affected by targeted epigenetic therapies. Most notably, immune-mediated diseases are expected to be significantly influenced by such reagents, as epigenetic changes have been widely noted to influence the immune system.
"It is expected that this study will lay the foundation for developing a new class of potent and effective cancer therapies and the development of reagents targeting epigenetic events in immune-mediated diseases as well as other epigenetically influenced diseases," concluded Dr. Alani, who also is chief of dermatology at Boston Medical Center.