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Unraveling the Mechanisms of Cyclin D1-Induced Replication Stress and DNA Damage Repair Dependencies in Mantle Cell Lymphoma: A Path to Novel Therapeutic Strategies for High-Risk Disease

Award Number: K08CA308863
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/06/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Unraveling the Mechanisms of Cyclin D1-Induced Replication Stress and DNA Damage Repair Dependencies in Mantle Cell Lymphoma: A Path to Novel Therapeutic Strategies for High-Risk Disease - PROJECT SUMMARY Dr. Jithma P. Abeykoon, a junior clinician-investigator at the Mayo Clinic, joined the staff in January 2024. To achieve independence as a laboratory-based clinician-investigator, he requires advanced training in molecular biology techniques related to studying DNA replication and to be proficient in the design and conduct of earlyphase clinical trials. This K08 (A1) resubmission strategically addresses these training needs through a comprehensive research and mentorship plan, thoughtfully revised to incorporate and respond to prior reviewer comments. Mantle cell lymphoma (MCL) is an aggressive, incurable subtype of non-Hodgkin lymphoma. There is an urgent need for novel therapeutic strategies, especially for patients with high-risk or relapsed disease. We have identified that Cyclin D1 (CCND1) overexpression—a hallmark of MCL—has been shown to induce replication stress (RS), leading to increased reliance on the microhomology-mediated endjoining (MMEJ) DNA repair pathway for survival (Abeykoon, JCI, 2025). This project builds on these findings and tests the central hypotheses that CCND1 overexpression perturbs DNA replication machinery, causing RS and DNA breaks at microhomology-rich regions in the genome, and that MMEJ inhibition will exert potent antitumor effects in high-risk MCL. Moreover, simultaneous inhibition of POLΘ—the primary polymerase of the MMEJ pathway—alongside targeted inhibitors of DNA double-strand break repair and RS response pathways, will result in synthetic lethality in high-risk MCL. Aim 1 will determine the mechanisms by which CCND1 overexpression induced RS perturb DNA replication and define the subsequent reliance on MMEJ-mediated DNA repair in MCL through characterizing replication fork dynamics, replisome composition, and profiling DNA damage throughout the cellular genome in MCL cells with and without POLΘ deficiency. Aim 2 will characterize RS and MMEJ activity through protein expression and multi-omic data analyses, and evaluate the therapeutic impact of MMEJ inhibition in primary high-risk MCL tumors. Through a genome-wide CRISPR-interference screen, it will also identify key molecules in DNA repair and proliferation that are synthetically lethal when co-inhibited with POLΘ. This innovative research bridges the gap between basic and translational science, with the potential to uncover novel therapeutic strategies for high-risk MCL and other CCND1-driven cancers, while supporting Dr. Abeykoon’s development as an independent clinician-scientist. Mouse xenograft models are essential to this project for evaluating the in vivo therapeutic efficacy and safety of POLΘ inhibition, both alone and in combination with DNA damage repair pathway inhibitors, in a physiologically relevant MCL system that cannot be adequately modeled in vitro. These studies are critical for establishing the preclinical rationale needed to advance POLΘ-targeted strategies into early-phase clinical trials for patients with high-risk MCL


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $324,272 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Research Manpower	000	1	8/6/2026	NEW	$324,272
														Subtotal = $324,272

Grand Total All Awards = $324,272

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Unraveling the Mechanisms of Cyclin D1-Induced Replication Stress and DNA Damage Repair Dependencies in Mantle Cell Lymphoma: A Path to Novel Therapeutic Strategies for High-Risk Disease

Award Number: K08CA308863

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/06/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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