Role of the Lipid Phosphatase INPP48 in the Development of Resistance to BRAF Pathway Inhibition
Abstract
This project focuses on melanoma, a Fiscal Year 2015 (FY15) Peer Reviewed Cancer Research Program Congressionally Directed Topic Area, and addresses one of the FY15 Military Relevance Focus Areas, namely gap in melanoma treatment strategies and prognosis biomarker identification. Objective and Rationale: Melanoma is one of the most aggressive cancer types in human. In America, melanoma is the fifth most common cancer in men and the seventh in women. Melanoma patients are limited in medical therapies and have a very poor prognosis. BRAF, a critical growth-promoting enzyme, is one of the most commonly mutated genes in melanoma. Over 50% of patients with melanoma have mutations in the BRAF gene. Vemurafenib and dabrafenib, two drugs that inhibit BRAF (BRAFi), are the current standard therapy for treating melanomas that bear this particular BRAF mutation. After initial response, unfortunately, most patients go on to develop drug resistance within 6 to 9 months. It is urgent to understand how this resistance develops in order to find new treatment strategies to overcome it. In addition, it is important to identify biomarkers that can predict which melanoma patients will likely achieve clinical benefit from vemurafenib and dabrafenib and that can monitor the development of drug resistance in patients prior to relapse so that other therapeutic options could be considered. INPP4B is an important enzyme that has tumor-suppressing activity. Loss of INPP4B in mice has been found to promote tumor formation. The overarching goal of this proposal is to understand how INPP4B works to suppress other enzymes that are important for the growth of melanoma and to explore whether loss of INPP4B may cause resistance to BRAFi drugs in melanoma. Research Applicability: The ultimate purpose of our research is to achieve meaningful discoveries that will not only enhance our knowledge of melanoma, particularly the roles of INPP4B in relation to the BRAFi resistance problem, but also lead to the discovery of drug targets and novel biomarkers with predictive and prognostic value. Melanoma patients harboring BRAF mutations, which account for about half of all melanoma patients, will benefit from our research. The outcome of this project may lead to new treatment strategies for these patients. In addition, it may help to monitor when a patient will be likely to relapse from vemurafenib or dabrafenib treatment, so that other therapeutic options could be considered. Finally, our research may help to predict and identify which patients are likely to achieve clinical benefit of vemurafenib or dabrafenib. If successful, our findings can be translated into clinical applications in 3-5 years. Military Relevance: Military Service men and women who work in sun-intense areas have great risks for developing melanoma. In fact, it has been demonstrated that the incidence of melanoma was higher in the military population than the general population in the United States. The success of our studies may lead to improved diagnosis and prognosis of melanoma patients, including in those that serve in the military.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610309
Entities
People
- Bin Zheng
Organizations
- Massachusetts General Hospital
- United States Army