化学药物治疗(化疗)是目前恶性消化道肿瘤的主要治疗手段,化疗耐药是制约肿瘤临床疗效的关键因素。大量研究显示肿瘤细胞和肿瘤干细胞的表观基因组异常改变直接参与了肿瘤化疗耐药的发生。低剂量去甲基化药物具有长期的表观修饰“记忆”效应，目前用于恶性血液系统肿瘤的治疗。本团队生物治疗病区率先注册了国际临床试验，探索低剂量去甲基化药物联合化疗治疗复发难治性实体瘤的可行性。前期基于27例化疗耐药的进展期消化道肿瘤的临床观察发现，该联合疗法可显著提高患者的疾病控制率，延长无进展生存期，提示低剂量去甲基化药物可改善/逆转消化道肿瘤化疗耐药。基于以上发现，本课题拟从体内、体外和临床角度验证低剂量去甲基化药物作为化疗增敏剂的效果，从分子、细胞、组织及整体水平阐明去甲基化药物逆转消化道肿瘤化疗耐药的关键机制，并建立优化的低剂量去甲基化药物联合化疗治疗耐药性消化道恶性肿瘤的整体治疗方案与疗效评估体系。

Chemotherapy is one of the mainstays of cancer therapy, but chemoresistance has become the largest obstacle to the success of cancer chemotherapies. The merging of laboratory and clinical data confirmed that the abnormal epigenomics of both cancer cells and cancer stem cells is the critical regulator of the malignant phenotypes of cancers including drug resistance. Low-dose demethylating drugs, which are mainly applied in hematological tumors in clinic, induced ‘‘memory’’ alterations in epigenomics of cancer. We have registered the clinical trial in the ClinicalTrials.gov database to determine the efficacy of the low-dose demethylating drug combined chemotherapy regimens in patients with chemotherapy resistant solid tumors. The clinical observations indicated that this combined antitumor therapy would promoted the disease control rate and prolonged the progression-free survival of patients with advanced chemoresistant gastrointestinal cancers, suggesting that low-dose demethylating drugs could prevent or reverse non-responsiveness to anti-cancer drugs. Therefore, we aim to confirm the efficacy of low-dose demethylating drugs as the sensitizer of chemotherapy, to illustrate the molecular mechanism of reversion of chemoresistance by demethylating drugs, and to establish and optimize the regimen and assessment system of low-dose demethylating drug combined with chemotherapy in patients with chemoresistant gastrointestinal cancers.