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    Unidentified gene key to melanoma progression

    Findings at California Pacific Medical Center Research Institute shed new light on how deadly skin cancer develops, and suggest novel strategies for preventing resistance to therapy

    February 25, 2015 (San Francisco, CA)

    The mainstay of targeted therapy for melanoma, BRAF inhibitors, has significantly improved the survival of patients with advanced stages of the illness. But resistance to therapy develops in most patients, causing them to stop therapy or switch to another agent. Multiple mechanisms have been proposed that may govern resistance to BRAF inhibitors.

    However, whether patients can continue to benefit from targeted therapies has been unclear—until now, with findings uncovered about the previously unidentified gene bromodomain PHD finger transcription factor (BPTF), and its role in tumor development and resistance to therapy. The study was published online today in the Journal of the National Cancer Institute.

    “This is the first evidence of the potent role played by BPTF in promoting tumor progression, and of its potential as a molecular diagnostic and prognostic marker,” said Mohammed Kashani-Sabet, MD, Director of the California Pacific Medical Center (CPMC) Center for Melanoma Research and Treatment, Senior Scientist at CPMC’s Research Institute, and senior author of the study.

    In the study, Dr. Kashani-Sabet and colleagues at CPMC and the Veterans Affairs Medical Center explored the functional and biological significance of BPTF—known to be important to the remodeling of genetic material and in the developing brain.

    The researchers used RNA interference to block the effects of BPTF in several melanoma cells lines, and then assessed the effects on key measures of cancer growth and metastasis. The gene’s functional role was investigated using an animal model of melanoma progression, and tissues from melanoma patients were examined for BPTF’s role as a prognostic biomarker. Levels of the gene were analyzed in tumor samples from eight patients with metastatic melanoma before and after therapy with two commonly used BRAF-inhibitors, vemurafenib and dabrafenib.
    Results showed that silencing BPTF significantly suppressed the proliferative capacity and metastatic potential of melanoma cells by two thirds. Suppressing BPTF increased the cells’ sensitivity to BRAF inhibitors, whereas overexpression of BPTF promoted resistance to these drugs.

    Elevated BPTF copy number was observed in 28 of 77 (36.4%) melanomas. In a cohort of 311 melanoma patients, BPTF over-expression predicted poor survival (distant metastasis-free survival, p=0.03, and disease-specific survival p=0.008), and promoted resistance to BRAF inhibitors in melanoma cell lines.

    “Surprisingly, when we examined the tumors of patients who had progressed on anti-BRAF therapy, they were composed of two groups of cells: those that showed no BPTF expression (indicating response to therapy), while other clones of cells had high BPTF expression (suggesting BRAF-resistant cells),” said Dr. Kashani-Sabet, noting the novel finding of intra-tumor molecular heterogeneity. “In contrast, examining tumors from these patients before treatment showed uniform expression of BPTF.”

    “Our results suggest that treatment with selective BRAF inhibitors may potentially be continued following the development of resistance, as part of combination therapy. In addition, BPTF-targeting may be a new approach to overcome resistance to BRAF inhibitors, including possible combination treatment for BRAF-mutant melanoma.”

    This year alone, more than 76,000 people will be diagnosed with melanoma in the U.S.
    The study was supported by United States Public Health Service Grants and by the Mary R. and Joseph R. Payden Foundation.