Research we fund

This grant proposal aims to uncover inherited resilience to clonal hematopoiesis (CH) and myeloid malignancies (MyMs). Our pilot work has identified a regulatory variant that significantly protects from CH/MyM through downregulation of MSI2 levels in human hematopoietic stem cells (HSCs). We seek to perform rigorous mechanistic studies to identify an RNA network that regulates human HSCs and is modulated through genetic variation to protect them from CH/MyMs.

Mutations in the RNA splicing factor gene SRSF2 occur in 25% of patients with MDS, 50% of patients with chronic myelomonocytic leukemia (CMML), and 25% of AML patients over the age of 65.

We recently developed a cell therapy directed against abnormal proteins on the surface of cells expressing mutant SRSF2. This proposal aims to improve this new form of immunotherapy and extend its benefit to the largest number of patients with myeloid blood cancers.

Certain genetic alterations in Diffuse Large B Cell Lymphomas (DLBCL) render these tumors highly aggressive. Aggressive DLBCLs may also form secondary lymphomas in the brain. The research proposed here will examine the role of a specific class of lipids in the growth of these lymphomas and assess the utility of strategies to lower these lipids or inhibit their production in halting tumor growth.

Acute myeloid leukemia (AML) is a heterogeneous group of diseases that require complex therapy and are difficult to cure.  AML is caused by the accumulation of DNA mutations in blood stem cells that alter their normal blood production. However, our groups have demonstrated that these genetic changes are not sufficient to cause leukemia. Rather, the cells must acquire additional, adaptive changes in cellular metabolism which includes the biochemical reactions that regulate cell growth.  Many of these biochemical reactions are regulated by mitochondria, which are referred to as the powerhouse of the cell.  We have demonstrated that these metabolic adaptations make AML cells resistant to chemotherapy.  In particular, AML cells adaptively increase their mitochondrial mass and energy production after chemotherapy. The biochemical reactions involved are complex and appear to vary between AML cells and normal blood stem cells. This suggests that if we fully understand the exact metabolic changes that regulate chemotherapy resistance, we can improve the efficacy of such therapy by inhibiting those metabolic responses.  To address this complex problems we have assembled a team of four investigators and three Core leaders with complementary skills in understanding AML metabolism, biology and chemotherapy resistance.  This group is uniquely capable due to their complementary skills in bringing metabolic targeting to the treatment of AML.

We have discovered that the tumor cells of the vast majority of follicular lymphoma cases have a unique tumor-specific feature in their major receptor. This is an essential modification that allows lymphoma cells to capture local support from tissue cells. Our investigation will add diagnostic and prognostic value and provide a new target for therapy. We will develop a new antibody approach which will improve the potency of existing treatments.

Follicular lymphoma (FL) affects ~110,000 Americans and is, unfortunately, frequently referred to as incurable, however, that may change in the near future.  Newer immune-based therapies induce remission in a majority of FL patients and the goal of FL therapy in 2024 should be durable remission or cure.  Immune therapies are, generally, more elegant than chemotherapies as they target specific proteins or ‘antigens’ expressed on tumor cells, e.g. the CD19 and CD20 antigens; however, these therapies thus share a common limitation: ‘antigen escape’ whereby rare tumor cells lacking the targeted antigen evade attack and cause relapse.

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.