Dr. Mangalvedhekar, working with the mentorship of Dr. Emily Cheng (Memorial Sloan Kettering Cancer Center), seeks to identify the genetic changes within advanced ccRCC that promote metastasis and therapeutic resistance. Primary ccRCC frequently results from genetic loss of the VHL tumor suppressor gene but can be characterized in a large cohort of cases by loss of PBRM1, also a tumor suppressor gene, which may augment tumor responsiveness to immunotherapy. Dr. Mangalvedhekar has established a unique mouse model in which both VHL and PBRM1 have been deleted, and found that these mice develop multiple primary ccRCC-like lesions in their kidneys – yet do not develop metastatic disease. These findings suggest that additional genes must be involved in the progression of ccRCC to advanced metastatic states. Dr. Mangalvedhekar proposed to generate a mouse cell line from these mice tumors, to systematically inactivate a list of approximately 50 tumor suppressor genes, already known to be affected in human metastatic ccRCC. Cells with inactivated genes will be grafted in the mouse to surveil for genes whose loss promotes the development of metastatic lesions. Similarly, a second screen of nearly 600 potential tumor suppressor genes will be undertaken to determine if their loss modifies the response to immunotherapy in the primary tumors. The information generated by Dr. Mangalvedhekar’s proposed study has the potential to dramatically improve our understanding of the genetics behind ccRCC progression and response to current therapy, providing opportunity for new avenues of intervention.