肿瘤干细胞决定了肿瘤自我更新及异质性并诱导了治疗耐受。TAS102由类似5-FU的曲氟尿苷（TFT）和胸苷磷酸化酶抑制剂达克罗宁（TPI）组成，TFT抑制了胸苷酸合酶活性，阻碍DNA的合成。TPI有效提高了TFT的生物利用度。其对5-FU治疗耐受的转移性结肠癌患者有效。Regorafenib（瑞格菲尼）是多靶点酪氨酸激酶抑制剂。二者近年被FDA批准用于耐药性转移性结肠癌治疗。我们报道了5-FU协同瑞格菲尼有效延长了难治性晚期结肠癌患者生存期。但TAS102联合瑞格菲尼治疗策略及对肿瘤干细胞作用还未见报道。前期研究发现TAS102和瑞格菲尼具有一定联合效应且TAS102显著抑制了肿瘤干细胞的生长。本课题拟开展如下研究：1）体内外实验评估二者单独及联合使用的治疗效应；2）二者单独及联合使用对肿瘤干细胞生长的影响；3)体内外实验分析二者联合用药的分子机制；以期为进展期结肠癌治疗提供新的策略。

Cancer stem cells (CSCs) account for tumor self-renewal, plasticity and heterogeneity. As a result, they contribute to tumorigenesis, progression and tumor resistance to chemoradiotherapies. TAS-102 is an oral formulation consisting of trifluridine (TFT) and tipiracil hydrochloride (TPI) .Trifluridine, like 5-FU, is a thymidine-based nucleoside analogue, which can impede DNA synthesis and induce DNA damage. Tipiracil hydrochloride is an inhibitor of thymidine phosphorylase, which protects degradation of trifluiridine and increases its bioavailability. TAS102 is a therapeutic effect for 5-FU-resistant metastatic colon cancer. Regorafenib, a novel multitargeted tyrosine kinase inhibitor, deregulates the activities of VEGFR2 and 3, Ret, Kit, PDGFR and Raf kinases and results in the inhibition of tumor angiogenesis and cell proliferation. Both TAS102 and Regorafenib have been approved to the treatment of metastatic colorectal cancer by FDA. We have reported that 5-FU in combination with regorafenib is effective in treatment of 2 patients with refractory metastatic colon cancer. However, the therapeutic effects and mechanisms of TAS102 in combination regorafenib have not been reported in colon cancer. Our data showed that TAS102 can synergize with regorafenib against colon cancer in vitro and in vivo. TAS102 can significantly alleviate the formation of colonosphere. Consequently, the project is aim at these directions as followed: 1) The therapeutic effects of TAS102 in combination with regorafenib against colon cancer in vitro and in vivo; 2) The single and combined effects of TAS102 and regorafenib on colorectal cancer stem cells. 3) To demonstrate the underlying mechanisms of TAS102 synergy with regorafenib. Collectively, we will demonstrate the therapeutic effects and mechanisms of TAS102 in combination with regorafenib in vitro and in vivo and the study’s insight is expected to provide a novel and effective therapy strategy in treatment of refractory metastatic colon cancer.