Dissecting the Roles of ARID2 Tumor Suppressor in Metastatic Melanoma
Abstract
Fiscal Year 2015 (FY15) Topic Areas and Military Relevance Focus Areas Addressed by This Proposal: This study focuses on melanoma, one of the Peer Reviewed Cancer Research Program (PRCRP) Topic Areas. As ARID2 inactivation mutations were also found in pancreatic cancer, colorectal cancer, and liver cancer, the results from this study could be applied to treat patients with these three other cancer types, all of which are PRCRP Topic Areas. The proposed studies will address several FY15 PRCRP Military Relevance Focus Areas, including addressing gaps in melanoma diagnosis, early detection, or treatment that may have a particularly profound impact on military health, and assessing heavy sun-exposure, a militarily relevant risk factor associated with the susceptibility, early detection, progression, and treatment of melanoma. Scientific Objective and Rationale: In the United States alone, an estimated 73,870 new cases and 9,940 deaths due to melanoma are projected for 2015, incurring a direct cost of more than 600 million dollars. The estimated rate of melanoma is higher for the more than 2 million Service members exposed to heavy sunlight in areas like Iraq and Afghanistan. There is clearly an unfortunate and serious potential for higher and long-term risk of melanoma for these Warfighters. In the case of melanoma, once metastasis has occurred, prognosis is poor as most current therapeutic interventions have little effect on survival. Despite the recent progress on BRAF-targeted therapy and immunotherapy, most patients either do not benefit from these treatment methods or develop resistance shortly after treatment. Therefore, it is necessary to identify new drug targets and develop alternative therapies to treat metastatic melanoma. Inactivating mutations of an epigenetic enzyme ARID2 occurs in ~14% of individuals with sun-exposed metastatic melanoma, suggesting that it is a new tumor suppressor. We further showed that ARID2 loss is in about 40% human patient-derived melanoma cells. We found a novel link between ARID2 loss and a targetable enzyme and will test the feasibility of targeting this enzyme to treat melanoma patients with ARID2 loss. As the inhibitors of this enzyme are available, the proposed work could be rapidly translated to the clinic. Applicability of the Proposed Research: Mortality of melanoma patients is mainly due to metastasis, and inactivating mutations of ARID2 occur in ~14% of individuals with sun-exposed metastatic melanoma. Our preliminary data suggest that the rate of ARID2 loss through other mechanisms is even higher. The proposed studies will benefit melanoma patients with ARID2 loss, and possibly patients with ARID2 loss caused pancreatic cancer, colorectal cancer, and liver cancer. These studies will reveal novel biomarkers of melanoma with ARID2 inactivation in 2 years and lead to a novel targeted treatment method against RBP2 in 5 years. Current anti-cancer drugs are mostly agents that target genetic abnormality, but not epigenetic processes. Targeting epigenetic aberrations has the potential of curing cancer without introducing genetic changes. The proposed studies will not only reveal the molecular mechanisms by which sun-exposure-induced mutations alter gene structure and expression through ARID2 inactivation, but could also reveal novel biomarkers of melanoma and provide the rationale to develop targeted treatment for melanoma. Impact for Military Service Members, Their Families and Other Beneficiaries: The results from this proposal will have major impact on melanoma patient care as the proposed work will provide novel biomarkers for melanoma with ARID2 inactivation and strong rationale for anti-melanoma therapies targeting RBP2. These findings could be translated to the clinic as novel methods of targeted cancer therapy, either alone or in combination with other chemotherapeutic agents. As the risk of melanoma is highly elevated by heavy sunlight exposure
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610326
Entities
People
- Qin Yan
Organizations
- United States Army
- Yale University