ERBB信号通路靶向抑制剂在胆囊癌个性化治疗中的探索研究

Gallbladder cancer (GBC) is the most common malignancy of the biliary tract. Its relatively low incidence and confounding symptomatology result in advanced disease at the time presentation, contributing to the poor prognosis and decreased survival associated with this disease. GBC is insensitive to the chemotherapy, and there is no available targeted therapy strategy for GBC. Our previous study revealed that 37% of GBC patients carried somatic mutation in ERBB signalling pathway. A dozen of medicines targeting ERBB family and their downstream pathways have achieved significantly success in lung cancer, breast cancer and colorectal cancers. This intrigues us an important question whether those ERBB signalling inhibitor would be effective in GBC therapy. Our study plans to screen and evaluate the sensitivity of 26 ERBB signalling pathway inhibitors (approved or under investigation for other type of caners) in GBC by utilizing the patient-derived cell models and xenograft mouse models. This study will provide evidence and insights to the targeted therapy in GBCs, which will hopefully improve treatment outcomes and affect overall survival for this highly morbid, poorly understood malignancy.

胆囊癌是胆道系统最常见的恶性肿瘤，早期发现困难，一经确诊往往处于晚期，导致手术切除率低。而且放化疗效果不佳，但迄今却没有任何一个可用的靶向治疗药物。我们前期的研究发现约37%的胆囊癌患者携带有ERBB信号通路的体细胞突变，而针对ERBB信号通路的靶向治疗药物在肺癌、乳腺癌、结直肠癌等肿瘤的治疗中已经取得了显著成功。本研究以胆囊癌中找到的ERBB信号通路突变为出发点，利用直接来源于胆囊癌患者的细胞模型和裸鼠移植瘤模型为工具，研究26种已经上市或正在研发中的ERBB信号通路靶向药物在胆囊癌中的敏感性，为探索基于基因突变/表达信息的胆囊癌个性化靶向治疗提供临床前的实验和理论依据。

胆囊癌是胆道系统最常见的恶性肿瘤，早期发现困难，一经确诊往往处于晚期，导致手术切除率低。而且放化疗效果不佳，但迄今却没有任何一个可用的靶向治疗药物。我们前期的研究发现约37%的胆囊癌患者携带有ERBB信号通路的体细胞突变。本研究以胆囊癌中找到的ERBB信号通路突变为出发点，研究26种已经上市或正在研发中的ERBB信号通路靶向药物在胆囊癌中的敏感性，为探索基于基因突变/表达信息的胆囊癌个性化靶向治疗提供临床前的实验和理论依据。. 我们在细胞系中和小鼠PDX模型中发现了靶向ERBB的新药KBP5209对胆囊癌的抑制作用，并且开展了一期临床试验。我们进一步通过更大规模的外显子测序实验发现，胆囊癌ERBB2/3突变可以通过上调PDL1促进胆囊癌免疫逃逸。此外，我们培养了多个胆囊癌原代细胞系，并进行了测序实验，发现了更多的潜在治疗靶点。. 我们的研究为胆囊癌的靶向治疗和免疫治疗提供了重要的理论基础，对于提高胆囊癌的诊疗水平具有非常重要的意义。