Abstract P2-02-11: Combinational treatment of biguanides and fatty acid β-oxidation inhibitor in triple-negative breast cancers Free

Among breast cancers (BCs), the driver pathways and therapeutic targets are still poorly understood for triple negative (TN) BCs. Advances in cancer metabolism research over the last decade have enhanced our understanding on metabolic reprogramming in cancer therapy. We have previously shown that metabolic reprogramming to fatty acid β-oxidation (FAO) is a major energy pathway in metastatic TNBC. Moreover, we reported that FAO regulates c-Src, one of the frequently upregulated oncopathways in TNBC via autophosphorylation of Src at Y419. Since FAO inhibitors alone cannot effectively control the tumor progression in TNBC, suitable combination therapies with other metabolic targets are necessary. Recently increasing evidences show that anti-diabetic biguanides have attractive anticancer effect in various cancer types including BC. However, its significance as an anticancer drug is not well established due to parallel metabolic pathways that support tumor growth.

Phenformin, a biguanide derivative similar to metformin, has a greater potency than metformin. Like metformin, phenformin also inhibits mitochondrial electron transport chain (ETC) through complex I inhibition. In addition, biguanides lead to the activation of AMPK, which plays a key role in insulin signaling and energy sensing. Importantly, AMPK is an upstream regulator of FAO pathway because it can phosphorylate ACC to activate FAO. Considering the dependency of TNBC to FAO, we evaluated the therapeutic significance of the combination of biguanides(ETC inhibitors) and FAO inhibitors in TNBC progression and metastasis. We hypothesize that blocking both 'arms' of the pathway can provide more pronounced and durable responses in TNBCs. Our different in vitro and in vivo studies using TNBC cell line and PDX models suggest that the combination of both inhibitors can provide better therapeutic significance in metastatic TNBCs. This is a rationale and cost-effective metabolic approach to manage the currently non-targetable metastatic TNBCs. Further investigation into the clinical effectiveness of this combination may provide better treatment opportunities for TNBC patients.

Citation Format: Park JH, Jung KH, Vithayathil S, Jia D, Kaipparettu BA. Combinational treatment of biguanides and fatty acid β-oxidation inhibitor in triple-negative breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-02-11.