A long–standing question across oncology is why the same cancer may be very aggressive in some patients but not in others. Researchers with the Kidney Cancer Program of UT Southwestern Medical Center’s Harold C. Simmons Comprehensive Cancer Center have uncovered how kidney cancer aggressiveness is determined.

The team, led by Dr. Payal Kapur and Dr. James Brugarolas, previously showed that kidney cancers can be classified into those with mutations in the BAP1 gene and those with mutations in the PBRM1 gene. They reported in Lancet Oncology that tumors with BAP1 mutations were very aggressive, but those with PBRM1 mutations were not. In subsequent studies with Mayo Clinic involving 1,400 patients, they showed that 90 percent of patients with PBRM1 tumors were alive 10 years after surgery for kidney cancer, but only 40 percent of those with BAP1 tumors.

To determine whether BAP1 and PBRM1 were not only associated with, but indeed responsible for the differences in aggressiveness, the investigators engineered mice with mutations in either BAP1 or PBRM1 in their kidneys. Interestingly, BAP1 mice developed kidney cancer in three months. In contrast, it took more than nine months for tumors to develop in the PBRM1 mice. Their features were similar to the human counterparts.

“These results show that the BAP1 and PBRM1 genes are responsible for more aggressive and less aggressive kidney cancers, respectively,” stated Dr. Brugarolas, Associate Professor of Internal Medicine and Leader of the Kidney Cancer Program, who is senior author of the Cancer Discovery study.

Further, Kidney Cancer Program investigators have developed a test that allows patients to find out whether their tumor is BAP1 mutant or not. “While only 10–20 percent of kidney cancers are the BAP1 type, patients are often anxious to know,” said Dr. Kapur, Associate Professor of Pathology and co–Leader of the Kidney Cancer Program, who developed the test.

This research was part of a Specialized Program of Research Excellence (SPORE) from the National Cancer Institute (NCI), one of two prestigious awards for kidney cancer in the country. By developing a mouse model of kidney cancer, investigators are now poised to find new treatments. “This is particularly important for the BAP1 cancers,” Dr. Brugarolas said. Better treatments, mean better outcomes. Notably, while nationally, 5–year–survival rates are 10 percent for patients with metastatic kidney cancer, 20 percent of the patients are alive in the Kidney Cancer Program. “This is likely due to a multiplicity of factors, including an exceptional team of urologists, medical oncologists, and radiation oncologists with dedicated expertise, the availability of the latest treatments in clinical trials, as well as an excellent support system that includes terrific patient advocates,” said Dr. Hans Hammers, Associate Professor of Internal Medicine and co–Leader of the Kidney Cancer Program.

Kidney cancer is the sixth most common cancer type affecting men and women. The Kidney Cancer Program at UT Southwestern includes more than 20 expert physicians and over 60 faculty conducting laboratory–based or translational research. Discoveries at the KCP have led to a new understanding of how kidney cancer develops, and are leading to new treatments. Dr. Brugarolas’ team previously discovered another gene mutated in kidney cancer, the TSC1 gene, which may identify patients most likely to respond to the drugs everolimus and temsirolimus.

In addition to identifying cancer genes, ongoing efforts within the Kidney Cancer Program at UT Southwestern focus on leveraging Nobel Prize–winning immunology research and include numerous clinical trials of immunotherapies.