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A Novel Glucose Metabolic Reprogramming Strategy in Treating Diabetes-associated TNBC

Award Number: R16CA317929
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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A Novel Glucose Metabolic Reprogramming Strategy in Treating Diabetes-associated TNBC - Project Summary The triple-negative breast cancer (TNBC) subgroup is the most aggressive, metastatic, and refractory because of the absence of the three characteristic receptors: Estrogen (ER), progesterone (PR), and human epidermal growth factor (Her2/neu). Diabetes is a growing public health problem directly related to the risk of breast cancer (BC) occurrence and worsened BC prognosis. Cancer cells import massive amounts of glucose, funneled through the overactive glycolysis metabolic pathway. Increased glycolytic flux in cancer cells produces high amounts of lactate. The increased intracellular lactate challenges the mechanisms to maintain intracellular pH (pHi) homeostasis. To overcome low pHi due to increased lactate, cancer cells remove lactate by monocarboxylate transporters (MCTs). Our recent results have shown that miR-206 potently inhibits both mRNA and protein expression of MCT4, suggesting it is a potential therapeutic approach for diabetes-associated BC. Our preliminary data showed: 1. MicroRNA profile in BC cells under high glucose (HG) conditions. 2. miR-206 directly targets and negatively regulates MCT4 expression in MDA-MB231 cells, and the MCT4 expression in MDA-MB-468 cells is highest, which was derived from a black female patient with metastatic adenocarcinoma of the breast. 3. Competitive endogenous absorption of miR-206 by MALAT1. Therefore, we hypothesize a novel miR-206-directed Metabolic Reprogramming Strategy (MRS), excessive glucose uptake upregulates the MCT4 through MALAT1/miR-206, meanwhile, promoting lactate production through Oxidative phosphorylation (OXPHOS) inhibition by metformin in combination with blocking lactate export through degrading MCT4 expression by miR-206, targets hyperglycemic BC, particularly in TNBC. The reasonable combination therapy of microRNA with metformin is promising because it can rapidly inhibit tumor cell growth with minimal effect on normal cells, holding promise as an anti-breast cancer treatment. Together, this study will impact the field by providing a novel idea for therapies targeting cancer cell metabolism. In the long term, these studies may reveal an effective therapeutic strategy for diabetes-associated BC. A genetically diabetic mouse model bearing orthotopic mammary tumors is essential to this work, as it is the only system that recapitulates the systemic hyperglycemic and metabolic environment needed to evaluate the in vivo efficacy, dosing, and safety of the miR-206-directed MRS therapy — effects that cannot be captured in cell culture alone.


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 = $180,625 )
2026	2026	CHARLES R. DREW UNIVERSITY OF MEDICINE AND SCIENCE	1731 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Cancer Biology Research	000	1	9/16/2026	NEW	$180,625
														Subtotal = $180,625

Grand Total All Awards = $180,625

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A Novel Glucose Metabolic Reprogramming Strategy in Treating Diabetes-associated TNBC

Award Number: R16CA317929

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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