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A novel metabolic reprograming strategy for the treatment of diabetes-associated breast cancer

Award Number: SC1GM135050
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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A novel metabolic reprograming strategy for the treatment of diabetes-associated breast cancer - PROJECT SUMMARY/ABSTRACT Diabetes increases the risk of breast cancer (BC) in women and mortality in patients with cancer. African- American (AA) women are disproportionately affected by diabetes and its complications. Concurrently, these women have worst outcome from BC. In addition, many women gain weight after BC treatment and end up with diabetes. AA and Hispanic/Latina women are even more affected by this. There exist some important distinctions between the BC patients with and without diabetes in the regimen selection and outcomes of cancer therapy. Currently there are no specific treatments to target diabetes-associated BC. Our long-term goals are to understand the fundamental mechanisms of diabetes-induced BC progression, and to develop personalized treatments for diabetes-associated BC. Based on the metabolic differences between normal and cancer cells, we for the first time propose this safe and effective therapeutic strategy targeting cancer metabolism to “poison” BC cells, with relatively non-toxicity to normal cells. The present project focuses on targeting lactate metabolism and transport to induce BC cell death. The central hypothesis of this strategy is that pharmaceutical induction of glucose import and glycolysis to even higher levels while blocking the products of glycolysis from entering the tricarboxylic acid (TCA) cycle, results in production of high amounts of lactate. Meanwhile, blocking the export of excessive lactate by inhibiting monocarboxylate transporter 4 (MCT4) leads to a metabolic crisis and acidification within the cancer cells, causing their death. Our preliminary in vitro results indicate that this metabolic reprogramming strategy (MRS) can successfully block cancer cells proliferation. Moreover, we have identified CB-2 as a novel small molecule MCT4 inhibitor (Patent Application Number: 62/662,637). CB-2 has shown a significantly inhibitory effect on lactate secretion and striking cytotoxic activity against triple-negative breast cancer (TNBC) cells, which have a high glycolytic rate/MCT4 expression. Guided by strong preliminary data, we propose to pursue three Specific Aims to test this hypothesis: (1) To investigate the effect of MRS on energy metabolic pathways of different BC cell lines and the possible reasons for sensitivity or resistance to this approach. (2) To confirm the mechanism of action and anticancer activity of CB-2. (3) To test the effectiveness, safety, and potential side effects of this MRS in diabetic mouse models bearing human BC xenografts. Collectively, these studies will allow us to gain a more in-depth understanding of cancer cell metabolism and may in the long term reveal an effective therapeutic strategy for diabetes-associated BC and TNBCs. The complex biology that contributes to the unequal cancer burdens needs to be investigated to increase our basic understanding of cancer health disparities. Hence, investigating glucose metabolism features in tumor cells would be a significant step in shedding light on this health disparity. Moreover, searching new drug targets and developing new treatment methods in diabetes-associated BC contribute to decreasing cancer health disparities.


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 = $0 )
2024	2023	CHARLES R. DREW UNIVERSITY OF MEDICINE AND SCIENCE	1731 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Biomedical Research and Research Training	000	8	9/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $358,750 )
2023	2023	CHARLES R. DREW UNIVERSITY OF MEDICINE AND SCIENCE	1731 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Biomedical Research and Research Training	000	8	4/26/2023	NON-COMPETING CONTINUATION	$358,750
														Subtotal = $358,750

Issue Date FY: 2022 ( Subtotal = $358,750 )
2022	2022	CHARLES R. DREW UNIVERSITY OF MEDICINE AND SCIENCE	1731 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Biomedical Research and Research Training	000	7	4/28/2022	NON-COMPETING CONTINUATION	$358,750
														Subtotal = $358,750

Issue Date FY: 2021 ( Subtotal = $358,750 )
2021	2021	CHARLES R. DREW UNIVERSITY OF MEDICINE AND SCIENCE	1731 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Biomedical Research and Research Training	000	6	5/24/2021	NON-COMPETING CONTINUATION	$358,750
														Subtotal = $358,750

Issue Date FY: 2020 ( Subtotal = $358,750 )
2020	2020	CHARLES R. DREW UNIVERSITY OF MEDICINE AND SCIENCE	1731 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Biomedical Research and Research Training	000	5	5/21/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$358,750
														Subtotal = $358,750

Grand Total All Awards = $1,435,000

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A novel metabolic reprograming strategy for the treatment of diabetes-associated breast cancer

Award Number: SC1GM135050

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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