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Mechanism of chemotherapy potentiation of muscle wasting in cancer cachexia

Award Number: R01CA249896
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/02/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Mechanism of chemotherapy potentiation of muscle wasting in cancer cachexia - Summary Chemotherapy is a mainstream treatment for most cancers, despite recent progress in the development of new therapies for cancer. A well-documented long lasting toxicity of some chemotherapy agents is their capacity to cause or intensify muscle wasting and fatigue in cancer patients, which are manifestations of cachexia. Cachexia is a metabolic disorder contributing significantly to cancer-related morbidity and mortality due to systemic wasting, as well as decreasing the efficacy while increasing the toxicity of chemotherapy. Consequently, patients suffering from chemotherapy-related muscle wasting may experience difficulty adhering to or completing treatment regimens and may require delays in treatment, dose limitation, or discontinuation of therapy. Further, chemotherapy-related muscle wasting and fatigue can persist for months to years after the cessation of chemotherapy. Thus, the interplay between chemotherapy and cachexia is a significant threat to cancer patient survival and quality of life. However, the underlying mechanism of the detrimental effects of chemotherapy on skeletal muscle is poorly understood, and there is no FDA-approved treatment for this chemotherapy toxicity. The current proposal aims to address this clinical paradox by testing a novel hypothesis for the mechanism through which fluorouracil (5-FU) and cisplatin, two widely prescribed chemotherapy agents, promote cancer’s capacity to induce muscle wasting in tumor-bearing mice. Previously, supratherapeutic doses of 5-FU were shown to promote muscle dysfunction directly in cancer-free animals by causing mitochondrial dysfunction and oxidative stress but not activating the ubiquitin-proteasome pathway that mediates muscle protein loss. Given that 5-FU is used in cancer patients, it is necessary to understand whether and how 5-FU promotes muscle wasting at therapeutically relevant doses in cancer hosts. Similarly, cisplatin has been shown to cause muscle dysfunction directly in cancer-free mice at a supratherapeutic dose, but whether and how it promotes muscle wasting in cancer hosts are undefined. These knowledge gaps prevent clinical intervention of chemotherapy- associated cachexia. Based on preliminary data, the current project is designed to test the hypothesis that 5- FU and cisplatin cause or intensify muscle wasting in cancer hosts indirectly by stimulating the intrinsic capacity of cancer cells to induce muscle protein degradation at therapeutic doses, and to elucidate the underlying mechanisms of this action. Leveraging these findings, experimental therapies will be carried out by repurposing existing pharmacological agents that inhibit 5-FU and cisplatin’s capacity to stimulate cancer-induced muscle wasting. If successful, these drugs can be quickly tested in clinical settings for intervention of chemotherapy- associated muscle wasting.


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 = $429,791 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$42,978
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	5	2/13/2025	NON-COMPETING CONTINUATION	$386,813
														Subtotal = $429,791

Issue Date FY: 2024 ( Subtotal = $408,303 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$21,490
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	4	1/25/2024	NON-COMPETING CONTINUATION	$386,813
														Subtotal = $408,303

Issue Date FY: 2023 ( Subtotal = $417,286 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	3	1/26/2023	NON-COMPETING CONTINUATION	$417,286
														Subtotal = $417,286

Issue Date FY: 2022 ( Subtotal = $417,286 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	1/13/2022	NON-COMPETING CONTINUATION	$383,222
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	2	4/28/2022	NON-COMPETING CONTINUATION	$34,064
														Subtotal = $417,286

Issue Date FY: 2021 ( Subtotal = $419,512 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	3/2/2021	NEW	$419,512
														Subtotal = $419,512

Grand Total All Awards = $2,092,178

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Mechanism of chemotherapy potentiation of muscle wasting in cancer cachexia

Award Number: R01CA249896

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/02/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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