Identification of novel therapeutic strategies for molecular subtypes of gastric cancer

胃癌（GC）是继肺癌、结肠癌和肝癌之后全球第四大癌症相关死亡原因。这种疾病很容易转移到远处器官，这是患者死亡的主要原因，治疗选择非常有限。虽然局部分期与良好的5年生存率相关，但在疾病转移扩散到远处器官后，预后急剧下降。虽然胃癌的遗传景观最近被描述，但这并没有导致总体生存率的提高。开发更好的治疗方法的一个主要障碍是相对缺乏忠实地概括GC生物学的临床前模型。我们最近开发了一种完全基于体细胞电穿孔的GC基因工程小鼠模型，这使我们能够模拟这种疾病的不同非病毒相关分子亚型。由此产生的肿瘤转移到临床相关器官，如肝脏、肺或卵巢，并在分子和组织病理学水平上再现人类疾病。已确定的亚型特异性差异突出了GC的异质性，强调了多模式治疗方法的必要性。我们现在建议利用这个临床前平台，并执行基于shRNA的功能性遗传筛选，以识别分子亚型特异性脆弱性。重要的是，shRNA文库是基于抑制相同基因的匹配小分子的遗传靶标。已确定的靶点将在我们具有免疫能力的临床前小鼠模型中进行验证，以确定并优先考虑这些靶点，这些靶点也会激活肿瘤微环境中的免疫监视机制。这些靶点指向靶向治疗与免疫调节剂的合理结合，并可能为晚期疾病患者带来新的治疗理念。

Gastric cancer (GC) is the fourth leading cause of cancer-associated death worldwide after lung, colon and liver cancer. The disease readily metastasizes to distant organs, which is the main cause of patient mortality, and treatment options are very limited. While the localized stages are associated with a good 5-year survival rate, the prognosis drops dramatically after metastatic spread of the disease to distant organs. Although the genetic landscape of gastric cancer has recently been described, this has not led to an improvement in overall survival. A major impediment to the development of better therapies is the relative lack of preclinical models that faithfully recapitulate the biology of GC. We have recently developed a fully somatic electroporation-based genetically engineered mouse model of GC, which allows us to model the different non-virus associated molecular subtypes of this disease. The resulting tumors metastasize to clinically relevant organs such as the liver, the lungs or the ovaries and recapitulate the human disease on a molecular and histopathological level. Identified subtype-specific differences highlight the heterogenous nature of GC, underlining the need for a multimodal treatment approach. We now propose to leverage this preclinical platform and to perform functional shRNA based genetic screens to identify molecular subtype-specific vulnerabilities. Importantly, the shRNA library is based on genetic targets for which there are matching small molecules inhibiting the same gene. Identified hits will be validated in our immune competent preclinical mouse models to identify and prioritize such targets that also activate immune surveillance mechanisms in the tumor microenvironment. These targets point towards the rational combination of targeted therapies with immune modulating agents and may result in novel therapeutic concepts for patients with advanced disease stages.