靶向调节肿瘤细胞能量代谢，开发具有选择性的抗肿瘤药物，是当前极具潜力的癌症治疗策略之一。有氧糖酵解和增强的脂肪酸合成是肿瘤细胞的重要代谢特征，它们促进肿瘤细胞的增殖、转移和免疫逃避，并赋予肿瘤细胞耐药特性。我们前期研究发现FV-429能够抑制AKT磷酸化、抑制有氧糖酵解而发挥抗肿瘤作用。进一步研究表明，FV-429还可以通过下调HIF-1α增强肿瘤细胞的化疗敏感性，且对正常组织及细胞毒性小。本项目基于肿瘤细胞异常代谢调控找寻FV-429增强化疗敏感性的关键分子事件，探讨AKT/mTOR/HIF-1α通路对FV-429调控糖酵解、脂肪酸合成及β氧化的干预作用，阐明FV-429增强肿瘤化疗敏感性的机制。本项目为FV-429多方面调控肿瘤细胞代谢网络的研究提供了新的思路，为将来临床肿瘤治疗过程中提供具有潜力的肿瘤耐药逆转剂奠定了前期药物研发基础。

Currently, targeting energy metabolism in cancer cells to develop novel anticancer drugs with selectivity is one of most potential strategies for cancer therapy. Aerobic glycolysis and increased fatty acid synthesis are important metabolic characteristics in cancer cells. They promote the proliferation, metastasis and immune escape in tumor cells, renders tumor cells capable of drug resistance. We previously reported that FV-429 can inhibit the phosphorylation of AKT, inhibit aerobic glycolysis and perform a function for preventing tumors. Further investigation found that FV-429 reverses the resistance by suppressing the HIF-1α and has low toxicity. This project is aims to looking for candidate targets of FV-429 enhancing chemotherapy sensitivity based on energy metabolism, demonstrate the intervention mechanisms of AKT/mTOR/HIF-1α pathway on glycolysis, fatty acid synthesis and fatty acid β-oxidation by FV-429. We will further elucidate the influences of energy metabolism on cell proliferation and cell cycle of cancer cells upon FV-429. On this basis, we will establish CDX and PDX transplantation tumor model in nude mice, then verify the enhancement of FV-429 on the antitumor effect of chemotherapeutic drugs in vivo by AKT/mTOR/HIF-1α pathway. This project will provide new insight for the cancer therapies targeting cancer mechanism networks of FV-429. These results provide the basis for the research of FV-429 to be a novel MDR modulator in clinical cancer therapy in future.