In Vivo Metabolic Catastrophe Is Induced By Acute Oncogene Inhibition (PQ #22)

描述（由申请人提供）：尽管我们对癌基因如何发出信号的理解迅速增长，但对急性失活癌基因后导致细胞周期突然停滞、细胞死亡和肿瘤消退的潜在机制知之甚少。该申请旨在解决NIH的挑衅性问题#22：为什么许多癌细胞在突然失去癌基因编码的蛋白质时死亡？我们认为，不同组织类型中不同癌基因的急性失活导致了共同的“代谢灾难”。“驱动癌基因的急性抑制导致肿瘤相关代谢重编程的广泛崩溃。所产生的肿瘤细胞的代谢状态既不能为它们提供足够的能量，也不能为它们提供代谢中间体，从而导致“代谢灾难”状态，导致肿瘤细胞死亡和癌症消退。该申请的目的是：1）使用创新的超极化13 C-丙酮酸成像来可视化与肿瘤消退相关的最早代谢事件。2)我们将对由MYC、RAS或MYC和RAS共同驱动的肝癌进行全球基因表达和代谢组学分析，以确定因急性癌基因失活而改变的代谢途径。3)我们将比较不同组织类型（包括乳腺、肺和肝肿瘤）中癌基因失活的代谢后果，以确定哪些癌基因调节的代谢途径在不同组织类型和驱动癌基因中是常见的。这些研究的首要目标是确定对肿瘤生存至关重要的代谢途径，针对这些途径可以开发新的治疗方法。 公共卫生相关性：癌症生物学中一个尚未回答的主要问题是，当起始癌基因被急性抑制时，肿瘤为什么以及如何消退。本申请试图通过检查不同致癌基因急性失活时发生的各种代谢变化来回答这个问题。我们将在乳腺、肺和肝肿瘤组织中检测失活两种典型癌基因MYC和RAS以及两者联合的效果。将采用创新方法研究肿瘤形成和消退;包括新型成像技术以及不同肿瘤类型的遗传和代谢分析。我们预计，从这些研究中获得的知识将迅速转化为针对人类癌症的新疗法的开发。

DESCRIPTION (provided by applicant): Despite our rapidly growing understanding of how oncogenes signal, relatively little is known about the underlying mechanisms that cause abrupt cell cycle arrest, cell death and tumor regression upon acutely inactivating an oncogene. This application seeks to address NIH's Provocative Question #22: Why do many cancer cells die when suddenly deprived of a protein encoded by an oncogene? We propose that acute inactivation of different oncogenes in diverse tissue types results in a common 'metabolic catastrophe.' Acute inhibition of driver oncogenes results in widespread collapse of tumor-associated metabolic reprograming. The resulting metabolic state of tumor cells can neither supply them with sufficient energy nor metabolic intermediates for anabolism resulting in a state of 'metabolic catastrophe' resulting in tumor cell death and regression of cancers. The aims of the application seek to: 1) Use innovative hyperpolarized 13C-pyruvate imaging to visualize the earliest metabolic events associate with tumor regression. 2) We will perform global gene expression and metabolomic profiling of liver cancers driven by MYC, RAS or MYC and RAS together to define metabolic pathways altered as a consequence of acute oncogene inactivation. 3) We will compare the metabolic consequences of oncogene inactivation in diverse tissue types, including breast, lung and liver tumors to define which oncogene-regulated metabolic pathways are common across different tissue types and driver oncogenes. The overarching goal of these studies is to identify metabolic pathways critical for tumor survival, against which novel therapeutics can be developed. PUBLIC HEALTH RELEVANCE: A major unanswered question in cancer biology is why and how tumors regress when the initiating oncogene is acutely inhibited. This application seeks to answer this question by examining diverse metabolic changes which occur when different oncogenes are acutely inactivated. We will test the effects of inactivating two canonical oncogenes, MYC and RAS and both combined, in breast lung and liver tumor tissues. An innovative approach to study tumor formation and regression will be employed; including novel imaging technology as well as genetic and metabolic profiling of diverse tumor types. We anticipate that knowledge gained from these studies will be rapidly translated to the development of novel therapeutics to target human cancer.