基于PDTT移植瘤的抗肿瘤血管生成靶向治疗弥漫性胃癌的研究

Diffuse-type gastric carcinoma is a highly metastatic cancer ,characterized clinically by rapid disease progression and poor prognosis, however, no admitted therapeutic regime except surgery has been established for it. Anti-angiogenesis was a potential valuable target therapy strategy for gastric cancer because of its comprehensive inhibition of tumor angiogenesis. FP3, a novel VEGF target drug has demonstrated its antitumor effect in xenograft model of gastric cancer in our previous study. The project is to establish series of diffuse-type gastric cancer tumor xenografts on nude mice which may represent the majority of diffuse-type gastric cancer patients and can be passaged stably, frozen and resuscitated. The animal models are to be treated with FP3,the therapeutic mechanism will be studied and the biomarkers for primary and secondary FP3 resistance will be screened on the basis of the efficacy. Further study will be conducted to identify the mechanism of resistance from the perspective of the tumor molecular signature, tumor stromal micro-environment and changing of tumor vessel morphology. The levels of circulating angiogenesis factors will be examined during the FP3 treatment for the sake of finding resistance related predictive circulation factors. The project will also study the efficacy of FP3 combination with chemotherapy or target therapy in the treatment of gastric cancer, in order to identify whether FP3 have synergistic effect and identify whether the mechanism was tumor vessel normalization. Meanwhile, the theraputic value of FP3 alternative combination with chemotherapy or target therapy will be assessed, which will provide a valuable information for the clinical treatment of diffuse-type gastric cancer patients.

弥漫性胃癌恶性度高而易发生转移，临床进展快而预后极差。除手术外尚无公认有效的治疗方法。抗血管生成药物因其广谱抑制肿瘤血管新生作用而成为胃癌潜在有效的靶向疗法。FP3是一类新型靶向VEGF的融合蛋白，在前期胃癌移植瘤模型研究中已证实有明确的抗肿瘤作用。本研究拟建立能代表弥漫性胃癌群体的裸鼠移植瘤模型体系，能稳定传代、冻存和复苏；用模型研究FP3治疗弥漫性胃癌的作用效果及其分子机制，筛选抗血管生成药物原发性耐药及继发性耐药的分子标记，并从肿瘤分子表达特征、肿瘤间质微环境和肿瘤血管形态改变研究耐药发生机制；检测治疗过程中循环血管生成因子的水平，筛选预测耐药的循环分子标记；研究FP3联合化疗药物及靶向药物治疗弥漫性胃癌的作用效果及其可能存在的协同效应，验证其及是否通过血管"正常化"而产生协同抗肿瘤作用；评估化疗或靶向与FP3联合应用对弥漫性胃癌的治疗作用，为临床弥漫性胃癌病人治疗方案提供重要信息。

血管生成是肿瘤多步骤发生发展过程中的八大标志之一。血管内皮生长因子(vascular endothelial growth factor，VEGF)是目前已知的唯一一个贯穿整个肿瘤生长周期的血管生长因子。FP3是一个靶向VEGF的全人源化的可溶性受体蛋白。前期研究发现FP3具有明显的体内抗血管生成作用及抑制移植瘤生长的作用。但是FP3的确切抗肿瘤血管生成作用的机制目前尚未明了。.本研究建立一系列胃癌患者新鲜肿瘤组织来源的裸鼠移植瘤模型(PDTT模型)用于为肿瘤患者筛选个体化的治疗药物和评价一个新型的抗肿瘤靶向药物，FP3; 筛选抗血管生成药物耐药的分子标记，借助PDTT模型评价FP3联合化疗药物及靶向药物治疗胃癌的作用效果及其可能存在的协同效应，验证其及是否通过血管"正常化"而产生协同抗肿瘤作用。.重要结果：本研究成功建立30例胃癌患者PDTT模型，该模型在组织形态、蛋白表达方面显示出与患者新鲜肿瘤组织高度的一致性。药物敏感性试验表明FP3均显示出对该模型的疗效，并筛选出药物相对敏感组与耐药组，发现药物敏感相关通路Hif-1α可能是耐药的关键分子。研究也发现其中筛选出化疗与FP3联合应用较单药应用具有明显疗效上的优势，可能的机制与血管正常化相关，肿瘤血管经FP3作用后显示出更为“正常”的特征。.科学意义：本研究成功建立胃癌患者PDTT模型，并用于个体化抗肿瘤治疗药物的筛选。本研究筛选出FP3的耐药标记物，为临床病人药物筛选及药物人群选择提供了重要理论依据。本研究提示化疗联合FP3抗肿瘤血管治疗优于化疗，并且和肿瘤血管正常化作用有关，为临床联合治疗提供的重要依据。