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)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1)
Program Officer
Forry, Suzanne L
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Wistar Institute
United States
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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
Faversani, Alice; Vaira, Valentina; Moro, Giacomina P et al. (2014) Survivin family proteins as novel molecular determinants of doxorubicin resistance in organotypic human breast tumors. Breast Cancer Res 16:R55
Dutta, Anindita; Li, Jing; Lu, Huimin et al. (2014) Integrin ?v?6 promotes an osteolytic program in cancer cells by upregulating MMP2. Cancer Res 74:1598-608
Lisanti, Sofia; Tavecchio, Michele; Chae, Young Chan et al. (2014) Deletion of the mitochondrial chaperone TRAP-1 uncovers global reprogramming of metabolic networks. Cell Rep 8:671-7
Farina, Nicholas H; Wood, Marie E; Perrapato, Scott D et al. (2014) Standardizing analysis of circulating microRNA: clinical and biological relevance. J Cell Biochem 115:805-11
Browne, Gillian; Taipaleenmäki, Hanna; Stein, Gary S et al. (2014) MicroRNAs in the control of metastatic bone disease. Trends Endocrinol Metab 25:320-7
Chae, Young Chan; Angelin, Alessia; Lisanti, Sofia et al. (2013) Landscape of the mitochondrial Hsp90 metabolome in tumours. Nat Commun 4:2139
Altieri, Dario C (2013) Hsp90 regulation of mitochondrial protein folding: from organelle integrity to cellular homeostasis. Cell Mol Life Sci 70:2463-72
Vaira, Valentina; Faversani, Alice; Martin, Nina M et al. (2013) Regulation of lung cancer metastasis by Klf4-Numb-like signaling. Cancer Res 73:2695-705
Caino, M Cecilia; Chae, Young Chan; Vaira, Valentina et al. (2013) Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells. J Clin Invest 123:2907-20

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