Research we fund

Immunotherapy using chimeric antigen receptor (CAR) T cells, or CARTs for short, holds great promise for improving outcomes and survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Next-generation “armored” CARTs that can overcome transforming growth factor beta (TGF-beta) dependent immune suppression in the tumor microenvironment may provide deeper and more durable disease control than the TGF-beta sensitive CART products currently in clinical use.

Telehealth could improve access for Medicaid patients with a blood cancer who experience barriers to specialty care, but not all specialists offer it. Using Medicaid data, this study will provide novel information on whether blood cancer specialists are continuing to use telehealth following the COVID-19 pandemic when telehealth use increased dramatically. This study will also examine if telehealth helps address inequities in access to specialists, including for racial/ethnic minoritized groups and those living in rural areas.

Bispecific antibodies are a new, highly effective immunotherapy for multiple myeloma. Most bispecific antibody therapies have been tested as continuous therapies in which patients continue receiving the treatment until the myeloma starts growing again. Preliminary results suggest that patients with good responses may be able to stop therapy and enjoy a period of time off-therapy with close observation, which may limit long term toxicities caused by continuous therapy. We propose a clinical trial to test this limited-duration approach with recently approved bispecific antibodies for multiple myeloma.

Our project’s goal is to change how multiple myeloma is understood and treated by interrogating a novel part of the cellular “soil” (the bone marrow adipocyte), in which myeloma cells, or “seeds”, land and grow. We will discover new forms of cancer drug resistance that are driven by adipocyte-derived factors and the fatty acid binding proteins. This work will expose new ways to overcome drug resistance to improve survival and quality of life for myeloma and other hematological cancer patients.

Outcomes for acute myeloid leukemia (AML) and multiple myeloma (MM) patients remain inadequate and new treatment options to combat resistance against existing agents are urgently needed. My research aims to identify and target selective vulnerabilities of AML and MM cells. I am particularly interested in epigenetic and metabolic pathways that control self-renewal and differentiation of hematopoietic cells and that can be leveraged to modulate cell fate for therapeutic benefit.

The primary focus of research is to better understand mechanisms of resistance to immunotherapies and design treatment approaches to improve outcomes. I hope to accomplish this by conducting clinical trials that concurrently target both BCMA and GPRC5D in patients with advanced multiple myeloma and by studying antigen expression, tumor genetics, and T cell characteristics to better understand mechanisms of resistance. The goal is to develop more effective immune treatments for myeloma.

Multiple myeloma is characterized by severe changes in chromosomes that result in gains or losses of genetic material. Several key events disrupt the genome of myeloma cells and are important in defining poor patient outcome, but the biological mechanisms of how they cause high-risk disease is not known. We will perform comprehensive genomic studies, involving six different cutting-edge techniques, to examine the interactions of these high-risk events and identify the mechanisms leading to them.

Blood cancers can be caused by aberrant regulation of genes that control cell growth and development. The root cause of this problem may be the presence of mutant regulator proteins in the cell and abnormal switching on or off of target genes. Our SCOR studies the molecular basis of this gene deregulation using cell cultured in the laboratory, in human specimen and animal models.

Melnick will study the complex of proteins evolve in looping DNA segments to put gene regulatory sequences in proximity of genes critical for the development of antibody producing B cells. Abnormalities of this apparatus lead to lymphoma. Roeder will study multi-protein complexes involved in “bookmarking” chromatin (the complex of DNA and histones found in the cell nucleus) by chemical modification. He studies the proteins that initiate transcription of DNA into RNA and that assure the passage of the polymerase that creates messenger RNA across genes. Soto-Feliciano studies TRIM28, a protein essential for growth of acute leukemia will identify its mechanisms and target genes. Licht will study the role of chromatin regulators in the response of the immune system to multiple myeloma and how inhibitors of chromatin regulator inhibitors affect the tumor immune response. Patel will study in explore the three-dimensional structures of these protein complexes critical for gene regulation in blood malignancies to understand their mechanisms and develop new small molecules to modulate their action.

Development of a strong anti-cancer immune response requires coordinated action of the innate and adaptive parts of the immune system, but cancer cells alter their environment to suppress virtually every step in this process, which promotes cancer progression and treatment resistance. One promising strategy could be to target Heat shock protein 70 (HSP70), which plays an important role in both innate and adaptive immunity, and we therefore developed a series of novel antibodies to HSP70, one of which cured mice of multiple myeloma. Based on strong preliminary data, we propose additional studies to better understand how this antibody activates various types of immune cells, how it works against both cancer cells and modifies the immune environment in mouse models, and how it could work even better in combination with other agents against myeloma. Since this antibody is already being developed into a drug for phase I clinical trials, these studies will directly inform its use in the clinic against multiple myeloma, and possibly against other blood-related cancers such as B-cell lymphomas.

We have investigated the consequences of p53 loss on stem cell properties, namely clonogenic growth, self-renewal, and drug resistance in multiple myeloma. We have found that both the level of Notch signaling and BCMA impact these properties, and we will explore novel strategies to improve outcomes in p53 mutant multiple myeloma.