Project 466580

Context: In recent years, an improved understanding of the biology of cancer paired with the development of therapies targeting known cellular culprits of cancer have revolutionized the treatment of this complex disease. And yet, broadly speaking, this promise of targeted therapy has still not fully materialized. One clear reason is our inability to design drugs when the cellular culprits they go after dont happen to fit certain criteria for druggability. One way to circumvent that is to target them indirectly, and an innovative approach to doing that is to bring together our culprit with another protein: the latter could modify the function of the cancer-driving protein and thus attack cancer cells ability to survive and proliferate.: In this context, my project will attempt to find proteins, called effectors, that can modulate the function of the protein MutL Homolog 1 (MLH1) when the two are brought together in close proximity. MLH1 is involved in a type of DNA repair called mismatch repair and is mutated in a variety of human cancers. By finding effectors of MLH1, we could be uncovering new ways to enhance the efficacy of immunotherapy, a type of drugs which use the bodys immune system to fight cancer cells. Experimental approach: My project will leverage a screening approach in which every single human protein will be physically brought in contact with MLH1 in live cells. Those that manage to impact MLH1 activity will be further studied to see if they are useful effectors. Perspectives: The goal is to identify and validate potential proximity-dependent effectors of MLH1. Ultimately, a drug discovery campaign will be initiated with the long-term goal of developing a treatment which can impact the survival and quality of life of cancer patients.