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

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA120964-06A1
Application #
8413956
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (O1))
Program Officer
Spalholz, Barbara A
Project Start
2006-04-01
Project End
2017-07-31
Budget Start
2012-09-21
Budget End
2013-07-31
Support Year
6
Fiscal Year
2012
Total Cost
$1,911,547
Indirect Cost
$263,897
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Akbay, Esra A; Koyama, Shohei; Liu, Yan et al. (2017) Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade. J Thorac Oncol 12:1268-1279
Li, Xinghui; Zhang, Zhibin; Li, Lupeng et al. (2017) Myeloid-derived cullin 3 promotes STAT3 phosphorylation by inhibiting OGT expression and protects against intestinal inflammation. J Exp Med 214:1093-1109
Housden, Benjamin E; Muhar, Matthias; Gemberling, Matthew et al. (2017) Loss-of-function genetic tools for animal models: cross-species and cross-platform differences. Nat Rev Genet 18:24-40
Lobbardi, Riadh; Pinder, Jordan; Martinez-Pastor, Barbara et al. (2017) TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia. Cancer Discov 7:1336-1353
Howell, Jessica J; Hellberg, Kristina; Turner, Marc et al. (2017) Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex. Cell Metab 25:463-471
Breitkopf, Susanne B; Taveira, Mateus De Oliveira; Yuan, Min et al. (2017) Serial-omics of P53-/-, Brca1-/- Mouse Breast Tumor and Normal Mammary Gland. Sci Rep 7:14503
Bowden, John A; Heckert, Alan; Ulmer, Candice Z et al. (2017) Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950-Metabolites in Frozen Human Plasma. J Lipid Res 58:2275-2288
Cao, Juxiang; Tyburczy, Magdalena E; Moss, Joel et al. (2017) Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation. J Clin Invest 127:349-364
Manning, Brendan D; Toker, Alex (2017) AKT/PKB Signaling: Navigating the Network. Cell 169:381-405
Lam, Hilaire C; Liu, Heng-Jia; Baglini, Christian V et al. (2017) Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells. Oncotarget 8:64714-64727

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