Alexander Valvezan receives Leukemia Research Foundation Award for project titled, “Repurposing IMPDH inhibitors for selective targeting of PTEN-deficient T-ALL cells”

September 7, 2021
Model diagram showing that mTOR complex 1 activation in PTEN-deficient T-cell acute lymphoblastic leukemia confers sensitivity to IMPDH inhibitor therapies.

The project is following up on a metabolic vulnerability I discovered as a postdoc that allows us to selectively kill tumor cells with high mTOR activity using clinically approved immunosuppressants. This project aims to test that vulnerability in PTEN-deficient leukemias, which have high mTOR activity as well.

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 we recently discovered in tumors with abnormal activation of mTOR complex 1 (mTORC1), which is activated to promote cell growth and proliferation in the majority of human cancers. We 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, we 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. The use of clinically approved therapeutics means that efficacy in these studies could lead to rapid repurposing of these drugs for leukemia patients.