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(PQD6)The Role of Immune Homeostasis in Protection from Cancer Cachexia

Award Number: R01CA185349
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/08/2014
PERIOD OF PERFORMANCE END DATE: 08/31/2018

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(PQD6)The Role of Immune Homeostasis in Protection from Cancer Cachexia - DESCRIPTION (provided by applicant): Cachexia is the term used to describe the severe weight loss and muscle wasting seen in patients with a variety of primary disorders including cancer. Cancer cachexia is the result of active protein degradation via the ubiquitin proteasome pathway, and a decrease in protein synthesis. Despite progress in understanding the mechanisms of cachexia treatment options remain limited. We propose that successful treatment for cachexia will require a combination of strategies aimed not only at inhibiting the ongoing protein degradation and tissue destruction, but also at replacing the lost tissue by skeletal muscle regeneration. We have recently discovered a novel CD4+ T cell subset identified by their very low density of CD44 (now called precursor cells) that are depleted in mice with cancer that are cachexic. Moreover, infusion of highly purified precursor cells, but not other CD4+ T cell subsets, inhibits cachexia and cachexia-associated lymphopenia. Protection from cachexia is associated with an increase in both skeletal muscle protein and DNA suggesting that the mechanism of protection is not simply to prevent protein degradation. We propose that CD4+ precursor cells inhibit cachexia by promoting skeletal muscle regeneration. This hypothesis will be tested by i) measuring the capacity of precursor cells to induce muscle stem cell (satellite cells, SC) differentiation and muscle growth in vivo and in vitro, and by ii) testig whether SC are required for precursor cell-mediated protection from cachexia (Specific Aim 1). Using DNA expression profiling we will also test the hypothesis that pathways relevant to skeletal muscle regeneration are upregulated in muscle protected from cachexia with precursor cells compared to muscle that is cachexic (Specific Aim 2). As part of the same aim we will identify immune biomarkers specific for muscle cachexia and precursor cell-mediated protection from cachexia. As such, this study will provide novel insight into the mechanism by which the regeneration machinery responds to CD4+ precursors cells during cachexia and the overall effect of this response on activation of muscle anabolic/catabolic pathways. Importantly, CD4+ T cells that express a very low density of CD44 are present in human blood. In Specific Aim 3 we will embark on a pilot study to test the hypothesis that cancer patients with cachexia have significantly fewer CD4+ CD44v.low cells compared to cancer patients without cachexia. We will also test whether biomarkers for cachexia identified in Specific Aim 2 are also associated with cachexia in human.


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: 2019 ( Subtotal = $0 )
2019	2016	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cancer Biology Research	000	3	1/17/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $96,000 )
2017	2017	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cancer Biology Research	000	3	8/10/2017	SUPPLEMENT FOR EXPANSION	$96,000
														Subtotal = $96,000

Issue Date FY: 2016 ( Subtotal = $499,720 )
2016	2016	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cancer Biology Research	002	3	8/4/2016	SUPPLEMENT FOR EXPANSION	$104,832
2016	2016	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cancer Biology Research	001	3	7/29/2016	NON-COMPETING CONTINUATION	$325,000
2016	2016	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cancer Biology Research	000	2	3/18/2016	SUPPLEMENT FOR EXPANSION	$69,888
														Subtotal = $499,720

Issue Date FY: 2015 ( Subtotal = $325,000 )
2015	2015	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cancer Biology Research	000	2	8/5/2015	NON-COMPETING CONTINUATION	$325,000
														Subtotal = $325,000

Issue Date FY: 2014 ( Subtotal = $325,000 )
2014	2014	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cancer Biology Research	000	1	9/8/2014	NEW	$325,000
														Subtotal = $325,000

Grand Total All Awards = $1,245,720

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(PQD6)The Role of Immune Homeostasis in Protection from Cancer Cachexia

Award Number: R01CA185349

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/08/2014

PERIOD OF PERFORMANCE END DATE: 08/31/2018

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