Discovery and therapeutic targeting of novel mechanisms driving Double Hit Lymphomas
Wendy Béguelin
PhDWeill Cornell Medicine
Project Term: July 1, 2023 - June 30, 2026
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.
B-cell lymphoma is a cancer that affects white blood cells, specifically B-lymphocytes, which normally help our body fight infections. These malignant B-cells can disseminate throughout the human body, where they can lodge in various tissues to form tumors. Malignant B-cells cannot live in isolation, and instead must hijack normal cells from other branches of the immune system to maintain their growth and survival. This mixture of tumor cells and their supporting normal cells is known as the tumor “microenvironment”.
High-grade B-cell lymphoma, also known as “double-hit lymphoma” (DHL) is an aggressive type of B-cell lymphoma characterized by rearrangements (parts of genes switch places within chromosomes) in two particular genes: one rearrangement involves the MYC gene, and the other involves the BCL2 gene. The microenvironment of these tumors is typically depleted of immune cells. These tumors have a very poor prognosis and are mostly refractory to chemotherapy. Because of this, it is of paramount importance to develop improved therapies for DHL, and we believe that the best route to achieve this is through understanding how this disease works so we can kill these tumors cells.
Many DHLs contain a mutation in a gene called EZH2. The EZH2 inhibitor tazemetostat is FDA-approved and already in use in follicular lymphoma, a specific type of B-cell lymphoma. Inhibition of EZH2 affects both the lymphoma cells and patients’ immune system. Our laboratory studies identified the specific ways in which EZH2 inhibitor modify the malignant B-cells as well as the immune system in ways that will enhance the immune system. For this proposal, we designed studies to build on our existing knowledge.
Herein, we will define the precise set of mechanisms through which DHL cells grow and survive. We predict that EZH2 inhibitors will have a double function of allowing tumor cell killing by chemotherapy and restoring normal T-cell function to attack and kill malignant B-cells, and this killing effect will be further enhanced through use of drugs that suppress any residual survival capacity of the DHL cells. We expect these aggressive tumors to respond to the combined R-CHOP (first-line chemotherapy for B-cell lymphomas) with anti-EZH2 and other mechanism-based therapies and therefore improve outcomes of DHL patients.