Researchers have identified a biomarker and a possible new therapy for melanoma.
Microphthalmia-associated transcription factor (MITF) is a protein that plays a pivotal role in the maintenance of the melanocyte (cells that make melanin) lineage, differentiation of normal and malignant melanocytes and the survival of melanoma cells.
“We have now detected the first useful chemical inhibitor of MITF,” said corresponding author Rhoda Alani, MD, the Herbert Mescon Chair of Dermatology.
While genetic mutations in human melanomas have been explored extensively over the past decade, the role of epigenetic alterations in melanoma development and progression has been less clearly defined.
The researchers found that inhibition of the epigenetic p300 Histone Acetyltransferase (HAT) enzyme prevents growth of human melanoma cells and cells with increased expression of MITF are most sensitive to this inhibition.
“When human melanoma cell lines were evaluated for growth effects using the chemical inhibitor of p300 HAT, the cell lines that were most sensitive to drug treatment were those that expressed high levels of MITF suggesting that MITF expression levels can predict melanoma sensitivity to such therapies,” explained Dr. Alani, who also is chief of dermatology at Boston Medical Center.
According to the researchers, this inhibitor may have broad implications for the treatment of pigmented lesions in the skin and could potentially be used topically to treat hyperpigmentation.
They hope this study will provide an incentive to pursue additional epigenetic approaches to cancers, both as direct agents targeting specific cancers as well as adjuvant therapies to improve responses to cancer immunotherapies.
In addition to Dr. Alani, Philip Cole, MD, PhD, professor of medicine and biological chemistry and molecular pharmacology at Harvard University is the other co-corresponding author.
These findings appear in the online journal Cancer Research.
Funding for this study was provided by Grant No R37GM62437 awarded by National Institutes of Health, a CTSA grant UL1TR001079 and FAMRI (Flight Attendant Medical Research Institute). A Jane Coffin Childs Fund postdoctoral fellowship and an ASA Medical Student Grant also provided support.
RMA is a cofounder and shareholder for Acylin Therapeutics Inc. which is developing p300/CBP HAT inhibitors. PAC is a cofounder, shareholder and paid consultant for Acylin Therapeutics Inc. which is developing p300/CBP HAT inhibitors. He is also a paid consultant for Abbvie Inc. which is pursuing the development of p300/CBP HAT inhibitors.