ω-3不饱和脂肪酸增强瑞戈菲尼（Regorafenib）治疗结肠癌的作用与机制研究

Regorafenib (Stivarga®), a multi-kinase inhibitor of angiogenesis and oncogenesis, was approved by FDA in 2012 for advanced colon cancer patients who are resistant to all standard therapies. However, a high-dose regorafenib (160 mg once daily) is clinically used, which could cause severe adverse effects such as hypertension and thus limit its therapeutic applications. In addition, for the patients who do not respond to regorafenib treatment, there are no other therapeutic options. Novel strategies to augment the anti-cancer effects and reduce the side effects of regorafenib would be a major advancement in colon cancer therapy. .Interestingly, we found that regorafenib is a potent inhibitor of soluble epoxide hydrolase, an enzyme mediating the hydrolysis of epoxide metabolites of polyunsaturated fatty acids (PUFAs), like epoxyeicosatrienoic acids (EETs, P450 metabolites from ω-6 PUFA) and epoxydocosapentaenoic acids (EDPs, P450 metabolites of ω-3 PUFA). Due to the inhibition of sEH, administration of regorafenib will result in an increase in circulation and tissue levels of EDPs and EETs. We found that 1) EDPs inhibit while EETs accelerate angiogenesis, tumor growth and metastasis in murine models of breast cancer and lung cancer; 2) administration of ω-3 PUFAs-rich diet lead to an increase in circulation and tissue levels of EPDs; 3)EDPs inhibit the colon cancer progression. Therefore, we hypothesis that co-administration of ω-3 PUFAs enhance the therapeutic effect of regorafenib in colon cancer, mainly due to the anti-tumor effects of the increased EDPs. To test our hypothesis, we plan to investigate the interaction of regorafenib and dietary ω-3/ω-6 PUFAs on AOM/DSS colitis-induced colon carcinogenesis, and MC38 colon cancer cell-induced primary tumor growth and metastasis in multiple murine models; we will then test the interaction of regorafenib and fat-1 transgenic mice, which have high levels of endogenous ω-3 PUFAs, on progression of colon cancer; finally we will investigate the functional roles of EETs and EDPs in the interactions of regorafenib and dietary ω-3/ω-6 PUFAs on colon cancer. By comprehensive analysis of the results mentioned-above, we will providing the better understanding in the interaction of ω-3/ω-6 PUFAs with regorafenib in carcinogenesis, progression and metastasis of colon cancer, providing novel strategy to augment the therapeutic effect and lower the drug adverse effects by a simple combined therapy in the treatment of advanced colon cancer.

瑞戈菲尼（Regorafenib）是目前晚期结肠癌患者临床用药的最后选择，副作用既多且重。瑞戈菲尼不仅是多激酶抑制剂，还是可溶性环氧水解酶抑制剂，故服用瑞戈菲尼可导致ω-3和ω-6不饱和脂肪酸（PUFAs）的环氧代谢产物EDPs和EETs增高。而我们发现：1 EDPs能抑制而EETs能促进乳腺癌和肺癌肿瘤的生成、发展和转移；2饲喂富含ω-3PUFAs饮食显著提高小鼠体内EDPs含量；3饲喂富含ω-3PUFAs饮食显著抑制小鼠结肠癌生长。故认为：ω-3PUFAs能增强瑞戈菲尼对结肠癌的治疗作用，其机制与增高体内的EDPs相关。故拟利用小鼠模型，深入研究富含ω-3/6 PUFAs饮食和内源性增高ω-3 PUFAs对瑞戈菲尼治疗结肠癌的疗效影响及机制。预期结果将阐明联合使用ω-3PUFAs和瑞戈菲尼对结肠癌的疗效及机制，为增强瑞戈菲尼治癌效果提供新思路，也为晚期结肠癌患者的化疗和食疗提供新策略。

结肠癌的发生率居胃肠道肿瘤的第三位，但致死率在所有肿瘤中排第二位。目前，药物治疗手段有限。瑞阁菲尼是晚期结肠癌病人最后一根延命稻草，如果病人对于该药没有响应，再没有其它方法可供选择。故本研究项目主要聚焦于探索结肠癌的发病机制和探索抗肿瘤治疗的新药物靶点，预期阐明结肠癌发生、发展和转移的重要致病机理，为结肠癌治疗提供新策略。研究内容主要包括两部分： 1） 代谢组学分析细胞色素P450单氧化酶代谢产物对结肠癌生长与转移的影响；2） 通过Cyp2c基因敲除及药物干预，明确细胞色素P450单氧化酶（CYP P450）代谢产物EpOME及阻滞剂对小鼠结肠癌肿瘤瘤生长与转移的影响。结果：1）细胞色素P450单氧化酶的代谢产物环氧脂肪酸，具有促进结肠肿瘤细胞增殖和转移的作用；2）细胞色素P450阻滞剂—SKF-525A和氯三苯甲咪唑，具有抗肿瘤作用。SKF-525A和氯三苯甲咪唑通过阻滞CYP P450，减少EpFA产生，从而起到抗肿瘤增殖因子、炎症因子的生成，并促进肿瘤细胞凋亡，抑制结肠癌的发生、发展。研究结果揭示了细胞色素P450单氧化酶的代谢产物对结肠癌生成、发展与转移的致病机理，明确CYP P450抑制剂—SKF-525A和氯三苯甲咪唑治疗结肠癌效果的作用，为结肠癌治疗提供新思路。