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Identification of key tumor cell-released factors that induce cachexia

Award Number: R01AR063786
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: 07/01/2013
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Identification of key tumor cell-released factors that induce cachexia - Project summary Cancer cachexia, characterized by muscle wasting, is seen in ~60% of cancer patients and a major contributor to the morbidity and mortality associated with cancer. Consequently, cachexia is the direct cause of ~1/3 of cancer-related deaths. We must manage cachexia because preserving muscle and body mass could promote response to cancer treatment, improve patient physical condition to withstand cancer treatment, and prolong survival. However, there is no standardized assessment or established treatment for cancer cachexia due to the poor understanding of its etiology. A major difficulty in understanding cachexia is the high complexity of cancer milieu, in which many contributing factors have been proposed, but the key mediators of cachexia remain elusive. Supported by R01 AR063786, we discovered recently that diverse types of cachexia-inducing tumors release high levels of extracellular Hsp70 & Hsp90 that are associated with extracellular vesicles (EVs), which is necessary and sufficient for the development of muscle wasting in mice due to their activation of Toll-like receptor 4 (TLR4) on muscle cells that activates protein degradation pathways. In addition, elevation of serum Hsp70 & Hsp90 in tumor-bearing mice is required for the elevation of inflammatory cytokines (TNFα and IL-6) that promote muscle wasting. These data indicate that elevated circulating Hsp70 & Hsp90 are the key driving force of cancer-induced muscle wasting and systemic inflammation, thus, could be biomarkers and therapeutic targets of cancer cachexia. These findings provide an opportunity for etiology-based diagnosis and intervention of cancer cachexia. However, animal models do not always recapitulate complex events that occur in cancer cachexia in humans, it will be important moving forward to validate the importance of circulating Hsp70 & Hsp90 in human cancer cachexia. Although multiple clinical studies found that serum Hsp70 & Hsp90 levels in cancer patients increase with the development of pathological grade and clinical stage, and the increase correlates with mortality, whether elevated serum Hsp70 & Hsp90 correlate with and cause human cancer cachexia are unknown. Therefore, we propose to test the hypothesis that tumor-released extracellular Hsp70 & Hsp90 are biomarkers and therapeutic targets of human cancer cachexia. We will conduct a longitudinal patient study to determine whether elevated serum Hsp70 & Hsp90 are biomarkers of human cancer cachexia that correlate with natural history of advanced malignancies and clinical outcome. In addition, we will determine whether human cancer cell release of extracellular vesicle-associated Hsp70 & Hsp90 are causal to muscle wasting and shortened survival by studying patient-derived primary cancer cells in vitro, and mice bearing patient-derived xenografts (PDX) of cancer in vivo. Finally, we will conduct experimental therapy of cachexia in PDX-bearing mice by blocking Hsp70 & Hsp90 release using a pharmacological strategy.


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 = $525,565 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	10	6/11/2024	NON-COMPETING CONTINUATION	$37,928
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	3/15/2024	NON-COMPETING CONTINUATION	$487,637
														Subtotal = $525,565

Issue Date FY: 2023 ( Subtotal = $545,250 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	3/15/2023	NON-COMPETING CONTINUATION	$545,250
														Subtotal = $545,250

Issue Date FY: 2022 ( Subtotal = $536,401 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	3/31/2022	NON-COMPETING CONTINUATION	$487,634
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	8	5/26/2022	NON-COMPETING CONTINUATION	$48,767
														Subtotal = $536,401

Issue Date FY: 2021 ( Subtotal = $525,564 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	4/1/2021	NON-COMPETING CONTINUATION	$487,636
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	7	6/22/2021	NON-COMPETING CONTINUATION	$37,928
														Subtotal = $525,564

Issue Date FY: 2020 ( Subtotal = $562,022 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	4/13/2020	COMPETING CONTINUATION	$562,022
2020	2017	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/4/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $562,022

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2017	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	5/13/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $323,000 )
2017	2017	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST STE 1006	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/30/2017	NON-COMPETING CONTINUATION	$323,000
														Subtotal = $323,000

Issue Date FY: 2016 ( Subtotal = $323,000 )
2016	2016	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	P.O. BOX 20036	HOUSTON	TX	77225	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/20/2016	EXTENSION WITH OR WITHOUT FUNDS	$323,000
														Subtotal = $323,000

Issue Date FY: 2015 ( Subtotal = $323,000 )
2015	2015	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	P.O. BOX 20036	HOUSTON	TX	77225	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/19/2015	NON-COMPETING CONTINUATION	$323,000
														Subtotal = $323,000

Issue Date FY: 2014 ( Subtotal = $323,000 )
2014	2014	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	P.O. BOX 20036	HOUSTON	TX	77225	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/26/2014	NON-COMPETING CONTINUATION	$323,000
														Subtotal = $323,000

Issue Date FY: 2013 ( Subtotal = $323,000 )
2013	2013	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	P.O. BOX 20036	HOUSTON	TX	77225	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/1/2013	NEW	$323,000
														Subtotal = $323,000

Grand Total All Awards = $4,309,802

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Identification of key tumor cell-released factors that induce cachexia

Award Number: R01AR063786

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: 07/01/2013

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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