Research We Fund

T cell cancers together comprise ~20% of acute leukemias and non-Hodgkin's lymphomas. A major challenge with currently available treatments for these is that the treatments themselves can damage or inhibit many of the patients healthy T cells that fight the cancer and prevent infections. Our strategy is to develop more personalized treatments that are better matched to each patient’s T cell cancer, improving efficacy and decreasing side effects.

A state-of-the-art therapy for blood cancers reprograms a patient’s T cells to kill tumor cells. This treatment, called CAR-T cell therapy, can work well, but the T-cells often reach a point where they are unable to kill any more tumor cells, and the cancer can return. We have found a way to modify CAR-T cells to become better at repeatedly killing tumor cells, and to last longer and make more copies of themselves. We are working to demonstrate that these special CAR-Ts can safely be used to improve treatment outcomes in patients with leukemia and lymphoma.

While beta-catenin forms transcriptional complexes to activate MYC-expression and proliferation in other cell types, our studies in B-lymphoid cells revealed repressive beta-catenin complexes to suppress MYC. Unlike other cell types, B-lymphoid cells critically depend on high-efficiency beta-catenin protein degradation, which requires concerted activity of the GSK3B and CK1a kinases, NEDD8-activating enzyme (NAE1), and immunoproteasome subunits (PSMB8). 

We propose three Aims, to evaluate the potency and safety of existing drugs targeting (1) phosphorylation by GSK3B and CK1a kinases, (2) NEDD8-connection by the NAE1 molecules and (3) the proteasome subunit PSMB8. The main impetus of this project is to compare these compounds against each other and then prioritize one of them for a systematic drug-repurposing effort for patients with refractory B-cell malignancies.

This project aims to enhance CAR T-cell therapy, a promising treatment for blood cancers, by leveraging the ketogenic diet and its key byproduct, beta-hydroxybutyrate (BHB). We found that BHB enhances the metabolism of CAR T cells, improving their effectiveness and durability in the body. Our study will explore this innovative approach using murine models of blood cancers and healthy donors, aiming to better understand how BHB can augment CAR T-cell function. The ultimate goal is to pave the way for more potent, accessible cancer therapies.