Alexander Valvezan, PhD

This project will test a new strategy for selectively killing a molecular subtype of T-cell acute lymphoblastic leukemia (T-ALL) using drugs that are already being used in humans as safe and well-tolerated immunosuppressants. This strategy exploits a molecular vulnerability that I recently discovered in tumors with abnormal activation of a critical group of proteins called mTOR complex 1 (mTORC1). mTORC1 is activated to promote cell growth and proliferation in the majority of human cancers. I discovered that tumor cells with active mTORC1 could be selectively killed, without affecting normal cells, in pre-clinical models of a genetic tumor syndrome called Tuberous Sclerosis Complex (TSC), in which tumor growth is driven by high mTORC1 activity. Due to key molecular similarities between cells in TSC tumors and T-ALL, I hypothesize that the same strategy could be effective in killing T-ALL cells in which mTORC1 is activated by specific genetic mutations which are common in leukemia and lymphoma. These studies will rigorously test this hypothesis in T-ALL cells, laying the foundation for in vivo testing of these drugs alone and in combination with current standard-of-care therapies to provide the pre-clinical rationale for clinical trials in patients with T-ALL. The use of clinically approved therapeutics means that efficacy in these studies could lead to rapid repurposing of these drugs for leukemia patients.