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A Next-Generation Nucleoside Prodrug for Diffuse Large B-Cell Lymphoma

Award Number: R01CA279364
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/18/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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A Next-Generation Nucleoside Prodrug for Diffuse Large B-Cell Lymphoma - Project summary Diffuse large B cell lymphoma (DLBCL), a non-Hodgkin’s lymphoma, is the most common hematologic malignancy in the United States, and occurs in both adults and children. Approximately 40% of adult DLBCL patients relapse or are refractory to current frontline therapy. This highlights an urgent need for new therapeutic options in DLBCL. Many DLBCL cell lines are highly sensitive to compounds that cause replicative stress and/or inhibit the DNA damage response (DDR). Thus, we chose to develop a novel nucleoside analog as a pre-clinical DLBCL therapeutic since this compound class typically induces replicative stress and are highly active in hematological cancers. Nucleoside analogs are the most widely successful drug-class and have been approved for treating hematological cancers, among other indications. Using phenotypical chemical biology combined with a high-throughput multiplexed 930 cancer cell line screen, we identified 4’-ethynyl-deoxycytidine (EdC) as a highly effective and unique pre-clinical therapeutic for DLBCL. EdC exhibits nanomolar potency in DLBCL (GCB and ABC subtypes) harboring alterations in epigenetic factors (KMT2D, EZH2), BCL2 and/or MYC and regresses DLBCL tumors in mice within 3-5 days without weight loss or toxicity. In contrast to traditional nucleoside analogs, EdC uniquely acts as a monophosphate and induces replicative stress by inhibiting de novo dCTP synthesis. To further characterize and develop EdC as a unique and highly promising pre-clinical therapeutic for DLBCL, we plan to develop the following Aims: 1. Elucidate the mechanism of action of EdC; 2. Characterize biomarkers for DLBCL sensitivity to EdC; 3. Investigate the efficacy of EdC on DLBCL in vivo. This proposal is expected to further elucidate the mechanisms, biomarkers, and in vivo efficacy of EdC as a new pre-clinical candidate for DLBCL.


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: 2025 ( Subtotal = $623,596 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	001	2	5/29/2025	NON-COMPETING CONTINUATION	$62,358
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	000	2	11/8/2024	NON-COMPETING CONTINUATION	$561,238
														Subtotal = $623,596

Issue Date FY: 2024 ( Subtotal = $623,596 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	000	1	12/18/2023	NEW	$623,596
														Subtotal = $623,596

Grand Total All Awards = $1,247,192

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A Next-Generation Nucleoside Prodrug for Diffuse Large B-Cell Lymphoma

Award Number: R01CA279364

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/18/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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