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

详细了解常见的致癌信号通路是如何组装成更大的信号网络的，对于制定治疗策略以有效地针对癌症中的这些通路以及解释靶向治疗的临床结果至关重要。虽然主导不同类型人类癌症的受影响的癌基因和肿瘤抑制基因可能有很大的差异，但少数高度 整合的信号节点在大多数人类癌症中都会受到影响，而不受组织起源的影响。重要的是要了解这些关键信号节点是如何调节的，以及下游对肿瘤的发展、进展和治疗有什么影响。在这个项目中，我们专注于一个这样的节点，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肿瘤综合征和最常见的散发性癌症中都受到异常调节。目前， 这个小G蛋白开关唯一已知的下游靶点是哺乳动物的雷帕霉素靶点(MTOR)。这个项目的目标将使用假设驱动的方法，基于本P01头4年的研究，以及无偏见的基因组和蛋白质组筛选。这些目标旨在1)揭示TSC-RHEB信号网络中的新成分、连接和下行靶点，2)识别和表征以前未探索的针对肿瘤网络的治疗策略，3)识别用于预测和监测治疗反应的新生物标记物，以及4)作为基于发现的平台来推动该计划项目的其他临床前元素。为了实现这些目标，我们将把果蝇的高通量技术(Perrimon实验室)与哺乳动物细胞和肿瘤模型的机械表征和验证(Manning实验室)紧密结合起来。

A detailed understanding of how common oncogenic signaling pathways are assembled into larger signaling networks is essential to developing therapeutic strategies to properiy 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. Currentiy, 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, and 4) serve as a discovery-based platform to fuel the other preclinical elements of the program project. 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).