Research we fund

This project aims to develop targeted therapies against peripheral T cell lymphoma (PTCL), a diverse group of aggressive blood cancers with poor clinical outcomes. This project is tightly relevant to cancer control and treatment, promising to advance our understanding on how blood cancers initiate and progress, and lead to new therapeutics for the treatment of peripheral T cell lymphoma (PTCL). We will develop targeted therapeutics to engage an oncogenic RHOA GTPase mutant to treat PTCL and other types of tumors with similar genetic backgrounds.

Project Term: July 1, 2023 - June 30, 2026

We observed that patients with many hematologic cancers expressed high levels of DKK1 and generated novel human DKK1-A2 CAR-T cells that can kill cancer cells from HLA-A2+ patients with myeloma, lymphoma, or leukemia. We also found that Th9-polarized T cells have enhanced antitumor effects in vivo. In this proposal, we will determine 1) whether and how Th9-polarized DKK1-A2 CAR-T cells are promising effector T cells for immunotherapy of human patients, and 2) whether Th9-polarized DKK1-A2 CAR-T cells are associated with reduced on- and off-target toxicities. Completing these studies are critical for developing new and effective CAR-T therapy for patients with hematologic malignancies who are still dying from the disease.

Project Term: July 1, 2023 - June 30, 2026

Our proposal aims to develop a novel strategy to improve therapeutic efficacy for patients with multiple myeloma by remodeling obesity-induced inflammatory microenvironment. We hypothesize that acetyl-CoA synthetase 2, which is stimulated by obesity, enhances inflammatory cytokine production from myeloma cells, leading to an inflammatory niche where anti-tumor function of CD8+ T cells is dampened, and tumor growth is promoted. Our study will be the first to explore a novel insight for how obesity impacts the interaction between myeloma cells and microenvironment. In preparation of using the inhibitor of acetyl-CoA synthetase 2 in the clinical setting, we will establish its potential as a single agent or in combination of other chemo- or immuno- drugs to treat myeloma.

Project Term: July 1, 2023 - June 30, 2026

The b-catenin/BCL9 transcriptional complex, is a novel dependency in multiple myeloma (MM). Disruption of this complex inhibits MM cell growth in culture and in MM xenograft models. Development of potent selective b-catenin/BCL9 inhibitors will provide valuable tools to further investigate their mechanism of MM inhibition. We have established a chemistry, structural biology, and molecular pathology platform to facilitate novel inhibitor development, and explore its translational potential in MM.

Project Term: July 1, 2023 - June 30, 2026

This proposal is to conduct a phase I (early phase) clinical trial to test whether the combination of the approved targeted therapy venetoclax with memory-like Natural Killer (NK) cells is safe and active in patients with acute myeloid leukemia (AML). Based on laboratory research at Dana-Farber Cancer Institute, we believe that the addition of memory-like NK cells obtained from an haploidentical (‘half matched’) donor will be able to eradicate residual leukemia cells left over after prior venetoclax treatment and hence prevent a future relapse of the disease. A total of 10 patients will be treated with two different doses of NK cells and a constant dose of venetoclax. We also plan scientific studies on patient samples to learn more about the function of NK cells when combined with venetoclax, evaluate for clearance of residual leukemia cells with this combination therapy and explore potential resistance mechanisms.

Project Term: July 1, 2023 - June 30, 2026

We will develop a novel T cell therapy strategy for multiple myeloma (MM) that will combine existing chimeric antigen receptors (CARs) with a novel designed biosensor responding to soluble factors abundantly present in the MM bone marrow environment in patients. The biosensor will be expressed as novel type of chimeric receptor in T cells concomitantly with the CAR and signal the T cells to persist longer and keep eliminating cancer cells from the body. We will deeply characterize the effects of our novel biosensor in CAR T cells to precisely understand how the treatment works. If successful, we expect that CAR T cell therapy for MM can be made more efficient, and the same strategy could potentially also be applied to other cancer types.

Project Term: September 1, 2023 - August 31, 2026

Although they represent a major therapeutic progress for blood cancers, CAR-T cells and other T-cell based therapies are subject to eventual development of resistance to many patients. Natural killer (NK) cell-based therapies are highly active against many types of blood cancer cells which are resistant to T cells, but in our CRISPR studies death receptor signaling defects emerge as a common downstream mechanism of resistance to both T- and NK-cell therapies. Building on extensive pharmacological and genomic screens, this project will specifically examine the role of SMAC mimetics and JAK/STAT inhibitors in enhancing the response of blood cancer cells (e.g., multiple myeloma, leukemias) to CAR-T or NK cell therapies. We will place emphasis of studies with patient-derived samples in vitro (Integrated Functional Immune Profiling Platform) and in vivo, including humanized bone marrow-like scaffolds, to provide a translationally-relevant simulation of the potential of these compounds to enhance the clinical activity of cell-based immunotherapies in blood cancers.

Project Term: July 1, 2023 - June 30, 2026

Our laboratory and those of others discovered highly recurring mutations in the gene MYD88 which are found in patients with various B-cell cancers including Waldenstrom’s Macroglobulinemia (95-97%), ABC Subtype of Diffuse B-cell Lymphoma (30-40%), Primary Central Nervous Lymphoma (80%), Marginal Zone Lymphoma (10%) and Chronic Lymphocytic Leukemia (5-10%). Our laboratory and those of others showed that mutated MYD88 triggers BTK, which is the target of BTK-inhibitors like ibrutinib, acalabrutinib and zanubrutinib though complete remissions are rare with these agents largely in part because other pro-survival molecules are activated by mutated MYD88 such as HCK and IRAK1. In these studies, we will develop potent and selective inhibitors to HCK and IRAK1, including PROTACs which inhibit and degrade these molecules, using lead molecules and scaffolds whose target selectivity and activity we previously validated. We will also investigate the mechanisms underlying the inactivation of the Inhibitor of BTK (IBTK) as a potential new target for development of inhibitors for use in MYD88 mutated lymphomas.

Project Term: July 1, 2023 - June 30, 2026

Inhibition of a tumor-triggered immune exhaustion pathway, termed PD-1 blockade, enables immune effector cells to attack cancers. In classic Hodgkin Lymphoma (cHL), PD-1 blockade is now a standard treatment for relapsed disease and a component of experimental frontline therapy. We have identified a major population of monocyte/macrophages in patients with cHL that inhibit tumor cell killing and limit the efficacy of PD-1 blockade. Our goal is to fully characterize these tumor-specific monocytes/macrophages and target their immunosuppressive and tumorigenic program for therapeutic benefit in patients with cHL and other lymphoid malignancies.

Project Term: June 30, 2023 - June 30, 2026

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.

Project Term: July 1, 2023 - June 30, 2026

We identified the adenine nucleotide regulator AK2 as a selective dependency in multiple myeloma (MM) that is more essential for survival of MM cells overexpressing the histone methyltransferase NSD2. Here, we propose a series of experiments to understand the role of AK2 in MM cell fitness and response to existing therapies and elucidate the molecular basis of the increased dependence on AK2 driven by NSD2 overexpression. This study will elucidate the effects of AK2 inhibition in MM and will credential the enzyme as a therapeutic target.

Project Term: July 1, 2022 - June 30, 2025

The impact of biological heterogeneity on treatment outcomes is evidenced by a large proportion of lymphoma patients who experience relapsed/refractory disease. To address this knowledge gap, we sequenced primary lymphoma samples and found recurrent mutations in the non-canonical NF-kB pathway (NC NF-kB) and uncovered the NIK kinase as a targetable candidate. Our next steps focus on using advanced genetic modelling approaches to provide preclinical rationale for targeting NC NF-kB in lymphomas.

Project Term: July 1, 2022 - June 30, 2025