Gene removal may aid melanoma treatment, research shows
- Date:
- March 25, 2015
- Source:
- Rutgers Cancer Institute of New Jersey
- Summary:
- There are nearly 10,000 melanoma deaths in the U.S. each year, and while treatment advances have been made, a majority of melanoma patients will die from their disease. Building on these advances, investigators have demonstrated that removal of a gene involved in the cellular self-cannibalization process of autophagy could provide therapeutic benefit to patients with melanoma.
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Nearly 10,000 deaths from melanoma -- the deadliest of all skin cancers -- occurred in the U.S. last year, according to the National Cancer Institute. And while treatment advances have been made in fighting melanoma, a majority of these patients will die from their disease. In an aim to build upon these advances, investigators at Rutgers Cancer Institute of New Jersey have demonstrated that removal of a gene involved in the cellular self-cannibalization process of autophagy could provide therapeutic benefit to patients with melanoma.
Half of all melanomas harbor an activating mutation in the BRAF gene that turns on the cancer signaling pathway in cells known as the MAP kinase pathway. Activation of the MAP kinase pathway promotes tumor growth and survival. Drugs designed to selectively block activated BRAF have led to significant improvement in clinical response and overall survival in melanoma patients, but resistance to these drugs often develops -- leading to recurrence. With this study, published in the current online edition of Cancer Discovery, senior author Janice M. Mehnert, MD, medical oncologist in the Melanoma and Soft Tissue Oncology Program at the Cancer Institute of New Jersey, in collaboration with Eileen White, PhD, associate director for basic science at the Cancer Institute and distinguished professor of molecular biology and biochemistry at Rutgers School of Arts and Sciences, aimed to identify mechanisms critical for melanoma that could be targeted in conjunction with BRAF inhibition.
Investigators tested the consequence of removing the autophagy gene known as ATG7 from laboratory models of BRAF-driven melanoma. Autophagy is a process in which intracellular components are recycled in order to help sustain cell growth. When ATG7 was removed from melanomas they found much smaller tumors with increased senescence, which is a known barrier to cancer that causes tumor cells to stop proliferating. Thus ATG7 promotes development of BRAF-mutated melanoma by overcoming senescence. They went on to show that loss of ATG7 potentiated the anti-tumor activity of a BRAF inhibitor in melanoma. The work demonstrates that BRAF-mutated melanoma requires autophagy for tumor development and blocking autophagy could have therapeutic value, particularly in combination with BRAF inhibition.
"This discovery that ATG7 promotes the growth of melanoma tumors underscores that the development of agents targeting autophagy may effectively inhibit melanoma growth," notes Dr. Mehnert, who is an associate professor of medicine at Rutgers Robert Wood Johnson Medical School. Clinical trials seeking to block the process of autophagy are ongoing at the Cancer Institute.
Story Source:
Materials provided by Rutgers Cancer Institute of New Jersey. Note: Content may be edited for style and length.
Journal Reference:
- X. Xie, J. Y. Koh, S. Price, E. White, J. M. Mehnert. Atg7 Overcomes Senescence and Promotes Growth of BrafV600E-Driven Melanoma. Cancer Discovery, 2015; DOI: 10.1158/2159-8290.CD-14-1473
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