Bromodomain Targeting of PBRM1, a P-BAF Chromatin Remodeling Complex Subunit Highly Mutated in Kidney Cancer
Abstract
Kidney cancer is the eighth most common cancer in the USA, representing 3% of new cancer cases each year and 4% of cancer deaths. Clear cell renal cell carcinoma (ccRCC) is the most common and lethal type of kidney cancer in adults, and military personnel, due to demographics and occupational exposures, are at an even higher risk of developing ccRCC than the rest of the US population. If caught early, ccRCC tumors can be cured via surgical removal of the kidney; however, metastatic ccRCC that has spread to other regions of the body is extraordinarily fatal. Many of the standard chemotherapy and radiation treatments that treat other metastatic cancers have no effect on ccRCC. Only recently, effective treatment options have become available for ccRCC that target pathways involved in oxygen sensing in cancer cells. The basis for developing these drugs came from studying VHL, the most commonly mutated gene in ccRCC tumors. While this has improved the outcome for ccRCC patients, the survival rate for metastatic renal carcinoma is still only 22 months. In addition, many patients fail to respond to these treatments. To more effectively treat patients with this disease, we need to better understand the mechanisms of ccRCC cancer development and figure out why some ccRCC tumors respond differently than others to the current drugs. To this end, significant efforts have gone into identifying other genes mutated in ccRCC. Polybromo-1 (PBRM1) is the second most commonly mutated gene in ccRCCs (~40%) and codes for an epigenetic regulator. Epigenetic regulators alter the expression of genes in response to internal and external signals to the cell. We aim to define which genes are regulated by PBRM1 in the kidney and how the regulation of these genes prevents ccRCC. Since most epigenetic changes are reversible, greater understanding of PBRM1 function in ccRCC can lead to new potential therapeutics for this subset of patients. In addition, our studies aim to define how PBRM1 mutation affects the response of ccRCC tumors to the currently used therapeutics in order to better diagnose the outcome for ccRCC patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710267
Entities
People
- Emily C Dykhuizen
Organizations
- United States Army
- University of Virginia