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

项目1 -摘要 虽然mTORC 1在大多数人类癌症中以不依赖生长因子的方式被激活， 有助于肿瘤的不受控制的合成代谢生长，mTOR抑制剂如雷帕霉素及其类似物 （雷帕霉素类似物）作为抗肿瘤剂的临床成功有限。此外，即使在 肿瘤对雷帕霉素类似物反应良好，例如遗传性肿瘤综合征结节性硬化症 (TSC)，其影响是可逆的，停止治疗后肿瘤会迅速再生。这种有限的反应是 至少部分是由于雷帕霉素类似物的严格的细胞抑制性质。为了确定治疗策略， 在肿瘤综合征和散发性癌症中改善mTOR抑制剂，我们必须系统地定义 对细胞和肿瘤固有的mTOR抑制剂的分子应答。因此，在这个项目中，我们使用 假设驱动和公正的组学方法，以揭示网络范围的性质和后果 转录（Aim 1）、肿瘤代谢（Aim 2）和蛋白激酶信号传导（Aim 3）的变化。 mTORC 1激活和抑制。我们的方法结合了果蝇中的联合收割机简化细胞和组织模型， 其中mTOR信号网络非常保守，同基因小鼠肿瘤模型部分驱动 不受控制的mTORC 1信号。在本P01的更广泛背景下，本项目以发现为基础， 该计划的总体目标是定义和定位连接 错构瘤综合征肿瘤抑制因子和mTORC 1，影响遗传肿瘤综合征和 大多数散发性癌症。通过我们的项目揭示的新的候选目标和机制服务于 作为所有三个项目的关键集成点。

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.