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

TSC-Rheb 信号网络的分子布线和治疗靶向

• 批准号: 9120329
• 负责人: BRENDAN D. MANNING
• 金额: $ 22.96万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120329
• 关键词: Affect; Biochemical Pathway; Bioinformatics; Cancer Etiology; Cells; Clinical; Complement; Complex; Databases; Development; Drosophila genus; Elements; Enzymes; Event; FRAP1 gene; Genetic; Genomic approach; Genomics; Global Change; Goals; Growth; Hamartoma; Human; Inherited; Laboratories; Libraries; Malignant Neoplasms; Mammalian Cell; Mammals; Measures; Metabolic; Modeling; Molecular; Monitor; Monomeric GTP-Binding Proteins; Mus; NF1 gene; Normal Cell; Nutrient; Oncogenes; Oncogenic; Orthologous Gene; Outcome; PTEN gene; Pathogenesis; Pathology; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Proteomics; Regulation; Research; Resistance; Role; STK11 gene; Signal Pathway; Signal Transduction; Sirolimus; Site; Syndrome; TSC1 gene; TSC1/2 gene; TSC2 gene; Therapeutic; Tissues; Tuberous sclerosis protein complex; Tumor Suppressor Genes; Tumor Suppressor Proteins; Validation; base; combinatorial; data integration; design; distributed data; fly; high throughput technology; inhibitor/antagonist; knock-down; member; neoplastic cell; novel; novel marker; novel therapeutics; phosphoproteomics; pre-clinical; programs; small hairpin RNA; targeted biomarker; targeted treatment; therapeutic target; treatment response; tumor; vector

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).

详细了解常见致癌信号通路如何组装成更大的信号网络，对于开发治疗策略以正确靶向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。虽然在不同类型的人类癌症中占主导地位的受影响的癌基因和肿瘤抑制因子可能差异很大，但少数高度表达的癌基因和肿瘤抑制因子可能在不同类型的人类癌症中占主导地位。 整合的信号传导节点在大多数人类癌症中受到影响，而与起源的组织无关。重要的是要了解这些关键信号节点是如何调节的，以及下游的后果是什么肿瘤的发展，进展和治疗在这个项目中，我们专注于这样的节点，涉及TSC 1-TSC 2复合物和Ras相关的小G蛋白Rheb，这是异常调节几乎所有的遗传肿瘤综合征和最常见的散发性癌症。目前， 这种小G蛋白开关的唯一已知下游靶是雷帕霉素的哺乳动物靶（mTOR）。该项目的目标将采用基于P01前4年研究的假设驱动方法，以及无偏倚的基因组和蛋白质组筛选。这些目标旨在1）揭示TSC-Rheb信号网络中的新组件、连接和下游靶点，2）识别和表征以前未探索过的治疗策略，以靶向肿瘤中的该网络，3）识别新型生物标志物来预测和监测治疗反应，以及4）作为一个基于发现的平台，为该计划项目的其他临床前元素提供动力。为了实现这些目标，我们将在果蝇（Perrimon实验室）中将高通量技术与哺乳动物细胞和肿瘤模型（Manning实验室）中的机制表征和验证紧密结合起来。