Molecular Pathogenesis of the Hamartoma Syndromes

描述（由申请人提供）：错构瘤综合征包括结节性硬化症（TSC），由TSC1或tsc2突变引起；PTEN突变导致的考登综合征和Bannayan-Riley-Ruvalcaba综合征；和peutz - jegers综合征，这是由于LKB1突变引起的。遗传上，这些基因以典型的肿瘤抑制基因方式发挥作用，单个等位基因的种系失活，随后在发展的肿瘤中剩余的野生型等位基因的第二次打击丢失。尽管种系突变引起这些遗传综合征，但这些基因中的每一种也参与典型成人恶性肿瘤的发展：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，各种癌症研究表明，mTOR信号通路是大多数癌症的一致靶点。在过去的4年里，我们一直专注于解剖这一通路的线路，治疗意义，并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，我们继续剖析这一途径，但已经将我们的重点转移到这些基因参与的肿瘤和癌症的转化和治疗策略上。项目1将更详细地解剖TSC1/TSC2节点的连接，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伙伴，并将研究结果转化为哺乳动物系统。项目2将剖析LKB1丢失和AMPK失活对下游的影响，以确定潜在的药物靶点，并探索LKB1丢失的代谢后果，并将这些发现转化为基因工程小鼠（GEM）模型的临床前研究，以确定能量应激靶向药物的基因型选择性。项目3将对错构瘤基因缺失的转录、磷蛋白组学和代谢影响进行综合分析，并合成致死筛选，以确定GEM模型和人类癌细胞系中由于这些基因缺失而导致的关键靶点。这三个项目都将开发新的治疗方法，并在GEM模型中进行测试。这些项目由核心A行政；核心B质谱，蛋白质组学和代谢组学，这是激酶和代谢组学研究的关键；核心C病理学和转化研究，这对转化为人类标本和GEM病理学分析至关重要。

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.