Genetics and Biology of Pancreatic Ductal Adenocarcinoma

描述(由申请人提供)：本次更新申请的目标是a)阐明致癌的Kras(Kras*)调节的代谢通路介导胰腺导管腺癌(PDAC)肿瘤维持，b)确定侧枝代谢依赖性，以及c)确定针对这些过程的干预措施如何影响肿瘤免疫，以便指导现有药物的临床试验设计和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，目标是通过结合免疫疗法靶向新陈代谢易损性来征服PDAC。项目1已经证明，PDAC中Kras*的消失会导致明显的肿瘤消退，这涉及到Kras*在代谢重编程中的关键功能。我们还鉴定了Kras*-消亡抵抗细胞(KRCs)，它们表现出戏剧性的适应性代谢变化(在OXPHOS和自噬中)，允许在Kras*失活后存活。因此，这些研究为在体内成功靶向Kras*并预测临床可能遇到的耐药机制提供了基准。因此，项目1的目标是通过鉴定Kras*介导的PDAC维持所必需的代谢靶点来杀死大量依赖Kras*的肿瘤细胞，并定义通过抑制自噬和OXPHOS生存机制来消除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，从而提供改进的治疗方法。项目2将确定溶酶体介导的循环途径的代谢输出，确定这些输出中的哪些在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的新的治疗组合。项目3定义了肿瘤微环境的深刻变化，包括在PDAC中Kras*消失后显著的CD8T细胞渗透。项目3将定义整个PDAC发生、退化和复发的免疫特征，并将确定CD8和CD4细胞在PDAC回归中的因果作用，以及探索新的机会来测试检查点阻断治疗的有效性，并评估潜在的免疫抑制相关适应机制。此外，项目3将确定代谢靶向治疗对肿瘤免疫的直接影响，并确定将这种治疗与免疫检查点阻断治疗相结合的有效方法。病理学、临床前治疗、计算和管理核心的高度创新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.