FUNCTIONAL GENOMIC IDENTIFICATION AND CHARACTERIZATION OF THERAPEUTIC TARGETS

胰腺导管腺癌（Pancreatic ductal adenocarcinoma， PDAC）是癌症死亡的主要原因之一，主要由Kras基因突变引起。尽管我们对PDAC发病机制的了解有所进展，但这种疾病仍然很难治疗。在本提案中，我们将采用基因组规模的方法来识别潜在的信号节点和可药物靶点，这些靶点将用于PDAC患者的治疗开发。根据我们的初步数据和技术能力，我们提出了以下具体目标。目的1)确定KRAS* PDAC联合治疗的共灭靶点。我们的目标

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death and is driven mostly by mutated Kras gene. Despite advances in our understanding of the pathogenesis of PDAC, the disease remains highly refractory to treatment. In this proposal, we will employ genome scale approaches to identify potential signaling nodes and druggable targets that will be used for therapeutics development for PDAC patients. Based on our preliminary data and technical capabilities, we proposed the following specific aims. Aim #1) To identify co-extinction targets for combination therapeutics against KRAS* PDAC. The goal of this aim is to identify candidate targets that when co-extinguished can lead to suppression or death of KRAS* PDAC tumor cells. Both genetic and pharmacological approaches will be used, taking advantage of strengths of both mouse and human systems, as well as leveraging the emerging comprehensive genomic data on human PDAC. Co-extinction target candidates identified in more than one system will be prioritized for in-depth biological, functional as well as clinical pathological validation. Aim #2) To identify resistance mechanism to KRas inhibition. The goal of this aim is to proactively anticipate and elucidate possible molecular basis for resistance in setting of Kras* inhibition. We will apply a novel in vivo context-specific genetic screen approach to identify and functionally validate genes that promote survival of PDAC cells following KRas inactivation, initially focusing on the kinases followed by genetic elements of interests defined by comprehensive genomics by ICGC PDAC project. Furthermore, we will engineer GEM models with the most promising resistant hits to validate resistance mechanism in vivo and to test new therapeutic strategy against such resistance mechanisms.