Abstract LB-405: Identification of master regulators driving advanced prostate cancer and treatment response through the assembly of mouse and human prostate cancer interactomes
Authors: Aytes Alvaro , Mitrofanova Antonina , Lefebvre Celine , Kinkade Carolyn W. , Shen Michael M. , Califano Andrea , Abate-Shen Cory 
Published: August 2012

Identification of master regulators driving advanced prostate cancer and treatment response through the assembly of mouse and human prostate cancer interactomes. Alvaro Aytes1,4, Antonina Mitrofanova2,4, Celine Lefebvre2,4, Carolyn W. Kinkade1,4, Michael M. Shen3,4, Andrea Califano2,4, and Cory Abate-Shen1,4. 1Departments of Urology, Pathology and Cell Biology, 2Biomedical Informatics and Center for Computational Biology and Bioinformatics, 3Medicine and Genetics & Development, 4Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032 We have developed new genetically-engineered mouse models (GEM) based on inducible prostate-specific deletion of Pten alone or together with activation of oncogenic Kras. These models recapitulate all stages of prostate tumorigenesis, including metastases. We have used these GEM models to develop unbiased molecular networks of transcriptional and post-translational interactions, namely interactomes. Importantly, interactomes are predicated on the availability of large gene expression profile (GEP) datasets representative of the phenotypic variability and genetic perturbations of prostate cancer. We have generated GEPs using a collection of prostate cancer mouse models from our laboratory, as well as from the mouse modeling community. Each model has been treated with a variety of drugs against members of the AR, MAPk, Akt/mTOR, JAK/STAT, NF-KB signaling pathways and other kinase inhibitors as well as chemotherapeutic agents. In parallel, a human prostate cancer interactome has been generated using publicly available datasets. Interrogation of these interactomes represents a new paradigm for ‘human to mouse to human’ analyses. In particular, we have used these interactomes to identify molecular mechanisms and biomarkers of response to combinatorial targeting of Akt/mTOR and MAPK pathways in our metastatic prostate cancer GEM model of Kras activation and Pten loss-of-function. Molecular profiles from these tumors parallel those of human prostate cancers, having poor prognosis, concomitant activation of Akt/mTOR and MAP kinase signaling and displaying robust phosphorylation (inactivation) of FoxO3a tumor suppressor. This combined therapy profoundly reduces tumor and metastatic burden, improves survival and decreases FoxO3a phosphorylation. Computational analyses show that combination therapy in mice shifts the malignant signature toward that of normal prostate, while cross-species analyses identify a two-gene signature downstream of FoxO3a, including FOXM1 and CENP-F that is expressed in human metastatic tumors and is predictive of clinical outcome. Our findings suggest that targeting the FoxO3a regulatory network may be particularly beneficial for patients who have failed conventional chemotherapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-405. doi:1538-7445.AM2012-LB-405