Identification of novel therapeutic strategies for molecular subtypes of gastric cancer

点击翻译按钮获取中文摘要

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.