This application represents a continuation of our efforts to utilize mouse models to understand the molecular mechanisms of human prostate cancer, as part of the NCI Mouse Models of Human Cancer Consortium. Our team of investigators includes long-standing members of our previous group (Drs. Cory Abate-Shen and Michael Shen), as well as new members (Drs. Andrea Califano and Carlos Cordon-Cardo) who will bring essential expertise in two key areas, systems/computational biology and systems pathology. At the heart of our program is a series of genetically-engineered mouse models of prostate cancer that have been generated and characterized to identify new biomarkers for biochemical recurrence of human prostate cancer, to characterize key signaling pathways responsible for hormone-refractory prostate cancer, and to pursue pre-clinical studies. In the current application, our objective is to use reverse-engineering of regulatory programs in mouse and human prostate cancer to develop accurate molecular interaction maps for human (human Prostate Cancer interactome, hPCi) and mouse (mPCi). We will employ innovative bioinformatics tools that will identify the """"""""drivers"""""""" that are causally responsible for tumor progression, as distinct from other discovery approaches that identify """"""""passenger"""""""" genes whose expression is simply correlated with a particular cancer phenotype. Thus, the human and mouse PCis will be interrogated using systems biology tools to elucidate key regulators of the genetic pathways that are dysregulated in cancer (Specific Aim 1) and to identify druggable targets that can affect such altered pathways (Specific Aim 2). Candidate key regulatory genes identified by these analyses will be biochemically and functionally validated for their causal role in tumorigenesis and tumor progression, and their relevance for human prostate cancer will be validated using systems pathology approaches. Finally, lead candidate druggable targets will be evaluated as potential therapeutic targets in pre-clinical trial programs, using our in vivo mouse models.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA084294-14
Application #
8306258
Study Section
Special Emphasis Panel (ZCA1-SRLB-Q (M1))
Program Officer
Marks, Cheryl L
Project Start
1999-09-30
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
14
Fiscal Year
2012
Total Cost
$753,359
Indirect Cost
$285,434
Name
Columbia University (N.Y.)
Department
Urology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Le Magnen, Clémentine; Dutta, Aditya; Abate-Shen, Cory (2016) Optimizing mouse models for precision cancer prevention. Nat Rev Cancer 16:187-96
Mitrofanova, Antonina; Aytes, Alvaro; Zou, Min et al. (2015) Predicting Drug Response in Human Prostate Cancer from Preclinical Analysis of In Vivo Mouse Models. Cell Rep 12:2060-71
Kobayashi, Takashi; Owczarek, Tomasz B; McKiernan, James M et al. (2015) Modelling bladder cancer in mice: opportunities and challenges. Nat Rev Cancer 15:42-54
Aytes, Alvaro; Mitrofanova, Antonina; Lefebvre, Celine et al. (2014) Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy. Cancer Cell 25:638-51
Wang, Jingqiang; Abate-Shen, Cory (2014) Analyses of tumor-suppressor genes in germline mouse models of cancer. Cold Spring Harb Protoc 2014:807-12
Abate-Shen, Cory; Pandolfi, Pier Paolo (2013) Effective utilization and appropriate selection of genetically engineered mouse models for translational integration of mouse and human trials. Cold Spring Harb Protoc 2013:
Aytes, Alvaro; Mitrofanova, Antonina; Kinkade, Carolyn Waugh et al. (2013) ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer. Proc Natl Acad Sci U S A 110:E3506-15
Jin, Feng; Irshad, Shazia; Yu, Wei et al. (2013) ERK and AKT signaling drive MED1 overexpression in prostate cancer in association with elevated proliferation and tumorigenicity. Mol Cancer Res 11:736-47
Shibata, Maho; Shen, Michael M (2013) The roots of cancer: stem cells and the basis for tumor heterogeneity. Bioessays 35:253-60
Irshad, Shazia; Abate-Shen, Cory (2013) Modeling prostate cancer in mice: something old, something new, something premalignant, something metastatic. Cancer Metastasis Rev 32:109-22

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