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: 8915507
• 负责人: BRENDAN D. MANNING
• 金额: $ 23万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915507
• 关键词: Affect; Biochemical Pathway; Bioinformatics; Biological Markers; Cancer Etiology; Cells; Clinical; Complement; Complex; Databases; Development; Drosophila genus; Elements; Enzymes; Event; Genetic; Genomic approach; Genomics; Global Change; Goals; Growth Factor; 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; mTOR protein; member; neoplastic cell; novel; novel therapeutics; pre-clinical; programs; response; small hairpin RNA; therapeutic target; 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。虽然在不同类别的人类癌症中占主导地位的受影响的癌基因和肿瘤抑制基因可能差异很大，但少数高度 无论组织来源如何，大多数人类癌症的整合信号传导节点都会受到影响。重要的是要了解这些关键信号转导节点是如何调节的，以及下游对肿瘤发生、进展和治疗的影响是什么。在这个项目中，我们重点关注这样一个节点，涉及 TSC1-TSC2 复合物和 Ras 相关的小 G Rheb 蛋白，在几乎所有遗传性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， 这种小 G 蛋白开关唯一已知的下游靶标是哺乳动物雷帕霉素靶标 (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，以及公正的基因组和蛋白质组筛选。目的旨在 1) 揭示 TSC-Rheb 信号网络中的新成分、连接和下游靶标，2) 识别和表征以前未探索的针对肿瘤中该网络的治疗策略，3) 识别新的生物标志物来预测和监测治疗回应，4) 作为一个基于发现的平台，为该计划项目的其他临床前要素提供动力。为了实现这些目标，我们将果蝇（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）的机制表征和验证紧密结合。