A detailed understanding of how common oncogenic signaling pathways are assembled into larger signaling networks is essential to developing therapeutic strategies to properly 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. Currently, 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, 4) serve as a discovery-based platform to fuel the preclinical elements in projects 2 and 3 of this program, and 5) bioinformatically analyze and integrate the large cross-species data sets generated within all projects of the program. 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

Public Health Relevance

In this project, we will define the molecular functions of a cancer-causing biochemical pathway that contributes to the development and progression of both inherited tumor syndromes and the most common forms of cancer. The research approach is geared toward identifying novel therapeutic strategies to target this pathway in tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA120964-08
Application #
8719039
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
8
Fiscal Year
2014
Total Cost
$233,240
Indirect Cost
$9,781
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Liu, Yang; Kwiatkowski, David J (2015) Combined CDKN1A/TP53 mutation in bladder cancer is a therapeutic target. Mol Cancer Ther 14:174-82
Lall, R; Ganapathy, S; Yang, M et al. (2014) Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response. Cell Death Differ 21:836-44
Menon, Suchithra; Dibble, Christian C; Talbott, George et al. (2014) Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156:771-85
Tchaicha, Jeremy H; Akbay, Esra A; Altabef, Abigail et al. (2014) Kinase domain activation of FGFR2 yields high-grade lung adenocarcinoma sensitive to a Pan-FGFR inhibitor in a mouse model of NSCLC. Cancer Res 74:4676-84
Bordoli, Mattia R; Yum, Jina; Breitkopf, Susanne B et al. (2014) A secreted tyrosine kinase acts in the extracellular environment. Cell 158:1033-44
Guo, Y; Chirieac, L R; Bueno, R et al. (2014) Tsc1-Tp53 loss induces mesothelioma in mice, and evidence for this mechanism in human mesothelioma. Oncogene 33:3151-60
Tyburczy, Magdalena E; Wang, Ji-An; Li, Shaowei et al. (2014) Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex. Hum Mol Genet 23:2023-9
González-Billalabeitia, Enrique; Seitzer, Nina; Song, Su Jung et al. (2014) Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. Cancer Discov 4:896-904
Kraus, Daniel; Yang, Qin; Kong, Dong et al. (2014) Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature 508:258-62
Yang, Ping; Cornejo, Kristine M; Sadow, Peter M et al. (2014) Renal cell carcinoma in tuberous sclerosis complex. Am J Surg Pathol 38:895-909

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