Targeting Unique DNA Structures to Repress Oncogenic Signaling in Lymphoma
Abstract
In this high-risk/high-reward Idea proposal, we aim to directly address the Fiscal Year 2021 (FY21) Peer Reviewed Cancer Research Program (PRCRP) Topic Area of lymphoma by providing a new perspective on the underlying biology of the most common non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma (DLBCL), and exploring an alternative therapeutic strategy. Both deployed and non-deployed military personnel potentially come into contact with carcinogenic environmental factors including infectious agents, radiation, and industrial solvents. Considering this exposure can trigger abnormal immune responses that likely leads to chronic stimulation of B-cells and an increased risk of developing lymphoma, our proposed work in DLBCL is highly relevant to current and previous Service Members. Aggressive subtypes of DLBCL make up almost half of the diagnosed cases and many of these patients fail to respond to existing chemotherapy and relapse, progress, or succumb to the lymphoma within 2 years. While not fully understood, these chemoresistant tumors frequently harbor overactive B-cell receptor signaling, which promotes tumor cell survival. Defining what drives the deregulation of this cancer-enabling pathway is critical to develop better therapies and advance the treatment of patients with refractory-prone DLBCL. We discovered a unique DNA structure forms within a regulatory region of a key B-cell receptor-associated gene. Based on our prior work with similar DNA structures, we propose this DNA structure, called the G- quadruplex or G4, acts as a genomic switch to turn gene expression on or off to control B-cell receptor signaling. Thus, directly targeting the G4 will disrupt these signals and inhibit DLBCL growth. We will test this hypothesis by first applying cutting-edge proteomic technology to identify proteins interacting with the G4 within DLBCL cells. We will validate and measure the effects of these interactions to tease out the mechanism for how the G4 regulates B-cell receptor signaling. For the second part of this study, we will investigate the ability to pharmacologically modulate G4 formation to block tumor cell proliferation and survival in DLBCL cell-based and mouse models using a drug-like molecule we recently identified in a drug-screen that stabilized the G4. Targeting the G4 offers a promising approach to shut down the activation of this potent oncogenic pathway exploited by DLBCL to increase effectiveness of current chemotherapy and response in patients with B-cell receptor-dependent tumors. In support of two FY21 PRCRP Overarching Challenges, we anticipate successful completion of this project will push the lymphoma field forward by: (1) revealing mechanistic insights into the epigenetic regulation and genetic basis behind aberrant B-cell receptor signaling and (2) positioning this G4 structure as a new target with the capability to transform cancer treatment against the lymphoma-specific pathway. As such, our research effort is responsive to the FY21 PRCRP Military Health Focus Area of mission readiness to allow Service Members a more timely return to duty by developing therapeutic agents with potential to lower the risk of refractory disease and cancer relapse to improve survival rates and quality of life for active-duty Service Members, Veterans, and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211031
Entities
People
- Samantha Kendrick
Organizations
- United States Army
- University of Arkansas for Medical Sciences