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了解迅速增长，但对导致细胞周期突然停滞、细胞死亡和癌基因急剧失活后肿瘤退化的潜在机制知之甚少。这项申请试图解决NIH的挑衅性问题#22：为什么许多癌细胞在突然失去由癌基因编码的蛋白质时会死亡？我们认为，在不同的组织类型中，不同癌基因的急性失活会导致一种常见的“代谢灾难”。驱动癌基因的急性抑制导致肿瘤相关代谢重新编程的广泛崩溃。由此产生的肿瘤细胞的代谢状态既不能为其提供足够的能量，也不能提供足够的代谢中间产物进行合成代谢，从而导致肿瘤细胞死亡和癌症的消退。该应用的目的是寻求：1)使用创新的超极化13C-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MYC、RAS或MYC和RAS共同驱动的肝癌进行全球基因表达和代谢谱分析，以确定因急性癌基因失活而改变的代谢途径。3)我们将比较癌基因失活在不同组织类型中的代谢后果，包括乳腺癌、肺癌和肝脏肿瘤，以确定哪些癌基因调节的代谢途径在不同组织类型和致癌基因之间是共同的。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，并针对这些途径开发新的治疗方法。 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，当启动的癌基因被强烈抑制时，肿瘤为什么以及如何退化。这项应用试图通过检测不同癌基因急剧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、肺和肝肿瘤组织中测试两种典型癌基因MYC和RAS及其组合失活的效果。将采用一种创新的方法来研究肿瘤的形成和消退；包括新的成像技术以及不同肿瘤类型的遗传和代谢图谱。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.