The mission of Dr. James Brugarolas’ lab is to 1) understand how kidney cancer develops at the molecular level, 2) translate the findings into new treatments for patients, and 3) train the next generation of physicians and scientists. Their research program spans from the genetics of renal cell carcinoma to the clinic. A pipeline has been assembled on 5 pillars: 1) molecular genetics, 2) signaling pathways, 3) drug screening, 4) animal models, and 5) clinical trials.
Dr. Brugarolas’ lab identified a new type of renal cancer, established the foundation for the first molecular genetic classification of the disease, and discovered a novel familial syndrome. In the area of signaling, they characterized a feedback loop linking the two dominant signaling pathways (the VHL/HIF and mTORC1 pathways), established that HIF is sufficient to inhibit mitochondrial respiration in vivo, and identified a novel mTORC1 effector that links anabolic and catabolic functions. The lab developed a chemical genetic screening platform, completed a 200,000-compound screen, and identified several promising leads. They generated the first animal model of kidney cancer that reproduces the drug responsiveness of patients and used it to show that an investigational agent is superior to several approved drugs. Finally, Dr. Brugarolas’ lab proposed a novel paradigm for the treatment of a rare kidney tumor, epithelioid angiomyolipoma, explored the therapeutic potential of glycolysis inhibition for the treatment of an unusual form of renal cancer resulting from mutations in fumarate hydratase, and opened an investigator-initiated phase II clinical trial to probe into mechanisms of resistance to mTORC1 inhibitors.