Departments of Oncological Sciences and Structural and Chemical Biology
Icahn School of Medicine at Mount Sinai
Our Combination of synthetic organic chemistry, structural biology, mass spectrometry, informatics, biochemistry and model organism genetics, allows us to create new tools to modulate and explore novel biological targets, and also develop new leads for drug discovery.
We would like to have a better understanding of the structural and mechanistic features of Ras-MAPK signaling, and new compounds to target this pathway in cancers.
Arvin Dar is an Assistant Professor of Oncological Sciences and Structural and Chemical Biology at the Icahn School of Medicine at Mount Sinai. Originally from Canada, he graduated with a B.Sc. in Chemistry from the University of Western Ontario. He then completed graduate studies at the University of Toronto graduating in 2006. His PhD thesis was done in the laboratory of Frank Sicheri where he solved the first crystal structure of a kinase in complex with an intact protein substrate. Dr. Dar conducted postdoctoral studies with Kevan Shokat at the University of California, San Francisco, where he developed small molecule tools to control kinase structure and signaling in normal and cancer cells. Dr. Dar’s current research focuses on the use of target-based and systems pharmacology approaches to generate new classes of small molecule modulators for the Ras pathway. Dr. Dar’s prior honors and awards include a Department of Defense Postdoctoral Fellowship, a UCSF Dean’s Prize, Innovator Awards from the NIH and the Damon-Runyon-Rachleff Foundation, and a Pew-Stewart Scholarship in Cancer Research.
Co-Targeting Catalytic and Scaffolding Activities of a Oncogenic Signaling Complex
Combination drugs are increasingly recognized as a therapeutic modality for a variety of complex diseases, and may be particularly important in cancers driven by mutant Ras. Indeed, Ras driven cancers remain difficult to treat and recalcitrant to pharmacological intervention. Mutations in two of the human Ras isoforms, K-Ras and N-Ras, are frequently observed in several cancers including pancreatic (71% K-Ras), colon (35% K-Ras), lung (19% K-Ras) and melanoma (18% N-Ras).
“It’s a huge honor, especially knowing the caliber of science from previous winners and also the highly respected and accomplished scientists who assess the applications. This quick inject of funds into my lab allows us to push forward our work and pursue our ideas at a very competitive rate. At the same time, the Pershing Prize allows us to pursue the innovative long-term experiments that we think could have the most significant impact on our field. Winning the PSSCRA will help my lab bridge new connections within both academics and industry here in the New York area, and overall will get us closer to our goals of developing new cancer therapies.”
Based on genetic studies, and known intrinsic or acquired mechanisms of resistance to current therapeutic approaches, we hypothesize that sufficient reduction in MAPK signaling in Ras-mutant cancers remains a major challenge. Kinase Suppressor of Ras (KSR) functions as a direct scaffold of the key Ras-MAPK enzymes RAF and MEK. My lab has created small molecule antagonists of KSR and our prelminary data suggests that we can use these compounds to improve the therapeutic index of current clinical MAPK inhibitors in Ras-dependent cancers. We propose to explore combination strategies as a means to selectively reduce mutant Ras signaling in various cell-based and animal models of cancer. If successful in translating this approach to the clinic, we will improve outcomes for as many as 1 in 4 of all cancer patients. In the US alone, this would represent over 100,000 patients per year.
“Innovation can be viewed in a few ways I believe. The best scientists not only tackle problems that few others have thought to tackle, they also come up with new ways of looking at problems, which frequently leads to novel experimental approaches. All of this leads to great leaps in their field of study, and moves our overall understanding and technological abilities forward.”