Grant: Project Grant

Cancers are driven by abnormal changes to the genetic material of various cell types in the human body. These changes frequently result in the production of mutated proteins, or an overproduction of proteins, leading to unregulated cell growth. The protein RAS has long been recognized as a key driver of human cancers with fully 30% having mutations in RAS genes, and significantly more showing high activity of associated pathways. RAS has thus been a vitally important target for drug development, but efforts have so far proven unsuccessful. Indeed, a lack of effective therapies for RAS-driven cancers is the major reason why lung, colon, and pancreatic cancers remain the most refractory to available treatments. Improved technological approaches, however, should allow a better understanding of mutant RAS and its associated proteins, and have massively revitalized interest in developing RAS-targeted therapeutics. I have developed new methods to study RAS function, and its connections with other proteins in cells. Targeting such associations is finally proving effective in treating some cancers, yet important relationships between RAS and some partners remain completely unstudied. This includes proteins that regulate the ability of cells to move, linked to metastasis, and proteins that lead to self-directed cell death, which I believe could be exploited as a novel cancer therapy. I use leading-edge techniques such as NMR spectroscopy and X-Ray crystallography to gain insight to the structure of proteins at a molecular level, and complement these data with studies in human cells to observe how mutations lead to cellular transformation. I propose to identify and characterize new therapeutic targets in the RAS pathway, and these efforts will be complemented by the drug discovery capabilities at IRIC. These studies are highly significance to many patients, particularly those with currently untreatable cancers such as pancreatic adenocarcinomas and lung NSCLCs.