Grants - V Scholar Grants - Illinois - 2014

Emily Dykhuizen, Ph.D.

Kidney cancer is the 8th most common cancer in the USA, representing 3% of new cancer cases each year and 4% of cancer deaths. Renal cell carcinoma (RCC) is the most common and lethal type of kidney cancer in adults, representing 90-95% of all kidney cancer cases. Approximately 90% of RCCs have mutations in the tumor suppressor gene, von Hippel-Landau (VHL), which is involved in the degradation of hypoxia-inducible factor (HIF) transcription factors. The mutation of VHL leads to huge increases in the levels of HIF, which promotes tumor growth by increasing the blood supply to tumors. Uncovering this pathway of tumor suppression has led to several targeted therapeutics that lower levels of HIF, and are currently used in the clinic. While this has improved the outcome for RCC, the median survival rate for metastatic renal carcinoma patients is still only 22 months. Uncovering additional mechanisms of tumor suppression and new therapeutic targets would bring us closer to our goal of eradicating these cancers. To this end, efforts to identify additional genes mutated in RCC have identified Polybromo-1 (PBRM1) as the second most commonly mutated gene in RCCs (~50%). PBRM1 is part of the SWI/SNF (BAF) chromatin remodeling complex, an important regulator of gene expression. While subunits of the BAF complex are mutated in a spectrum of cancers, mutations in PBRM1 seem to be fairly specific to RCC. We aim to understand the mechanism of tumor suppression by PBRM1 in RCC by 1) uncovering how PBRM1 deletion affects the function of the BAF chromatin remodeling complex, 2) identifying genes regulated by PBRM1 deletion, and 3) identifying pathways important in RCC progression that we can target with novel or known therapeutics.