Using xenograft mice as avatars of patients with melanoma, scientists demonstrated that a previously ineffective targeted drug may be quite potent in halting disease progression in certain patients. Their findings were published in Clinical Cancer Research (doi:10.1158/1078-0432.CCR-15-1762).
Melanoma often responds initially to a treatment but finds an alternative pathway to grow and spread. Though melanoma accounts for less than 2% of all skin cancers in the United States, the American Society for Clinical Oncology states that melanoma accounts for most of the deaths from skin cancers.
The growth and proliferation of melanoma is due to specific mutations, so targeted drugs such as BRAF inhibitors are an attractive treatment option. Unfortunately, melanoma develops alternatives to survive despite the targeted treatment.
“There are about fifteen routes of escape that we’ve identified in melanoma patients, and it is never easy to predict which one will be used in any given patient,” said Meenhard Herlyn, DVM, DSc, director of the Melanoma Research Center and Caspar Wistar Professor in Melanoma Research at The Wistar Institute in Philadelphia, Pennsylvania, and lead author of the study. “These melanoma cells will do anything to get reactivated.”
This study described patient-derived xenograft (PDX) mouse models, in which tumor samples from patients are implanted into mice, thereby creating avatars for individual patients. A pool of mouse avatars is used to study 1 tumor, allowing tumor responses to different drugs and drug combinations to be studied.
The PDX models tested tumors from patients who had relapsed after treatment with a BRAF inhibitor. The scientists observed mutations in the NRAS and MAP2K1 genes, along with amplification of MET. They tested a combination of targeted therapies, including the MET inhibitor capmatinib combined with encorafenib (a BRAF inhibitor) and binimetinib (a MEK inhibitor hitting the BRAF pathway). This combination led to complete and sustained tumor regression in all the animals.
“Historically, MET inhibitors have not shown much activity in melanoma patients,” said Clemens Krepler, MD, research assistant professor in the Herlyn Lab at The Wistar Institute, and first author of the study. “While our findings need to be validated in more robust trials, this study provides evidence that MET inhibitors given either after or at the same time as BRAF inhibitors appear to successfully halt the progression of the disease and may considerably lengthen response and overall survival in melanoma patients.”