Despite progress in the identification of cancer genes and their pathways, the development of new therapies for metastatic prostate cancer has lagged behind. This refiects the extraordinary heterogeneity of advanced disease, which makes it difficult to identify unique oncogenic lesions suitable for therapeutic intervenfion. Conversely, agents that target fundamental pathways of tumor maintenance may offer better therapeutic prospects. Recent studies have uncovered a fundamental mechanism of tumor cell survival exploited in prostate cancer. This is centered on the recruitment of Heat Shock Protein-90 (Hsp90) molecular chaperones to mitochondria ofthe transformed prostatic epithelium, but not normal prostate, in vivo. In tum, Hsp90 chaperones bind components of the mitochondrial permeability transition pore, especially Cyclophilin D, block its function, and suppress apoptosis. To target this pathway for cancer therapy, we synthesized a novel class of small molecule Hsp90 inhibitors selectively targeted to mitochondria, designated Gamitrinibs (GA Inhibitors of the mitochondrial matrix). Gamitrinibs are direct 'mitochondriotoxic'agents, kill androgendependent or -independent prostate cancer cells, but not normal prostatic epithelium, and inhibit localized and bone metastatic prostate cancer growth, in vivo, without systemic or organ toxicity. Therefore, a unifying hypothesis can be formulated that mitochondrial Hsp90 chaperones orchestrate a fundamental pathway of prostate cancer progression, and this provides a novel therapeutic target for advanced disease. Experiments in specific aim 1 will dissect the requirements of Hsp90 chaperones in maintaining mitochondrial integrity, promote drug resistance, and contribute to disease progression mediated by avpe integrin.
Specific aim 2 will elucidate the mechanism(s) of differential import of Hsp90 chaperones in tumor versus normal mitochondria, map the role of survivin in orchestrating a cytoprotective chaperone network In mitochondria, and test the impact of this pathway on transformation ofthe prostatic epithelium.
In specific aim 3, preclinical studies will test the activity of Gamitrinibs in molecular and genetic models of localized and metastatic prostate cancer, including prostate-specific Ren conditional knockout mice, transgenic TRAMP mice, and immunocompromised mice implanted in the bone with prostate cancer cells. The approach merges mechanistic elucidation of a novel pathway of prostate cancer progression with preclinical evaluation of its novel inhibitors. The studies have high impact as they may pave the way to the use of Gamitrinibs as novel molecular therapy for patients with advanced prostate cancer.

Public Health Relevance

Although eariy phase prostate cancer is typically managed successfully, advanced disease is associated with metastasis, drug resistance and poor outcome. Therapeutic options for these patients are minimal, and none meaningfully prolongs survival. We have now synthesized Gamitrinibs, the first class of small molecule inhibitors of the mitochondrial pool of Hsp90 in tumor cells. By disabling a fundamental pathway of Hsp90 cytoprotedion, Gamitrinibs may provide new molecular therapies for advanced prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA140043-05
Application #
8526414
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$497,511
Indirect Cost
$225,534
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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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