Molecular wiring and therapeutic targeting of the TSC-Rheb signaling network

项目总结（见说明）：详细了解常见的致癌信号通路如何组装成更大的信号网络，对于制定治疗策略以适当地靶向癌症中的这些信号通路以及解释靶向治疗的临床结果至关重要。虽然受影响的癌基因和肿瘤抑制因子在不同类型的人类癌症中占主导地位，但在大多数人类癌症中，无论起源组织如何，都有少数高度整合的信号节点受到影响。了解这些关键信号节点是如何调控的，以及肿瘤发生、进展和治疗的下游后果是很重要的。在这个项目中，我们重点研究了一个这样的节点，涉及TSC1-TSC2复合体和ras相关的小G蛋白Rheb，它在几乎所有的遗传性肿瘤综合征和最常见的散发性癌症中都是异常调节的。目前，这种小G蛋白开关的唯一已知下游靶点是雷帕霉素（mTOR）的哺乳动物靶点。该项目的目标将采用假设驱动的方法，基于P01前4年的研究，以及无偏倚的基因组和蛋白质组学筛选。这些目标旨在1)揭示TSC-Rheb信号网络中的新成分、连接和下游靶点；2)确定和表征以前未探索的治疗策略，以靶向肿瘤中的该网络；3)确定新的生物标志物，以预测和监测治疗反应；4)作为一个基于发现的平台，为该项目2和3的临床前要素提供动力。5)从生物信息学上分析和整合该计划所有项目中产生的大型跨物种数据集。为了实现这些目标，我们将紧密结合果蝇（Perrimon实验室）的高通量技术与哺乳动物细胞和肿瘤模型（Manning实验室）的机制表征和验证

PROJECT SUMMARY (See instructions): A detailed understanding of how common oncogenic signaling pathways are assembled into larger signaling networks is essential to developing therapeutic strategies to properly target these pathways in cancer and for interpreting clinical outcomes from targeted therapeutics. While the effected oncogenes and tumor suppressors that predominate different classes of human cancer can vary greatly, a small number of highly integrated signaling nodes are affected in the majority of human cancers, regardless of tissue of origin. It is important to understand how these key signaling nodes are regulated and what the downstream consequences are for tumor development, progression, and treatment. In this project, we focus on one such node, involving the TSC1-TSC2 complex and the Ras-related small G protein Rheb, which is aberrantly regulated in nearly all genetic tumor syndromes and the most common forms of sporadic cancer. Currently, the only known downstream target of this small G protein switch is the mammalian target of rapamycin (mTOR). The aims of this project will employ both hypothesis-driven approaches, based on studies from the first 4 years of this P01, and unbiased genomic and proteomic screens. The aims are designed to 1) reveal new components, connections, and dowstream targets within the TSC-Rheb signaling network, 2) identify and characterize previously unexplored therapeutic strategies to target this network in tumors, 3) identify novel biomarkers to predict and monitor therapeutic responses, 4) serve as a discovery-based platform to fuel the preclinical elements in projects 2 and 3 of this program, and 5) bioinformatically analyze and integrate the large cross-species data sets generated within all projects of the program. To achieve these goals, we will closely integrate high-throughput technologies in Drosophila (Perrimon laboratory) with mechanistic characterization and validation in mammalian cell and tumor models (Manning laboratory