Project 1: Identifying new therapeutic avenues to selectively target tumors with uncontrolled mTORC1 activation

项目 1：确定新的治疗途径，选择性靶向 mTORC1 激活失控的肿瘤

• 批准号: 10715599
• 负责人: DAVID J. KWIATKOWSKI
• 金额: $ 53.08万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-24 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715599
• 关键词: Adult; Antitumor Response; Atlases; Biochemical Pathway; Cell Culture Techniques; Cell model; Cells; Clinical; Cytostatics; Data; Development; Drosophila genus; Elements; Event; FRAP1 gene; Genetic; Genetic Transcription; Goals; Growth; Growth Factor; Hamartoma; Heart; Human; Inherited; Insulin; Intestines; Kidney; Malignant Neoplasms; Mammalian Cell; Metabolic; Metabolism; Modeling; Molecular; Mus; Nature; Nutrient; PTEN gene; Pathogenesis; Physiological; Proliferating; Property; Protein Kinase; Proteomics; Pyrimidine; Research; Resistance; Role; Signal Transduction; Sirolimus; Substrate Specificity; Syndrome; TSC2 gene; Testing; Therapeutic; Tissue Model; Tissues; Tuberous Sclerosis; Tumor Suppressor Proteins; Validation; analog; antitumor agent; experimental study; fly; improved; in vivo; inhibitor; lipidomics; mTOR Inhibitor; melanoma; metabolomics; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; nucleotide metabolism; pharmacologic; phosphoproteomics; programs; response; stem cells; success; synergism; transcription factor; tumor; tumor growth; tumor metabolism; tumor microenvironment

Project 1 – Abstract While mTORC1 is activated in a growth factor-independent manner in most human cancers and is believed to contribute to the uncontrolled anabolic growth of tumors, mTOR inhibitors such as rapamycin and its analogs (rapalogs) have had limited clinical success as anti-tumor agents. Furthermore, even in settings in which tumors respond favorably to rapalogs, such as with the genetic tumor syndrome tuberous sclerosis complex (TSC), the effects are reversible, with rapid tumor regrowth upon halting treatment. This limited response is due, at least in part, to the strictly cytostatic nature of rapalogs. In order to identify therapeutic strategies to improve on mTOR inhibitors in both tumor syndromes and sporadic cancers, we must systematically define the molecular response to mTOR inhibitors inherent to cells and tumors. Thus, in this project, we use both hypothesis-driven and unbiased omics approaches to reveal the nature and consequences of network-wide changes in transcription (Aim 1), tumor metabolism (Aim 2), and protein kinase signaling (Aim 3) upon mTORC1 activation and inhibition. Our approaches combine reductionist cell and tissue models in Drosophila, where the mTOR signaling network is very well conserved, with syngeneic mouse tumor models driven in part by uncontrolled mTORC1 signaling. Within the broader context of this P01, this project is discovery-based and foundational to the overarching goal of the program to define and target the signaling network that connects the hamartoma syndrome tumor suppressors and mTORC1, impacting both genetic tumor syndromes and the majority of sporadic cancers. The novel candidate targets and mechanisms revealed through our project serve as a key point of integration for all 3 projects.

项目 1 – 摘要 虽然 mTORC1 在大多数人类癌症中以不依赖生长因子的方式被激活，并且被认为 mTOR 抑制剂（例如雷帕霉素及其类似物）会导致肿瘤不受控制的合成代谢生长 此外，即使在这样的情况下，雷帕霉素类似物（rapalogs）作为抗肿瘤药物的临床成功也有限。 肿瘤对rapalogs有良好的反应，例如遗传性肿瘤综合征结节性硬化症 (TSC)，效果是可逆的，停止治疗后肿瘤会快速再生。 至少部分是由于rapalogs的严格细胞抑制性质，以便确定治疗策略。 为了改善 mTOR 抑制剂在肿瘤综合征和散发性癌症中的作用，我们必须系统地定义 对细胞和肿瘤固有的 mTOR 抑制剂的分子反应因此，在这个项目中，我们同时使用这两种药物。 假设驱动和公正的组学方法来揭示网络范围内的本质和后果 转录（目标 1）、肿瘤代谢（目标 2）和蛋白激酶信号传导（目标 3）的变化 我们的方法结合了果蝇中的还原细胞和组织模型， 其中 mTOR 信号网络非常保守，部分由同基因小鼠肿瘤模型驱动 在这个 P01 的更广泛的背景下，这个项目是基于发现的并且 该计划的总体目标是定义和定位连接的信号网络的基础 错构瘤综合征肿瘤抑制因子和 mTORC1，影响遗传性肿瘤综合征和 我们的项目揭示的新候选靶点和机制适用于大多数散发性癌症。 作为所有 3 个项目整合的关键点。