基于大肠癌类器官培养技术的化疗敏感性与药物筛选的转化研究

Colorectal cancer (CRC) is a serious malignancy threating to people health. Chemotherapy is a basic treatment of CRC, but the response rate of current chemotherapy is low, resulting in the treatment failure of chemotherapy which is a major cause of death of CRC patients. There is no effective predicting method to evaluate the outcome of chemotherapy so far. Predictive biomarkers of chemotherapy have several limitations in clinical practice, either with low positive rate or poor accuracy; whereas drug screening based on animal models is not only time-consuming and expensive, but also heterogenetive with human tumors. The development of organoid culture technology is expected to solve the above problems. Organoid culture of CRC can be used to simulate the growth characteristics and microenvironment of tumor tissues in vivo. Moreover, it can be used to construct a drug screening platform in a short time. Our laboratory systematically studied organoid culture of CRC in predicting chemosensitivity. We proposed the study to deeply investigate organoid culture in drug screening and drug resistance genes.

大肠癌是严重威胁人民群众身体健康的恶性肿瘤。化学治疗是大肠癌最基本的治疗手段之一，但现有的化疗方案有效率较低，肿瘤耐药导致的化疗失败是进展期大肠癌病人死亡的主要原因，目前临床上缺乏预测大肠癌化疗效果的有效手段。现有的预测大肠癌化疗疗效的标志物在临床应用过程中存在很大的局限性，受到阳性率低和准确性差的制约；而应用动物成瘤模型进行的药物敏感性试验费时费力，缺乏临床应用的时效性，且与人体肿瘤存在一定的差异。类器官培养技术的发展有望解决上述问题。大肠癌的类器官培养能够模拟体内肿瘤组织的生长特点和微环境，客观地反映对肿瘤组织对药物的反应过程。更重要的是，类器官培养能够在短期内完成大肠癌细胞体外增殖和药物筛选平台的构建，及时快速地进行药物敏感性检测与药物筛选。我实验室系统地研究了大肠癌的类器官培养与化疗疗效预测，拟通过本研究深入探讨类器官培养对于大肠癌化疗疗效预测的价值并有望筛选化疗耐药基因。

结直肠癌是常见的恶性肿瘤之一，结直肠癌根治手术后复发转移是结直肠癌术后死亡的主要原因。结直肠癌手术后的辅助治疗，是防止发生局部复发和远处转移。目前临床上缺乏预测肠癌化疗效果的有效手段。本研究构建了肠癌的体外类器官培养的技术平台，利用肠癌体外类器官培养进行药物敏感性检测，评估与临床化疗疗效的相关性。我们研究表明，类器官对于化疗药物的敏感性与性别、年龄、分期及原发灶部位等无显著相关。肠癌原发灶体外类器官药敏结果可以反映体内原发灶对于化疗药物的敏感性。不同个体对于药物的敏感性呈现显著差异。同一患者不同病灶之间对于药物的反应呈现显著差异，同一患者同一转移器官中的不同灶呈现异质性。肠癌原发灶类器官药敏实验不能反映转移灶的体内药物敏感性。因此，肠癌类器官药敏平台有望成为预测临床化疗疗效的有力工具，能及时快速地进行药物敏感性检测与药物筛选。