The mechanistic basis of prostate cancer progression is poorly understood, and therapeutic options in these settings are limited, and only marginally effective. The present Program Project application is a multidisciplinary team effort designed to address these needs by elucidating fundamental mechanisms of prostate cancer growth (i), and credentialing novel molecular therapies for advanced disease, in vivo (ii). Our approach focuses on a prostate cancer signaling 'network'important for disease progression. This network connects three fundamental pathways of cellular homeostasis: mitochondrial control of cell survival by molecular chaperones, pleiotropic signaling by integrin adhesion receptors, and local regulation of gene expression in bone metastasis. Project 1 (Altieri) will dissect the function of mitochondria-localized Heat Shock Protein-90 (Hsp90) chaperones in survival of prostate cancer cells, Project 2 (Languino) will study the mechanism of prostate cancer progression mediated by a{v}B{6} integrin, and Project 3 (Stein and Lian) will elucidate the mechanistic requirements of Runx2-dependent gene expression in metastatic prostate cancer to the bone. Each project embeds preclinical evaluation of a novel class of """"""""network inhibitors"""""""" in molecular and genetic models of localized and metastatic prostate cancer, in vivo. These agents include small molecule Hsp90 antagonists subcellularly targeted to mitochondria (Project 1), a function-blocking monoclonal antibody to a{v}B{6} (Project 2), and gene therapy silencing of Runx2 by short hairpin RNA (Project 3). All three projects are thematically integrated, rely on a long-standing track record of collaboration between the participating investigators, and share common experimental strategies, in vitro, and genetic disease models, in vivo. Three discovery-oriented Cores support equally the proposed experimental aims. Core A (Administration and Biostatistics: Altieri and Hsieh) will ensure programmatic integration, and provide biostatistics support for the preclinical studies. Core B (Animal Models: Bogdanov and Jones) will maintain quality control of the various genetic mouse models of prostate cancer, and provide state-of-the-art molecular imaging for analysis of tumor responses, in vivo. Core C (Pathology: Leav and Jiang) will oversee quantitative tissue analysis and evaluation of molecular biomarkers for pathway and target validation of """"""""network inhibitors"""""""", in vivo. The overall application is designed to merge molecular and translational prostate cancer research in a single, integrated and multidisciplinary platform. The overarching goal is to credential novel molecular therapies for patients with advanced and metastatic prostate cancer.

Public Health Relevance

Despite recent gains in the understanding of cancer genes and their pathways, advanced prostate cancer remains a deadly disease with no viable therapeutic options. The present application will unravel fundamental mechanisms of prostate cancer progression and characterize new agents as therapeutics for localized and disseminated disease. The results will pave the way for the introduction of novel molecular therapies for patients with advanced prostate cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Program Officer
Forry, Suzanne L
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Wistar Institute
United States
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Caino, M Cecilia; Altieri, Dario C (2016) Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy. Clin Cancer Res 22:540-5
Lisanti, Sofia; Garlick, David S; Bryant, Kelly G et al. (2016) Transgenic Expression of the Mitochondrial Chaperone TNFR-associated Protein 1 (TRAP1) Accelerates Prostate Cancer Development. J Biol Chem 291:25247-25254
Lu, Huimin; Wang, Tao; Li, Jing et al. (2016) αvβ6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor. Cancer Res 76:5163-74
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Chae, Young Chan; Vaira, Valentina; Caino, M Cecilia et al. (2016) Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming. Cancer Cell 30:257-72
Singh, Amrita; Fedele, Carmine; Lu, Huimin et al. (2016) Exosome-mediated Transfer of αvβ3 Integrin from Tumorigenic to Nontumorigenic Cells Promotes a Migratory Phenotype. Mol Cancer Res 14:1136-1146
Farina, Nicholas H; Zingiryan, Areg; Akech, Jacqueline A et al. (2016) A microRNA/Runx1/Runx2 network regulates prostate tumor progression from onset to adenocarcinoma in TRAMP mice. Oncotarget :
Chae, Young Chan; Angelin, Alessia; Lisanti, Sofia et al. (2015) Corrigendum: Landscape of the mitochondrial Hsp90 metabolome in tumours. Nat Commun 6:7605
Zhang, Xuhui; Akech, Jacqueline; Browne, Gillian et al. (2015) Runx2-Smad signaling impacts the progression of tumor-induced bone disease. Int J Cancer 136:1321-32
Forno, Irene; Ferrero, Stefano; Russo, Maria Veronica et al. (2015) Deregulation of MiR-34b/Sox2 Predicts Prostate Cancer Progression. PLoS One 10:e0130060

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