Identifying Metabolic Vulnerabilities in Pancreatic Cancer

项目总结/摘要 尽管近年来在癌症治疗方面取得了进展，但胰腺癌（PDA）仍然是一种毁灭性的疾病 发病率越来越高。PDA对当前的护理标准是高度难治的，这部分是由于 重建代谢，支持在严峻的肿瘤微环境中生长。因此，阐明 对于肿瘤生长至关重要的代谢途径对于理解PDA生物学的复杂性至关重要， 以及发现新的治疗机会。然而，有新的证据表明，体外代谢 可能不能完全反映肿瘤的代谢需求。由于学习困难 在体内代谢与常规技术，功能性遗传CRISPR筛选方法， 用于确定PDA肿瘤的代谢负债，并全面定义临界代谢 原发性肿瘤生长和转移的途径。 在该提案的F99阶段，我分析了CRISPR筛选数据，以创建PDA代谢图谱。 体内的依赖性。我现在将使用这张PDA代谢依赖图来确定关键途径， 支持肿瘤生长并在原位小鼠模型中评估这些途径作为潜在治疗靶点 胰腺癌我还将确定一种支持生长的代谢途径 在体外不需要体内。CRISPR筛选的初步分析表明，血红素生物合成是 在体内需要，但在体外对PDA细胞的生长不是必需的。我设计了一系列实验 确定血红素生物合成如何支持肿瘤生长，以及这种依赖性如何被体外 培养条件 在本提案的K 00阶段，我将把重点从代谢原发肿瘤转移到转移， 免疫系统.动脉导管未闭是高度转移性的，转移是大多数癌症死亡的主要原因 患者了解原发性和转移性癌症代谢之间的差异将提供 深入了解如何治疗转移性肿瘤以及如何靶向癌细胞代谢以增加免疫力 监测循环肿瘤细胞。 这项工作将是第一次全面分析支持PDA在体内生长的途径 并将有助于确定治疗干预的候选人。这些实验也将决定 原发性和转移性肿瘤之间的代谢差异以及癌细胞代谢如何与肿瘤细胞相互作用。 宿主的免疫系统。这些数据将告知哪些代谢途径导致免疫逃避，以及是否靶向 这些途径在治疗上将导致降低的原发性肿瘤生长和转移性肿瘤负荷。

Project Summary/Abstract Despite recent advances in cancer treatment, pancreatic cancer (PDA) remains a devastating disease with increasing incidence. PDA is highly refractory to the current standards of care which is due, in part, to a rewired metabolism that supports growth in an austere tumor microenvironment. Therefore, elucidating the metabolic pathways critical for tumor growth is imperative to understanding the complexities of PDA biology as well as identifying novel therapeutic opportunities. There is emerging evidence, however, that in vitro metabolism may not be entirely reflective of the metabolic requirements of a tumor. Due to the difficulties of studying metabolism in vivo with conventional techniques, a functional genetic CRISPR screening approach was employed to determine the metabolic liabilities of PDA tumors and comprehensively define critical metabolic pathways for primary tumor growth and metastasis. In the F99 phase of the proposal, I analyzed CRISPR screening data to create a map of PDA metabolic dependencies in vivo. I will now use this map of PDA metabolic dependencies to determine critical pathways to support tumor growth and evaluate these pathways as potential therapeutic targets in orthotopic mouse models of pancreatic cancer. I will also determine the mechanism by which a metabolic pathway that supports growth in vivo is not required in vitro. Preliminary analysis of the CRISPR screen suggest that heme biosynthesis is required in vivo but is not essential to growth of PDA cells in vitro. I have designed a series of experiments to determine how heme biosynthesis supports growth in tumors and how this dependency is masked by in vitro culture conditions. In the K00 phase of this proposal, I will shift focus from the metabolism primary tumor to metastasis and the immune system. PDA is highly metastatic and metastasis is the primary cause of mortality for most cancer patients. Understanding the differences between the metabolism of primary and metastatic cancer will offer insight into how to treat metastasized tumors and how to target cancer cell metabolism to increase immune surveillance of circulating tumor cells. The proposed work will be the first comprehensive analysis of pathways that support PDA growth in vivo and will help identify candidates for therapeutic intervention. These experiments will also determine the metabolic differences between primary and metastatic tumors and how cancer cell metabolism interacts with the host’s immune system. These data will inform what metabolic pathways lead to immune evasion and if targeting these pathways therapeutically will lead to a reduced primary tumor growth and metastatic tumor burden.