Research we fund

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive leukemia in adults with 5-year survival rate of only about 10% in patients with relapsed/refractory (R/R) disease, but LCK and BCL2 are novel therapeutic targets. In this project, we aim to conduct a Phase II clinical trial evaluating LCK inhibitor, ponatinib and BCL2 antagonist, venetoclax combination therapy in R/R T-ALL, with correlative biology studies to define biological mechanisms of drug response and resistance.

Innovations in gene engineering have made it possible to reprogram immune cells to attack specific targets on cancer cells, allowing the first adoptive cellular immunotherapies, known as CAR T cells, to be approved by the FDA for the treatment B lymphoblastic leukemia. A similar approach is currently under development for AML, but in contrast to B-ALL, there is no leukemia-specific target which would be amenable to targeting by immune cells without incurring severe adverse effects. Here, we aim to modify normal bone marrow stem cells used for allogeneic transplantation to make them resistant to CAR-T cells, thus enabling targeting proteins essential for tumor survival without the risk of severe toxicity on the healthy tissue counterpart.

Richter’s transformation (RT) refers to the development of an aggressive lymphoma in patients with a prior diagnosis of chronic lymphocytic leukemia (CLL) that remains uncured, even with the current T-cell based immunotherapy such as chimeric antigen receptor (CARs) T cells. Fibroblastic reticular cells (FRCs) modulate T cells in secondary lymphoid organs (SLOs) via toll-like receptors (TLR) and promote the expression of PD-L1 and PD-L2 to modulate and suppress T cells especially cytotoxic T cells, however, the role of FRCs is not well defined in CLL or RT. Here, we propose to perform mechanistic and translational studies to understand if and how TLR9 plays a critical role in FRC-modulated suppressive T cell activities, and to determine whether targeting TLR9 in FRCs can reactivate T cell immunity and improve treatment outcome in RT.

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.

Despite an array of promising immunotherapies, the blood cancer multiple myeloma still remains without any known cure. Patients with high-risk disease in particular still relapse most frequently after current BCMA-targeting therapies such as CAR-T cells. Here we identify CD70 as an alternative CAR-T target in these high-risk patients who need new treatment options, and further use innovative artificial intelligence-inspired strategies to develop a best-in-class CAR-T design targeting CD70. The goal of our proposal is to perform additional validation studies to prove the efficacy and safety of this novel CAR-T cell, with the goal of moving toward near-term clinical trials in high-risk myeloma by the completion of the award period.

The identification of critical therapeutic targets in myeloproliferative neoplasm (MPN) cells will have a significant impact on the development of much needed treatments for the 300,000 MPN patients in the U.S. Deregulated activity of a protein called JAK2 is an important factor that contributes to MPN formation, but currently approved drugs targeting JAK2 have had limited success, as disease-driving cells persistently survive therapy, and thus these drugs can not readily induce remission in patients. After four decades of the identification of the importance of a protein called RAS in cancer, which is also involved in the cancer causing signaling of JAK2 in MPN, an innovative drug has just been developed (in 2024) to directly block RAS activity. This proposal will investigate the potential this exciting new drug may have in novel therapeutic approaches to improve the lives and the long term health and outcomes of MPN patients.

Our objective is to develop a highly specific T-cell engaging therapy to treat a subtype of leukemia that currently lacks effective treatment. We also aim to minimize toxicity to healthy blood cells, a common challenge with existing leukemia immunotherapies.