An estimated 70,000 new cases of metastatic melanoma are diagnosed each year in the United States, and of those 8,000 will die of the disease. About 50 percent of these men and women (or 35,000 a year) have a mutated protein called a BRAF mutation, which in most cases allows melanoma to eventually build up a resistance to many drug therapies.
In the new study led by UCLA Jonsson Comprehensive Cancer Center member Dr. Antoni Ribas and colleague Dr. Siwen Hu-Lieskovan, UCLA scientists combined targeted therapies utilizing a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) with immunotherapy. The three together are shown to be more effective treatments by sensitizing the patients’ own immune system to enhance immunotherapy, and reduce the probability of the melanoma eventually developing resistance.
This is a significant advance compared to previous drug combination findings, in which a combined BRAF inhibitor (vemurafenib) with immunotherapy (ipilimumab) caused serious liver toxicity in some patients, and the targeted therapies (BRAF and/or MEK inhibitors) became less effective and reactivated cancer cell growth.
“The two drug combination of BRAF and MEK inhibitors works synergistically and decreases the side effects of the BRAF inhibitor or normal cells. We reasoned that this combo would allow us to synergize with immunotherapy without increasing toxicities,” said Ribas, a professor of hematology and oncology. “We have made incredible progress in the last three years of treating advanced melanoma, with six new drug therapies approved by the FDA. Half are immunotherapies and the other half are BRAF or MEK inhibitors. The next step is to figure out how to rationally combine them and merge their benefits in the clinic.”
“The triple combination of targeted therapies BRAF (dabrafinib) and MEK (trametinib) inhibitors with immunotherapy (tumor antigen-specific adoptive cell transfer or anti-PD1 antibody) makes immune therapy more effective at killing cancerous tumors and causes less toxicity ” said Hu-Lieskovan, a UCLA clinical instructor of hematology and oncology. “We’re trying to take advantage of the high response rate of the targeted therapy and durability of the immune therapy to induce a response that lasts in the majority of patients.”
Ribas and Hu-Lieskovan have opened two clinical trials to test the effectiveness of the triple combination therapy in advanced melanoma patients. The first reported findings will be presented at the American Society of Clinical Oncology (ASCO) annual meeting in May 2015.
The study will be available online Wednesday, March 18th in the journal Science Translational Medicine.
About UCLA’s Jonsson Comprehensive Cancer CenterUCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2013, the Jonsson Cancer Center was named among the top 12 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 14 consecutive years. For more information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu.
Targeted Therapy and Immunotherapy Definitions:BRAF:A human gene that makes a protein BRAF inhibitor (dabrafenib): A drug that causes cancerous tumors to shrink in people whose metastatic melanoma has a BRAF gene change.MEK Inhibitor (trametinib): A drug that prevents the disturbance of the MAPK/ERK pathway, a chain of proteins in the cell that communicates with the cell’s receptor and DNA in the nucleus, that causes overactive cancer cells. BRAF + MEK Inhibitors Targeted Therapy: Combined BRAF (vemurafenib) or (dabrafinib) and MEK (trametinib) inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have metastatic melanoma.Immune Therapy or Immunotherapy: Treatment that uses your body's own immune system to help fight cancer
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