Research we fund

Double-hit lymphoma (DHL) is an aggressive form of diffuse large B-cell lymphoma (DLBCL) defined by co-occuring MYC and BCL2 rearrangements. DHL has been linked to very poor outcomes when treated with R-CHOP chemotherapy. Effective treatments to prevent treatment failure remain a critical unmet need. This proposal will develop novel, mechanism-based therapeutic regimens for DHL that overcome chemotherapy resistance and defective immune surveillance to improve outcomes.

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.

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.

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.

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.

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.

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.

Patients with blood cancers from racial and ethnic minority groups are more likely to experience suboptimal end-of-life (EOL) care. These disparities may be partially driven by health insurance differences but there is limited research examining insurance access as a potential contributor to EOL care disparities for this population. We will leverage complementary local and national datasets to assess the relationship between insurance status and type with EOL quality measures. We will also develop a Blood Cancer Health Insurance Initiative to translate our research findings to policy initiatives to dismantle disparities in access to high-quality EOL care for patients with blood cancers. We will translate our research findings to policy initiatives to dismantle disparities in access to high-quality EOL care for patients with blood cancers.

This project will evaluate the association of insurance type with insurer rejection and patient abandonment of new OAM prescriptions for blood cancers, overall and by sociodemographic factors. It will also evaluate the association of cost sharing with patient abandonment of OAM prescriptions for blood cancers and conduct simulations under alternative cost sharing scenarios to inform policy reform proposals among commercially insured enrollees. Finally, the study will evaluate the effect of cost-sharing reductions under the Inflation Reduction Act on patient abandonment of new OAM prescriptions for blood cancers among Medicare Part D enrollees, overall and by sociodemographic factors.

In this proposal we will investigate the association between insurance coverage and access to care, survival, and financial hardship among patients across Non-Hodgkin lymphoma (NHL) subtypes and to what extent insurance coverage explains and modifies racial disparity in access to care and outcomes. To this end, we will use the Optum Clinformatics DataMart database, the Texas Cancer Registry, the Harris Health System Cancer Database and Data from the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study. These four databases will provide a sample that covers a diverse patient population in terms of insurance coverage, race and ethnicity, and geographic regions. The LEO Cohort Study also provides information on self-reported financial toxicity that is not available in cancer registries, administrative claims data, or surveys. This study will reveal whether insurance coverage, neighborhood socioeconomic factors and healthcare resources are associated with access to care and outcomes of NHL patients.