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 #
5P01CA140043-04
Application #
8376244
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$512,491
Indirect Cost
$248,192
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Karpel-Massler, Georg; Ishida, Chiaki Tsuge; Bianchetti, Elena et al. (2017) Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses. Cancer Res 77:3513-3526
Bryant, Kelly G; Chae, Young Chan; Martinez, Rogelio L et al. (2017) A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy. Oncotarget 8:112184-112198
Zingiryan, Areg; Farina, Nicholas H; Finstad, Kristiaan H et al. (2017) Dissection of Individual Prostate Lobes in Mouse Models of Prostate Cancer to Obtain High Quality RNA. J Cell Physiol 232:14-8
Ishida, Chiaki Tsuge; Shu, Chang; Halatsch, Marc-Eric et al. (2017) Mitochondrial matrix chaperone and c-myc inhibition causes enhanced lethality in glioblastoma. Oncotarget 8:37140-37153
DeRita, Rachel M; Zerlanko, Brad; Singh, Amrita et al. (2017) c-Src, Insulin-Like Growth Factor I Receptor, G-Protein-Coupled Receptor Kinases and Focal Adhesion Kinase are Enriched Into Prostate Cancer Cell Exosomes. J Cell Biochem 118:66-73
Caino, M Cecilia; Seo, Jae Ho; Wang, Yuan et al. (2017) Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer. J Clin Invest 127:3755-3769
Kumar, Vinit; Donthireddy, Laxminarasimha; Marvel, Douglas et al. (2017) Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors. Cancer Cell 32:654-668.e5
Lu, Huimin; Wang, Tao; Li, Jing et al. (2016) ?v?6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor. Cancer Res 76:5163-74
Caino, M Cecilia; Seo, Jae Ho; Aguinaldo, Angeline et al. (2016) A neuronal network of mitochondrial dynamics regulates metastasis. Nat Commun 7:13730
Sayeed, Aejaz; Lu, Huimin; Liu, Qin et al. (2016) ?1 integrin- and JNK-dependent tumor growth upon hypofractionated radiation. Oncotarget 7:52618-52630

Showing the most recent 10 out of 68 publications