Identifying the vulnerabilities in Mdm2 overexpressing cancer cells

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Abstract Perturbation of the p53 pathway is a common theme in most if not all human cancers. While attenuation of the pathway occurs most often through mutation or deletion of the p53 gene itself, amplification or over production of two important p53 inhibitors, MDM2 and MDM4 also occurs in a number of cancers. The research program funded by R01 CA47296 investigates the pathways of tumor suppression with emphasis on the role of Mdm2 and Mdm4 in p53 regulation and is currently in its 31st year of funding. This R50 application requests salary support for Vinod Pant, Ph.D. to continue providing research support to the program. Dr. Pant works as a non- tenure Assistant Professor in the laboratory of Dr. Guillermina Lozano, Unit Director on this application. Dr. Pant has more than 15 years of experience in cancer research and has a broad background in molecular biology, developmental biology, bio-chemistry and mouse genetics. Dr. Pant has made significant contributions to the program and has published multiple research articles in well-regarded journals. Relevant to this application, Dr. Pant is proficient in murine studies and in conducting CRISPR/Cas9 functional screens. Dr. Pant has carried out preliminary screens to identify the factors that allow cells to tolerate high levels of MDM2 which are otherwise toxic for normal cell growth. Dr. Pant is proceeding with secondary screens to further refine the results. In addition, Dr. Pant will perform genetic screens in MDM2 overexpressing liposarcoma cells to identify the vulnerabilities in these cancer cells. Identified factors will be validated by in vitro and in vivo studies and subsequently tested as therapeutic targets for potential treatment strategy. Dr. Pant's contribution is essential for successful completion of the aims of R01 CA47296 research program.