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DEVELOPMENT OF TARGETED APPROACHES IN PREVENTION OF CANCER-CACHEXIA

Award Number: R01AR075794
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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DEVELOPMENT OF TARGETED APPROACHES IN PREVENTION OF CANCER-CACHEXIA - PROJECT SUMMARY Cancer-cachexia (CC), loss in muscle mass that cannot be fully reversed through nutritional intervention, is understudied relative to other muscle pathologies, affects up to 80% of patients and is responsible for 20-40% of cancer-related deaths. Unfortunately, therapeutic approaches to prevent CC lack efficacy. We recently demonstrated muscle metabolic health, specifically degeneration and dysfunction of the mitochondrial network, is compromised well before muscle loss in Lewis Lung Carcinoma-induced (LLC) CC. Specifically, we observed enhanced mitochondrial reactive oxygen species (ROS) emission and depressed Opa1 protein 1 wk following tumor implant with subsequent degeneration of the mitochondrial network at 2 wks, and impaired respiratory function and induction of mitophagy protein BNIP3 at 3 wks with muscle loss at 4 wks. Our preliminary evidence suggests attenuation of CC is possible by targeting mitochondrial quality (e.g., Opa1 activation, BNIP-3, mitochondrial antioxidants). These data provide novel insight to potential mechanisms that may be targeted to prevent onset of CC and highlight the need for preventive measures. The overarching goal of our laboratory and this proposal is to utilize characterization of key steps in development of CC to identify mechanisms and efficacious therapeutic approaches. However, many questions remain: 1) Does this course of events persist across models of cachexia? 2) How does the tumor-bearing state interact with chemotherapy on CC? 3) Can we specifically target pre-wasting effects to prevent CC? 4) Can we specifically deliver drugs to muscle to prevent CC? To answer these questions, we will pursue the following aims (Fig 1): Aim 1. Define development of cancer-induced muscle wasting across additional pre-clinical models and in conjunction with chemotherapy. Aim 2. Determine if nodal points identified in development of CC may be targeted to prevent or attenuate muscle wasting. Aim 3. Determine if mitochondria-targeted or muscle-specific delivery of therapeutics prevents CC.


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: 2024 ( Subtotal = $313,850 )
2024	2024	UNIVERSITY OF ARKANSAS	1125 W MAPLE ST STE 316	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/12/2024	NON-COMPETING CONTINUATION	$313,850
														Subtotal = $313,850

Issue Date FY: 2023 ( Subtotal = $325,354 )
2023	2023	UNIVERSITY OF ARKANSAS SYSTEM	1125 WEST MAPLE STE 210	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/29/2023	NON-COMPETING CONTINUATION	$325,354
														Subtotal = $325,354

Issue Date FY: 2022 ( Subtotal = $322,114 )
2022	2022	UNIVERSITY OF ARKANSAS SYSTEM	1125 WEST MAPLE STE 210	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/20/2022	NON-COMPETING CONTINUATION	$322,114
														Subtotal = $322,114

Issue Date FY: 2021 ( Subtotal = $315,621 )
2021	2021	UNIVERSITY OF ARKANSAS SYSTEM	1125 WEST MAPLE STE 210	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/25/2021	NON-COMPETING CONTINUATION	$315,621
														Subtotal = $315,621

Issue Date FY: 2020 ( Subtotal = $337,895 )
2020	2020	UNIVERSITY OF ARKANSAS SYSTEM	1125 WEST MAPLE STE 210	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/25/2020	NEW	$337,895
														Subtotal = $337,895

Grand Total All Awards = $1,614,834

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DEVELOPMENT OF TARGETED APPROACHES IN PREVENTION OF CANCER-CACHEXIA

Award Number: R01AR075794

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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