Research we fund

RAS/MAPK mutations are the key drivers in MM, which occurs in 50% of newly diagnosed and higher in relapsed MM patients. However, RAS remains undruggable in MM. We found that RAS mutation MM growth is highly dependent on germinal center kinase(GCK). The goal of this project is to develop small molecule inhibitors against GCK with the expected outcome to provide novel treatments for relapsed/refractory and especially multi-drug resistant MM with RAS mutation, as well as other B-cell malignancies.

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.

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.

The focus of my research is to elucidate the core molecular regulators of malignant stem cell generation in multiple myeloma. My approach addresses the tumor cell-intrinsic versus niche-dependent mechanisms of myeloma regeneration by exploring transcription factor expression and stemness profiles within single cells from primary samples and patient-derived models. The central goal of my research is to uncover novel therapeutic strategies and translate these into new myeloma treatments.

The goal of the Clinical Trial Network of South Texas is to expand access to high quality clinical trials for under-represented minority (African American and Hispanic) patients with lymphoid cancers who receives care at the UT San Antonio Mays Cancer Center (MCC) and community oncology centers in South Texas. To achieve this goal, we will leverage the existing partnership between MD Anderson Cancer Center (MDACC) and its robust clinical trial infrastructure to identify and deploy suitable clinical trials. We also will strengthen the research infrastructure at MCC and community sites, including providing equipment, clinical trial navigation support, and oversight to successfully deploy trials. By establishing MDACC/MCC as a hub for clinical trials, developing the necessary research infrastructure at community oncology centers, and allowing patients to participate in clinical trials at their local oncology centers, this IMPACT program has the potential to improve clinical outcomes.

City of Hope (COH) has embarked on a strategic initiative to optimize our clinical network and increase research capacity at our Community and Affiliate Network (CAN) sites in Southern California. I would like to spearhead this endeavor for the Hematology program at our new Irvine campus in Orange county, which is set to open in August 2022. We are employing a hub-and-spokes model, in which the Duarte main campus is the main research center, with 3-5 multi-disciplinary CAN sites ultimately designated as research hubs. These CAN sites (hubs) will serve geographically proximal practice sites (spokes), which will refer patients for treatment on clinical trials at either the CAN site itself or at the main Duarte campus. Following a 6-month pilot for optimizing staffing, investigational pharmacy setup, specimen and data collection in Irvine, an additional CAN site will be initiated each year over a 5-year period to allow a wider area of Southern California residents to have access to high quality and impactful clinical trials in Hematology. Our ultimate goal is to accrue 20-50 patients per year from the community, depending on the number of sites activated each year.

Advances in multiple myeloma (MM) therapy have improved survival, but serial cycles of response and relapse still lead to treatment-refractory and fatal disease in nearly all patients. To specifically target mechanisms of MM relapse, we propose to develop an immunotherapy targeting Sox2, a stem-cell transcription factor implicated in clonogenic MM growth that enables relapse.

Despite the promise of CAR-T cell immunotherapy for patients with lymphoma and multiple myeloma, a significant proportion of patients fail to respond or relapse following treatment. This project will focus on the clinical translation of a new treatment designed to improve durable response rates by combining CAR-T cell therapy with a new class of anticancer drugs called SMAC-mimetics. The results will provide the evidence base to drive a first-in-human clinical trial of this combination strategy.

In February 2021, LLS made an equity investment in Caribou Biosciences to support "A Phase 1, Multicenter, Open-Label Study of CB-011, a CRISPR-Edited Allogeneic Anti-BCMA CAR-T Cell Therapy in Patients With Relapsed/Refractory Multiple Myeloma." 

Caribou is a leading clinical-stage biotechnology company, co-founded by CRISPR pioneer and Nobel Prize winner Jennifer Doudna, Ph.D., using next-generation CRISPR genome-editing technology to develop “off-the-shelf” (allogeneic) CAR therapies for hard-to-treat blood cancers.

CB-011, Caribou’s second allogeneic CAR-T cell therapy, targets BCMA for the treatment of relapsed/refractory multiple myeloma and is immunologically cloaked for enhanced persistence. The CaMMouflage Phase 1 clinical trial, a multicenter, open-label study to evaluate the safety and efficacy of a single dose of CB-011 in adult patients with relapsed or refractory multiple myeloma (r/r MM), is currently enrolling (NCT05722418).