Tumor-Specific Lymphoma Organoids for Understanding the MALT1 Pathway for Targeted Drug Therapies
Abstract
Despite advances in clinical care, many mature B cell lymphomas, or cancers of the immune system, remain incurable. The lack of treatment is in part due to the heterogeneous cancerous gene mutations in B cell lymphomas. However, it primarily is caused by the complex growth and survival signaling provided by tumor microenvironment, or the various cells, proteins, and chemical factors surrounding the tumor. A major bottleneck in the field is that the tumor microenvironment is not well understood, especially in terms of how chemical and physical signals not only exist in space and time within the tumor microenvironment but also their ensuing effect on lymphoma growth and response to therapy. This unfamiliarity is attributed to the lack of a lymphoma tumor microenvironment-mimicking models, as conventional 2D cell cultures lack the structure and protective signaling provided by the tumor microenvironment. Therefore, the long-term goal is to develop an ex vivo biomaterials-based, lymphoma subtype-specific model to understand the role of lymphoma tumor microenvironment in tumor growth and the ensuing response to therapies. Specifically, we begin by focusing on diffuse large B cell lymphoma (DLBCL), the most common form of lymphoma. Improved therapies are needed for all DLBCLs but most urgently for activated B cell (ABC)-DLBCLs, which are the most chemo-resistant (5-year overall survival ~ 30%). In particular, targeting common mutated pathways in ABC-DLBCL, such as those controlled by the transmembrane protein B cell receptor (BCR) and Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), has the potential to impact a broad cross-section of ABC-DLBCL patients. These pathways play a critical role in tumor progression, as demonstrated by the Principal Investigator?s (PI?s) mentor, Dr. Ari Melnick. However, given that the impact of targeting specific molecular pathways can only be fully evaluated within the physiological tumor microenvironment, understanding the dosing kinetics in lymphoma tumor microenvironment is critical for successful clinical translation. The PI?s laboratory recently developed the first 3D adaptable lymphoma organoids that presented lymphoma-specific survival signals to ABC-DLBCL to modulate their progression and response to cancer drugs. These observations were contradictory to conventional 2D cultures. In this proposal, the PI?s goal is to use this system to understand the role of lymphoma tumor microenvironment in driving aberrant growth promoting signals and in the therapeutic response of ABC-DLBCLs to MALT1 pathway inhibitors. Major aims include first understanding the effect of ligand presentation and tumor on the activation of BCR-MALT1-NFkappaB pathways in ABC-DLBCLs cultured in 3D lymphoma micro-organoids as compared to 2D cultures. Second, to determine the sensitivity of ABC-DLBCL to short-term and long-term exposure of MALT1 inhibitors in micro-organoids and benchmark against 2D cultures and mouse xenografts. As an Assistant Professor at Cornell University, the PI is committed to make substantial contributions to the field of lymphoma in an academic environment. His long-term goal is to understand the role of the tumor microenvironment in lymphoma and then use this understanding to create curative engineering strategies for lymphoma. Through the research plan in this proposal and under the direct mentorship of Dr. Melnick, he will develop a more comprehensive mechanistic understanding of lymphomas, role of complementary pathways, epigenetics, and other skills pertaining to DLBCL. Mechanisms from the proposed research will increase the ?predictive power? of preclinical MALT1 inhibitors within the duration of this project, provide potential biomarkers for correlative studies in MALT1 inhibitor clinical trial over the next 5 years, and provide clues towards mechanisms that might induce resistance to MALT1 inhibitors by more faithfully representing patient biologica
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710215
Entities
People
- Ankur Singh
Organizations
- Cornell University
- United States Army