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Developing mechanism-based strategies to treat chemotherapy-induced peripheral neuropathy

Award Number: R37CA267905
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/13/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Developing mechanism-based strategies to treat chemotherapy-induced peripheral neuropathy - Project Summary/Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a common, frequently dose-limiting side-effect of chemotherapeutic drugs. CIPN can be excruciatingly painful, profoundly debilitating, cause permanent disability, and lead some patients to elect to end life-saving treatment. In contrast to other side effects, CIPN frequently lasts well beyond the duration of treatment and can cause permanent disability. Consequently, therapies are urgently needed as they would not only enhance the quality of life of cancer patients both during and after treatment, but also improve cancer therapy by permitting effective chemotherapeutic dosing. To address this need we have developed mechanism-based interventional strategies for CIPN. Chemotherapy-induced neuropathies are characterized by axonal degeneration, which leads to the unpleasant symptoms of neuropathies. We have shown that vincristine and bortezomib, two widely used chemotherapeutic agents with different mechanisms of action act via the neuronal protein SARM1, the central executioner of a genetically encoded axon degeneration program. Activated SARM1 cleaves the metabolic cofactor NAD+, leading to local NAD+ depletion, followed by metabolic collapse and axon fragmentation. We here present several new strategies to block this final common pathway to axon degeneration. We generated a SARM1 dominant/negative that potently inhibits SARM1 function and axon degeneration. We will utilize adeno- associated virus (AAV) -mediated expression of a SARM1 dominant-negative to block SARM1 activity and will assess the effect of SARM1-dominant/negative on axon degeneration, neuroinflammation and functional outcomes. We have shown in vitro that boosting the synthesis of NAD+ strongly protects against vincristine and bortezomib-induced axon degeneration. We will use virus-mediated expression of enzymes of the NAD+ salvage pathway to boost NAD+ synthesis, which counters the axon destructive effects of SARM1. As a further step to translation to the clinic, we will evaluate in mouse models of cancer whether our therapeutic strategies interact with the cancer or chemotherapy and are effective in cancer-bearing mice. Success of our experiments will lead directly to clinically viable means to prevent and treat CIPN.


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 = $377,467 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	5	3/3/2026	NON-COMPETING CONTINUATION	$377,467
														Subtotal = $377,467

Issue Date FY: 2025 ( Subtotal = $419,407 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	4	2/12/2025	NON-COMPETING CONTINUATION	$377,467
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	001	4	5/22/2025	NON-COMPETING CONTINUATION	$41,940
														Subtotal = $419,407

Issue Date FY: 2024 ( Subtotal = $396,506 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Treatment Research	000	3	12/22/2023	NON-COMPETING CONTINUATION	$375,638
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Treatment Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$20,868
														Subtotal = $396,506

Issue Date FY: 2023 ( Subtotal = $411,659 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	2	1/30/2023	NON-COMPETING CONTINUATION	$411,659
2023	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	001	1	3/6/2023	NEW	$0
														Subtotal = $411,659

Issue Date FY: 2022 ( Subtotal = $419,474 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	1	1/13/2022	NEW	$419,474
														Subtotal = $419,474

Grand Total All Awards = $2,024,513

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Developing mechanism-based strategies to treat chemotherapy-induced peripheral neuropathy

Award Number: R37CA267905

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/13/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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