Molecular Pathogenesis of the Hamartoma Syndromes

错构瘤综合征的分子发病机制

• 批准号: 8413956
• 负责人: DAVID J. KWIATKOWSKI
• 金额: $ 191.15万
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413956
• 关键词: Adult; Alleles; Award; Bannayan Syndrome; Cancer cell line; Development; Dissection; Drosophila genus; Drug Delivery Systems; Endometrial Carcinoma; Event; Genes; Genetic; Genetically Engineered Mouse; Genotype; Germ-Line Mutation; Hamartoma; Human; Lead; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Mass Spectrum Analysis; Metabolic; Molecular; Multiple Hamartoma Syndrome; Mutation; Neoplasm with Perivascular Epithelioid Cell Differentiation; Neuroendocrine Tumors; PTEN gene; Pancreas; Pathogenesis; Pathology; Pathway interactions; Patient Care; Peutz-Jeghers Syndrome; Phosphorylation; Phosphotransferases; Proteomics; STK11 gene; Specimen; Stress; Syndrome; Synthetic Genes; System; TSC1 gene; TSC1/2 gene; TSC2 gene; Techniques; Testing; Therapeutic; Translating; Translational Research; Translations; Tuberous Sclerosis; Tumor Suppressor Genes; bladder Carcinoma; cancer type; gene function; mTOR Signaling Pathway; malignant breast neoplasm; metabolomics; mouse model; novel therapeutic intervention; preclinical study; tumor

DESCRIPTION (provided by applicant): The hamartoma syndromes include tuberous sclerosis (TSC), due to mutations in TSC1 orTSC2; Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, due to mutations in PTEN; and Peutz-Jeghers syndrome, due to mutations in LKB1. Genetically, these genes function in classic tumor suppressor gene fashion, with germline inactivation of a single allele, followed by second hit loss of the remaining wild type allele in the tumors that develop. Although germline mutations cause these genetic syndromes, each of these genes is also involved in the development of typical adult malignancies: TSC1 - bladder carcinoma; TSC2 - PEComas pancreatic neuroendocrine tumors, and bladder cancer; PTEN - many adult cancers, including breast, lung, and bladder cancer; and LKB1 - lung cancer and endometrial cancer. In addition, a variety of cancer studies have shown that the mTOR signaling pathway is a consistent target in the majority of cancers. During the past 4 years of this award, we have focused on dissection of the wiring of this pathway, treatment implications, and translation of the findings to the care of patients with the hamartoma syndromes. In this renewal application, we continue to dissect this pathway, but have shifted our focus to translational and therapeutic strategies for the tumors and cancers in which these genes are involved. Project 1 will dissect the wiring of the TSC1/TSC2 node in greater detail, and use advanced high-throughput techniques in Drosophila to identify phosphorylation events and synthetic lethal genetic partners, and translate the findings to mammalian systems. Project 2 will dissect effects downstream of LKB1 loss and AMPK inactivation to identify potential druggable targets, as well as explore the metabolic consequences of LKB1 loss, and translate these findings to preclinical studies In genetically-engineered mouse (GEM) models to define the genotype selectivity of energy stress targeted drugs. Project 3 will use integrated analyses of transcriptional, phosphoproteomic, and metabolic effects of loss of hamartoma genes, and synthetic lethal screens to identify l<ey targets due to loss of any of these genes in both GEM models and human cancer cell lines. All three projects will lead to development of novel therapeutic approaches and testing in GEM models. The projects are supported by Core A Administrative; Core B mass spectroscopy, proteomics and metabolomics, which is critical for the kinase and metabolomic studies to be performed; and Core C Pathology and Translational Research, which is critical for translation to human specimens and analysis of GEM pathology.

描述（由申请人提供）：错构瘤综合征包括由于 TSC1 或 TSC2 突变引起的结节性硬化症 (TSC)； Cowden 综合征和 Bannayan-Riley-Ruvalcaba 综合征，由 PTEN 突变引起；和 Peutz-Jeghers 综合征，由于 LKB1 突变。从遗传学上讲，这些基因以经典的肿瘤抑制基因方式发挥作用，单个等位基因的种系失活，随后在形成的肿瘤中剩余野生型等位基因的第二次打击丢失。尽管种系突变会导致这些遗传综合征，但这些基因中的每一个也与典型成人恶性肿瘤的发展有关：TSC1 - 膀胱癌； TSC2 - PEComas 胰腺神经内分泌肿瘤和膀胱癌； PTEN——许多成人癌症，包括乳腺癌、肺癌和膀胱癌； LKB1 - 肺癌和子宫内膜癌。此外，多种癌症研究表明，mTOR 信号通路是大多数癌症的一致靶点。在获得该奖项的过去 4 年中，我们专注于剖析该通路的连接、治疗意义以及将研究结果转化为错构瘤综合征患者的护理。在这个更新的应用中，我们继续剖析这个途径，但将我们的重点转移到涉及这些基因的肿瘤和癌症的转化和治疗策略上。项目 1 将更详细地剖析 TSC1/TSC2 节点的接线，并在果蝇中使用先进的高通量技术来识别磷酸化事件和合成致死遗传伴侣，并将这些发现转化为哺乳动物系统。项目2将剖析LKB1缺失和AMPK失活的下游影响，以确定潜在的药物靶点，并探索LKB1缺失的代谢后果，并将这些发现转化为基因工程小鼠（GEM）模型中的临床前研究，以确定能量应激靶向药物的基因型选择性。项目 3 将利用对错构瘤基因缺失的转录、磷酸化蛋白质组和代谢影响的综合分析，以及合成致死筛选来识别由于 GEM 模型和人类癌细胞系中任何这些基因缺失而导致的靶标。所有三个项目都将导致新型治疗方法的开发和 GEM 模型的测试。这些项目得到核心 A 行政支持； Core B 质谱、蛋白质组学和代谢组学，这对于要进行的激酶和代谢组学研究至关重要；核心 C 病理学和转化研究，对于人类标本的转化和 GEM 病理学分析至关重要。