Analyses structurales et systémiques des protéines modulatrices de la signalisation RAS oncogénique pour de nouvelles approches thérapeutiques contre les cancers humains

 

Matthew Smith

Institut de recherche en immunologie et cancérologie (IRIC)

 

Domaine : cancer

Programme Chercheurs-boursiers - Junior 1

Concours 2016-2017

Cancers are driven by anomalous changes to the genetic material of various cell types. These changes frequently result in the creation of mutated proteins or an overproduction of proteins leading to unregulated cell growth and cancer. The protein RAS has long been recognized as a key driver of human cancers with fully 30% of tumours having RAS mutations, making it a major target for drug development.

Unfortunately, attempts have proven largely unsuccessful and a lack of effective therapies for RAS-driven cancers is the reason lung, colon, and pancreatic cancers remain the most refractory to available treatments. Improved technological approaches, however, should allow a better understanding of how mutant RAS functions in cells. I have developed and published novel methods to study RAS and its relationship with other cellular proteins. Targeting such associations has proven effective in treating some cancers, yet important connections between RAS and many partner proteins 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 will attempt to coopt as a cancer-fighting strategy. 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.

Through these efforts I will advance novel therapeutic strategies for RAS pathway defects, in hopes of improving outcomes for patients with RAS-driven tumours.