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Pharmacogenetics of Nucleobase and Nucleoside Analog Drugs

Award Number: R35GM141947
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/02/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Pharmacogenetics of Nucleobase and Nucleoside Analog Drugs - Abstract Synthetic nucleobase and nucleoside analogs (NNA) represent an important class of therapeutic agents with a variety range of indications, with 41 NNA drugs approved by the US Food and Drug Administration (FDA) for anti-cancer and/or anti-viral therapy. However, most NNA drugs are associated severe adverse effects that can be life-threatening, and there is a wide inter-patient variability in their pharmacologic effects. Therefore, there is a pressing need to understand the biological basis of the variance in NNA drug toxicity and response, to develop ways to more safely and more effectively use this important class of drugs. To address these challenges, our NIGMS-funded work in the past 5 years focused on pharmacogenetics of thiopurines, an NNA drug widely used to treat leukemia and autoimmune diseases. We discovered genetic variants in a novel drug metabolism gene NUDT15 associated with severe myelosuppression during thiopurine treatment in children with leukemia, elucidated the pharmacological mechanism by which NUDT15 modulates thiopurine cytotoxicity, systematically identified pharmacogenetic variants in NUDT15, and also led the development of clinical guides for NUDT15-guided thiopurine dosing. More recently, we have identified two anti- viral drugs, namely acyclovir and ganciclovir, as novel substrates of NUDT15, indicating that NUDT15 can promiscuously metabolize a variety of NNA drugs. In fact, NUDT15 belongs to a large class of human NUDIX enzymes that dephosphorylate native or chemically modified nucleotides. Based on these findings, I hypothesize that NUDIX enzymes (including NUDT15) are potentially important metabolizing enzymes for NNA drugs, primarily by regulating dephosphorylation of nucleotide drug metabolite. To this end, I plan to rationally expand my research program to study pharmacogenetics of NNA drugs broadly, with the overarching objectives to identify novel pharmacogenetic markers for NNA drug response and then use this information to develop approaches for genetics-guided treatment individualization. In the next funding cycle, I will pursue research in two distinctive but related directions: 1) to identify NUDT15 variants associated with ganciclovir drug inactivation and develop NUDT15 genotype-guided approaches to individualize anti-viral therapy, and 2) to broadly examine human NUDIX enzymes for their role in the activity of NNA drugs, focusing on 14 FDA-approved anti-cancer agents. Given the large number of NNA drugs used clinically and the pressing need to use NNA drugs more safely and effectively, my research program addresses a significant scientific challenge and is substantive in scope and appropriate for long-term pursuit. I am confident that sustained progress in the next funding cycle is likely with continuation of the NIGMS support.


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 = $0 )
2026	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	5	11/6/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $574,400 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	001	5	2/19/2025	NON-COMPETING CONTINUATION	$516,960
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	002	5	8/20/2025	NON-COMPETING CONTINUATION	$57,440
2025	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	4	11/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $574,400

Issue Date FY: 2024 ( Subtotal = $574,400 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	4	2/5/2024	NON-COMPETING CONTINUATION	$516,960
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	001	4	7/30/2024	NON-COMPETING CONTINUATION	$57,440
														Subtotal = $574,400

Issue Date FY: 2023 ( Subtotal = $574,400 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	3	6/9/2023	NON-COMPETING CONTINUATION	$574,400
														Subtotal = $574,400

Issue Date FY: 2022 ( Subtotal = $574,400 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	001	2	6/23/2022	NON-COMPETING CONTINUATION	$57,440
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	2	1/27/2022	NON-COMPETING CONTINUATION	$516,960
														Subtotal = $574,400

Issue Date FY: 2021 ( Subtotal = $574,400 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	1	4/2/2021	NEW	$574,400
														Subtotal = $574,400

Grand Total All Awards = $2,872,000

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Pharmacogenetics of Nucleobase and Nucleoside Analog Drugs

Award Number: R35GM141947

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/02/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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