PROJECT SUMMARY Dr. Madhavika N. Serasinghe is an Instructor in the Department of Oncological Sciences at the Icahn School of Medicine at Mount Sinai (ISMMS). She has a strong background in biochemistry, molecular and cell biology, and extensive research experience in mitochondrial biology. During her post-doctoral studies and as an Instructor she studied the role of mitochondrial biology in oncogenic RAS-MAPK mediated transformation, with special focus on melanoma. The RAS- MAPK pathway is frequently hyper-activated in cancer through mutations in the receptor tyrosine kinases, RAS GTPase (e.g. RASG12V), or the BRAF kinase (e.g. BRAFV600E). The mitochondrial fission protein DRP1 is requisite for RASG12V mediated transformation of mouse embryonic fibroblasts, and phosphorylated DRP1 (DRP1S616?) serves as a predictive biomarker for BRAFV600E positive melanoma progression. In the proposed project Dr. Serasinghe hypothesizes that DRP1 is required for melanocyte transformation by BRAFV600E, and that mitochondrial fission mediated by DRP1 plays an important role in overcoming oncogene induced senescence and progression of nevi to melanoma. In aim 1, she will examine the mechanistic impact of DRP1 mediated changes to mitochondrial biology on malignant transformation using a lentiviral BRAFV600E expression /PTEN knockdown model of primary human melanocytes. Her second aim will focus on translating her findings to a clinically relevant context. In collaboration with the Center for Therapeutic Antibody Development at ISMMS, she will develop a human specific monoclonal antibody as a basis for a prognostic assay to determine subsets of patients who require regular clinical monitoring for early detection and management of melanoma. As a part of aim 2, she will develop DRP1 specific small molecule inhibitors with potential therapeutic value in melanoma and other cancers. In collaboration with the Experimental Therapeutics Institute at ISMMS, utilizing structure-guided approaches to virtually screen a library of >20 million compounds, she will select and validate potential binders using in vitro and cell-based DRP1 activity and binding assays. These translational aims will provide Dr. Serasinghe hands-on experience in the drug discovery process as well as biomarker assay development, and allow her to acquire new skill sets and technical expertise for future translational research. The projected clinical aspects of these studies will enable her to gain further exposure to bench-to-bedside translation of basic research. Dr. Serasinghe?s immediate career goal is to develop an independent research program under the mentorship of Dr. Jerry Chipuk, obtain federal funding, and establish a laboratory at an academic cancer research institute as a tenure track faculty member to conduct high quality cancer research. At ISMMS, she will receive excellent mentorship, exceptional scientific and career development training, and opportunities to develop multidisciplinary collaborations to advance the scope of her research. Dr. Serasinghe?s long term career goal is to become a leader in melanoma research, and dedicate her efforts to discovering innovative preventative, prognostic, and therapeutic modalities against melanoma. The NCI-K22 award will provide Dr. Serasinghe valuable support to achieve her research and career goals, make important contributions to cancer research, and support the mission of the NIH and NCI.