Genetics and Biology of Pancreatic Ductal Adenocarcinoma

描述（申请人提供）：本次更新申请的目的是a）阐明介导胰腺导管腺癌（PDAC）肿瘤维持的致癌Kras（Kras*）调节代谢途径，B）定义附带代谢依赖性，以及c）确定靶向这些过程的干预措施如何影响肿瘤免疫，以指导现有药物的临床试验设计，并确定新的治疗攻击点。我们的P01计划包括3个高度相互依赖和协作的项目和4个基本核心，其目标是通过靶向代谢漏洞结合免疫治疗来征服PDAC。项目1已经证明，PDAC中的Kras* 消失导致明显的肿瘤消退，这涉及Kras* 在代谢重编程中的关键功能。我们还鉴定了Kras*-灭绝抗性细胞（KRC），其显示出显著的适应性代谢变化（在OXPHOS和自噬中），允许在Kras* 失活后存活。因此，这些研究提供了成功靶向Kras* 体内和预测可能在临床上遇到的耐药机制的基准。因此，项目1的目标是通过识别Kras* 介导的PDAC维持所必需的代谢靶点来杀死大量Kras* 依赖性肿瘤细胞，并定义通过抑制自噬和OXPHOS生存机制消除KRC的方法。项目2已经发现PDAC依赖于溶酶体依赖的营养清除途径来实现代谢稳态和肿瘤生长，并且已经确定了激活这些过程的转录程序。项目2的目标是破译溶酶体清除如何支持PDAC生长，以及癌细胞如何摆脱对这些过程的依赖，从而为改进的治疗方法提供信息。项目2将确定溶酶体介导的再循环途径的代谢产物，确定这些产物中哪些在PDAC生长中发挥作用，并探索代谢逃逸途径，以确定与溶酶体抑制协同作用的新型治疗组合。项目3已经确定了肿瘤微环境的深刻变化，包括PDAC中Kras* 消退后显著的CD 8 T细胞浸润。项目3将定义PDAC发生、消退和复发过程中的免疫特征，并确定CD 8和CD 4细胞在PDAC消退中的因果作用，以及探索新的机会来测试检查点阻断疗法的疗效，并评估免疫抑制相关的适应性机制。此外，项目3将确定代谢靶向治疗对肿瘤免疫的直接影响，并确定将此类治疗与免疫检查点阻断治疗联合收割机相结合的有效方法。病理学、临床前治疗学、计算和管理核心的高度创新核心将使这些项目成为可能。

DESCRIPTION (provided by applicant): The goal for this renewal application is to a) elucidate oncogenic Kras (Kras*)-regulated metabolic pathways mediating pancreatic ductal adenocarcinoma (PDAC) tumor maintenance, b) define collateral metabolic dependencies, and c) establish how interventions targeting these processes influence tumor immunity, in order to guide the design of clinical trials with existing drugs and to identify new therapeutic points of attack. Our P01 program comprises 3 highly interdependent and collaborative projects and 4 essential cores with the goals of conquering PDAC through targeting metabolic vulnerabilities in conjunction with immunotherapy. Project 1 has demonstrated that Kras* extinction in PDAC leads to pronounced tumor regression that involves critical functions of Kras* in metabolic reprogramming. We have also identified Kras*-extinction resistant cells (KRCs), which show dramatic adaptive metabolic changes (in OXPHOS and autophagy) allowing survival upon Kras* inactivation. These studies thereby provide benchmarks for successfully targeting Kras* in vivo and predicting resistance mechanisms that may be encountered in the clinic. Thus, the goal of Project 1 is to kill the bulk Kras*-dependent tumor cells through identification of metabolic targets essential for Kras*-mediated PDAC maintenance and to define methods to eliminate KRC through inhibiting autophagy and OXPHOS survival mechanisms. Project 2 has discovered that PDAC is dependent on lysosome-dependent nutrient scavenging pathways for metabolic homeostasis and tumor growth, and has identified a transcriptional program that activates these processes. The goal of Project 2 is to decipher how lysosomal scavenging supports PDAC growth and how cancer cells can escape their dependence on these processes, thereby informing improved therapeutic approaches. Project 2 will identify the metabolic outputs of lysosomal mediated recycling pathways, establish which of these outputs play roles in PDAC growth, and explore metabolic escape pathways in order to identify novel therapeutic combinations synergizing with lysosomal inhibition. Project 3 has defined profound alterations in the tumor microenvironment, including a prominent CD8 T cell infiltration following Kras* extinction in PDAC. Project 3 will define the immune profiles throughout the genesis, regression and recurrence of PDAC and will determine the causal role of CD8 and CD4 cells in PDAC regression, as well as explore new opportunities to test the efficacy of checkpoint blockade therapy and assess the associated adaptive mechanisms underlying immune suppression. Furthermore, Project 3 will determine the direct impact of metabolically targeted therapy on tumor immunity and define effective methods to combine such therapies with immune checkpoint blockade therapy. Highly innovative cores for Pathology, Preclinical Therapeutics, Computation, and an Administrative Core will enable these Projects.