Sunday, November 24, 2024 11/24/2024

Determining the mechanisms by which calorie restriction alters macrophage polarization to promote an anti-tumor environment in epithelial ovarian cancer

Award Number: R01CA249188
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

ABSTRACT Epithelial Ovarian Cancer (EOC) is the leading cause of gynecologic cancer death in the United States, and despite the advances made in EOC therapy, the five-year survival rate has been stagnant at approximately 45% for decades. The current standard therapeutic approach is accompanied by toxic side effects, and the high cost of chemotherapy places an enormous financial burden on patients, reducing their quality of life. Thus, there is a critical need to identify low-cost approaches that can both enhance responses to current therapies and improve survival by inhibiting tumor progression. Calorie Restriction has a strong capacity to alter the responses of cancer cells and host cells in the tumor microenvironment, yet the mechanisms of such cross-talk are elusive. Our long- term goal is to identify dietary mechanisms that can be modulated to impede EOC progression and thus be translated into the development of more effective therapies and lifestyle changes for EOC patients. Our studies show that 30% calorie restriction (CR), without malnutrition, in a mouse model of EOC decreases tumor burden, ascites, and metastases. Additionally, our preliminary data strongly suggest that CR inhibits EOC due to a decrease in alternatively-activated pro-tumorigenic (M2-like) macrophages and a corresponding increase in classically-activated anti-tumor macrophages (M1-like), resulting in an increased M1/M2 ratio. This is important as 50% of cells in EOC ascites are pro-tumorigenic macrophages (M2-like) and an increased M1/M2 ratio is an indicator of better prognosis in EOC patients. Macrophage polarization is regulated, in part, through metabolic reprogramming, with M1-like macrophages mainly relying on glycolysis and M2-like macrophages primarily utilizing aerobic respiration. AMPK, a well-known regulator of energy metabolism, controls the balance between glycolysis and mitochondrial respiration and our studies demonstrate that mice fed a CR diet have increased AMPK activity. The overall objective of the proposed research is to determine the mechanism by which a CR diet regulates macrophage polarization in EOC. Our central hypothesis is that the increased activity of AMPK due to a CR diet remodels the glycolysis-tricarboxylic acid (TCA) pathway to promote an M1 (anti-tumor) phenotype, thus leading to a robust anti-tumor immune response and reduction of the tumor. This hypothesis will be tested in two aims: Aim 1 will identify the effects of increased AMPKα1 activity due to CR on the EOC progression, and Aim 2 will determine the mechanisms underlying CR-mediated macrophage polarization in EOC. The proposed study is expected to have a translational impact by elucidating how the simple approach of dietary intervention can cause metabolic regulatory changes responsible for macrophage plasticity during EOC. Ultimately, this process could be exploited to tailor novel complementary therapeutic strategies and life-style modifications to curb progression of EOC and other types of cancer.


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 = $327,056 )
2024	2024	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	5	4/29/2024	NON-COMPETING CONTINUATION	$327,056
														Subtotal = $327,056

Issue Date FY: 2023 ( Subtotal = $337,383 )
2023	2023	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	4	5/10/2023	NON-COMPETING CONTINUATION	$337,383
														Subtotal = $337,383

Issue Date FY: 2022 ( Subtotal = $337,383 )
2022	2022	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	3	4/28/2022	NON-COMPETING CONTINUATION	$337,383
														Subtotal = $337,383

Issue Date FY: 2021 ( Subtotal = $344,269 )
2021	2021	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	2	5/5/2021	NON-COMPETING CONTINUATION	$344,269
														Subtotal = $344,269

Issue Date FY: 2020 ( Subtotal = $344,269 )
2020	2020	HENRY FORD HEALTH SYSTEM	1 FORD PLACE	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	1	3/25/2020	NEW	$344,269
														Subtotal = $344,269

Grand Total All Awards = $1,690,360

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Determining the mechanisms by which calorie restriction alters macrophage polarization to promote an anti-tumor environment in epithelial ovarian cancer

Award Number: R01CA249188

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer