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Modulating dietary zinc to prevent cachexia and improve survival in cancer

Award Number: R01CA231239
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Modulating dietary zinc to prevent cachexia and improve survival in cancer - ABSTRACT. More than 80% of metastatic cancer patients experience a progressive and debilitating loss of muscle mass and function by a process known as cachexia. Cachectic patients suffer deterioration of diaphragm and cardiac muscles and often die prematurely due to respiratory and cardiac failure. The prognosis for these patients is further diminished by the fact that they are often too weak to tolerate standard doses of anti-cancer treatments. Our long-term goal is to identify and exploit the underlying mechanisms that drive the development of cachexia to improve treatment response, survival and quality of life in metastatic cancer patients. We recently identified a conserved mechanism of muscle wasting in mice and patients with metastatic cancers in which the metal ion transporter, called SLC39A14 (ZIP14), is upregulated in cachectic muscles (Wang et al., Nat Med, 2018). Muscle- specific loss of ZIP14 alleviates the development of cachexia in these mouse models. Zinc is an essential micronutrient that is often taken as a dietary supplement but in tumor bearing mice, excess supplementation accelerates muscle wasting. In addition to cancer-induced cachexia, we now find that certain chemotherapeutic drugs commonly used in patients (e.g. doxorubicin-cyclophosphamide and cisplatin) can also cause Zip14 upregulation in the muscles of healthy mice and that Zip14 is critical for chemotherapy-induced muscle atrophy in this context. Based on our preliminary studies, our central hypothesis is that a subset of chemotherapeutic drugs perturbs metal-ion homeostasis and promotes muscle wasting through the upregulation of Zip14 in muscle cells. Which chemotherapy agents induce Zip14, how Zip14 is induced and the role of ZIP14 in chemotherapy-induced muscle wasting remains to be explored. The proposed studies are expected to fill this gap and further our understanding of the functions of ZIP14 in cancer- and chemotherapy-induced cachexia. Based on our preliminary studies, in Aim 1, we will determine which chemotherapies promote muscle wasting through the ZIP14 axis and whether Osteopontin, a candidate protein from serum profiling, regulates chemotherapy-induced Zip14 expression in muscle cells. In Aim 2, we will develop strategies to prevent chemotherapy-induced, Zip14-dependent muscle wasting in metastatic cancer models. These studies could inform the development of new dietary intervention strategies to prevent or reverse cachexia, with the aim of prolonging survival, improving treatment response and quality of life in cancer patients with cachexia, in line with the objectives of the PQ11 and NCI.


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 = $0 )
2026	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Biology Research	001	5	11/21/2025	NON-COMPETING CONTINUATION	$0
2026	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Biology Research	000	5	10/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Biology Research	000	5	9/29/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $363,164 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Biology Research	000	5	5/17/2023	NON-COMPETING CONTINUATION	$363,164
														Subtotal = $363,164

Issue Date FY: 2022 ( Subtotal = $363,164 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Biology Research	000	4	5/10/2022	NON-COMPETING CONTINUATION	$363,164
														Subtotal = $363,164

Issue Date FY: 2021 ( Subtotal = $370,575 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Biology Research	000	3	5/12/2021	NON-COMPETING CONTINUATION	$370,575
														Subtotal = $370,575

Issue Date FY: 2020 ( Subtotal = $370,575 )
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Biology Research	000	2	5/12/2020	NON-COMPETING CONTINUATION	$370,575
														Subtotal = $370,575

Issue Date FY: 2019 ( Subtotal = $370,575 )
2019	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Biology Research	000	1	3/22/2019	NEW	$370,575
														Subtotal = $370,575

Grand Total All Awards = $1,838,053

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Modulating dietary zinc to prevent cachexia and improve survival in cancer

Award Number: R01CA231239

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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