Genetics and Biology of Pancreatic Ductal Adenocarcinoma

项目总结（见说明） 本次更新申请的目标是深入了解PI 3 K和RAS-MAPK信号传导与胰腺导管腺癌（PDAC）的合作途径，以指导突出药物开发候选药物的临床试验，并确定这些途径中的新治疗攻击点。该计划项目由基础和临床研究人员组成的多学科团队组成，他们在肿瘤生物学，小鼠遗传学，癌症代谢，PI 3 K信号传导和功能基因组学方面具有良好的合作记录和互补优势。该计划包括3个高度互动的项目（项目1：DePinho。哈恩和阿成DFCi：项目2：Cantley。BIDMC和Bardesy。MGH：项目3：杰克和货车德海登。MIT），其整合目标是确定KRAS* 合成致死基因在PDAC发展和维持中的作用、PI 3 K/MEK途径在PDAC中的共灭绝的作用和相关的耐药机制、MEK/PI 3 K抑制对PDAC代谢的影响以及抑制谷氨酰胺代谢对PDAC的作用。项目1将采用全基因组RNAi和生物信息学分析来鉴定和验证与MEKi或Pi 3 Ki协同抑制KRAS* PDAC的可药物化共灭绝靶点。此外，将进行背景特异性功能获得的体内遗传筛选，以鉴定潜在获得性抗性或与Pi 3 K/MEK信号传导起协同作用的其他可药用靶标。项目2将阐述中心假设，即KRAS* 驱动的PDAC以冗余方式利用PI 3 K和MAPK途径来驱动肿瘤生长，并且这些途径的关键作用涉及维持肿瘤代谢。项目2将确定MEKi/PiSKi对PDAC细胞信号传导、代谢和治疗反应的影响。这些努力将与MEK/Pi 3 K信号传导的代谢生物标志物的研究和治疗抗性机制的鉴定相结合，这对指导该领域未来的治疗试验至关重要。项目3将通过开发用于细胞培养和移植模型的条件性RNAi系统以及旨在允许原位肿瘤中基因的条件性缺失的复杂基因工程小鼠模型来研究一系列潜在治疗靶点在肿瘤维持中的重要性。这些项目将通过分子成像的高度创新核心来实现（Weissleder。MGH）。实验病理学（Loda/Chu. DFCl）。生物银行（Thayer. MGH）。和小鼠工程（DePinho/Homer. DFCi）：并由一个行政核心协助，提供科学和财政监督（DePinho，DFCI）。

PROJECT SUMMARY (See Instructions) : The goal for this renewal application is to gain in-(depth knowledge of PI3K and RAS-MAPK signaling with cooperating pathways governing pancreatic ductal adenocarcinoma (PDAC) to guide clinical trials with prominent drug development candidates and to identify new therapeutic points of attack in these pathways. The program project consists of a multiple-disciplinary team of basic and clinical investigators with a strong track record of working together and with complementary strengths In tumor biology, mouse genetics, cancer metabolism, PI3K signaling and functional genomics. The Program consists of 3 highly Interactive projects (Project 1: DePinho. Hahn and Chin. DFCi: Project 2: Cantley. BIDMC and Bardeesy. MGH: Project 3: Jacks and Van der Heiden. MIT) with the integrating goals of determining the roles of KRAS* synthetic lethal genes in PDAC development and maintenance, the effect of co-extinction of PI3K/MEK pathways In PDAC and associated drug resistance mechanisms, the Impact of MEK/PI3K inhibition on PDAC metabolism, and the effect of inhibiting glutamine metabolism on PDAC. Project 1 will employ whole genome RNAi and bioinformatics analyses to identify and validate druggable coextinction targets that synergize with MEKi or Pi3Ki in suppressing KRAS* PDACs. In addition, context specific gain of function in vivo genetic screens Will be performed to identify additional druggable targets underlying acquired resistance or playing cooperative roles with Pi3K/MEK signaling. Project 2 will address the central hypothesis that KRAS*-driven PDAC utilizes the PI3K and MAPK pathways in a redundant way to drive tumor growth and that a critical role for these pathways involves the maintenance of tumor metabolism. Project 2 will determine the impact of MEKi/PiSKi on PDAC cell signaling, metabolism, and therapeutic response. These efforts will be coupled with an investigation of metabolic biomarkers for MEK/Pi3K signaling and identification of mechanisms of therapeutic resistance which would be critical in guiding future therapeutic trials In this area. Project 3 will investigate the importance of a series of potential therapeutic targets in tumor maintenance by developing both conditional RNAi systems for use in cell culture and transplant models as well as sophisticated genetically-engineered mouse models designed to allow conditional deletion of genes in autochthonous tumors. These Projects Will be enabled by highly innovative cores for Molecular Imaging (Weissleder. MGH). Experimental Pathology (Loda/Chu. DFCl). Biobank (Thayer. MGH). and Mouse Engineering (DePinho/Homer. DFCi): and assisted by an administrative core to provide scientific and fiscal oversight (DePinho, DFCl).