FUNCTIONAL GENOMIC IDENTIFICATION AND CHARACTERIZATION OF THERAPEUTIC TARGETS

胰腺导管腺癌（PDAC）是癌症死亡的主要原因之一，主要由突变的Kras基因驱动。尽管我们对PDAC的发病机制的理解有所进展，但该疾病仍然非常难治。在这项提案中，我们将采用基因组规模的方法来确定潜在的信号节点和可药物化的目标，这些目标将用于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）鉴定针对KRAS* PDAC的组合疗法的共灭绝靶标。目标 该目的的一个目的是鉴定当共熄灭时可导致KRAS* PDAC肿瘤细胞抑制或死亡的候选靶标。将使用遗传和药理学方法，利用小鼠和人类系统的优势，并利用人类PDAC的新兴综合基因组数据。在多个系统中确定的共灭绝候选靶点将优先进行深入的生物学、功能和临床病理学验证。目的#2）鉴定对KRas抑制的抗性机制。本研究的目的是前瞻性地预测和阐明Kras* 抑制背景下耐药的可能分子基础。我们将应用一种新型的体内背景特异性遗传筛选方法来识别和功能验证促进KRas失活后PDAC细胞存活的基因，首先关注激酶，然后关注ICGC PDAC项目的综合基因组学定义的感兴趣的遗传元件。此外，我们将设计具有最有希望的耐药命中的GEM模型，以验证体内耐药机制并测试针对此类耐药机制的新治疗策略。

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.