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 The tumor suppressor genes TSC1, TSC2, PTEN, and LKB1 cause several genetic tumor syndromes, and are involved in several types of cancer. This application seeks to understand the effects of loss of these genes in both the hamartoma syndromes and in cancer, and to develop targeted therapy for each gene.Public Health Relevance
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