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Compounds Targetting Androgen Receptor to Treat Castration Resistant Prostate Cancer

ID 02501, 03119

BackgroundCastration-resistant prostate cancer (CRPC) is currently incurable and makes prostate cancer the second most common cause of cancer death among men in the United States. Multiple studies have shown that the androgen receptor (AR) is activated via multiple mechanisms including AR overexpression, mutation, hypersensitization, and/or intratumoral androgen synthesis in patients relapsed after androgen deprivation therapy (ADT). Overexpression and knockdown studies have shown that AR is a key molecular determinant and an excellent therapeutic target for CRPC.

Technology DescriptionInnovators at the University of Pittsburgh have identified novel small molecules that block the nuclear localization and function of the androgren receptor in CRPC cells. The compounds are not cytotoxic and decrease AR levels in CRPC cells. Xenograft studies using these small molecules showed inhibition of castration-resistant growth of C4-2 and 22Rv1 xenograft tumors in SCID mice. This work demonstrates the potential of these compounds in CRPC tumor therapy. A second class of compounds significantly decreases cell proliferation in AR-positive cell lines while they have no effect on proliferation in AR-negative cell lines. Stage of Development

In-vivo and In-vitro studies

Applications

-Potential to inhibit endogenous AR signaling in CRPC cells

-Potential to inhibit the growth of CRPC tumors

Advantages -No cytotoxicity

- Very effective in blocking AR nuclear localization

Innovators Zhou Wang, PhD

Peter Wipf, PhD

Patent Applications Filed WO2013055793 A1

Cancer therapy

-Lead compounds are effective against all tested AR-positive prostate cancer cell lines

-Potential to inhibit androgen dependent tumors

Dr. Zhou Wang is a Professor in Urology, Pathology and Pharmacology. He is also the director of Urological research in addition to holding UPMC Chair in Urological research. Being a well published scientist , he is a recipient of multiple awards, the most recent of which is the NIH/NIDDK MERIT award. His research interests lie in androgen signal transduction in the prostate neoplastic progression with a long term goal of identifying new targets and preventive care for the same.

Contact InformationAndrew Remes, PhD, CLPLicensing ManagerLife Sciences412-624-3134aremes@pitt.edu

Office of Technology Management200 Gardner Steel Conference CenterThackeray & O’Hara StreetPittsburgh, PA 15260412-648-2206www.otm.pitt.edu

Featured Innovators

Publications

1. Pascal, L. E., J. Ai, K. Z. Masoodi, Y. Wang, D.Wang, K. Eisermann, L. H. Rigatti, K. J. O’Malley,H. M. Ma, X. Wang, J. A. Dar, A. V. Parwani, B.W. Simons, M. M. Ittman, L. Li, B. J. Davies andZ. Wang (2013). “Development of a reactivestroma associated with prostatic intraepithelialneoplasia in EAF2 deficient mice.” PLoS One8(11): e79542.

2. Su, F., B. R. Correa, J. Luo, R. Z. Vencio, L. E. Pascaland Z. Wang (2013). “Gene Expression ProfilingReveals Regulation of ERK Phosphorylationby Androgen-Induced Tumor SuppressorU19/EAF2 in the Mouse Prostate.” CancerMicroenviron 6(3): 247-261.

3. Qiao, Z., D. Wang, J. Hahn, J. Ai and Z. Wang(2014). “Pirin down-regulates the EAF2/U19protein and alleviates its growth inhibition inprostate cancer cells.” Prostate 74(2): 113-120.

4. Parikh, R. A., L. E. Pascal, B. J. Davies and Z. Wang(2014). “Improving intermittent androgendeprivation therapy: lessons learned from basicand translational research.” Asian J Androl.

Dr. Peter Wipf is a Distinguished University Professor of Chemistry and a Professor of Pharmaceutical Sciences and Bioengineering. He also serves as the co-Leader of the UPCI Molecular Therapeutics and Drug Discovery Program. He has received more than 30 national and international, academic and industrial awards, and he is a Fellow of the American Association for the Advancement of Science, the American Chemical Society, and the Royal Society of Chemistry. He serves on several editorial and scientific advisory boards, and he has been an Associate Editor of ACS Medicinal Chemistry Letters since 2009. He has published 450 scientific articles, and holds more than 30 US patents. One of his compounds, a PI-3 kinase inhibitor, is currently in Phase II clinical trials for the treatment of SCCHN, CRC, BRAF-mutant melanoma, and prostate cancer in the US and Canada.

Zhou Wang , PhD

Peter Wipf , PhD

Wei, N., E. Chu, P. Wipf and J. C. Schmitz (2014). "Protein kinase d as a potential chemotherapeutic target for colorectal cancer." Mol Cancer Ther 13(5): 1130-1141.

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6. Greenberger, J. S., H. Berhane, A. Shinde, B. H.Rhieu, M. Bernard, P. Wipf, E. M. Skoda and M.W. Epperly (2014). "Can RadiosensitivityAssociated with Defects in DNA Repair beOvercome by Mitochondrial-TargetedAntioxidant Radioprotectors." Front Oncol 4: 24.

7. Shinde, A., M. W. Epperly, S. Cao, D. Franicola, D.Shields, H. Wang, P. Wipf, M. M. Sprachman andJ. S. Greenberger (2014). "Effects of theBifunctional Sulfoxide MMS350, a RadiationMitigator, on Hematopoiesis in Long-term BoneMarrow Cultures and on Radioresistance ofMarrow Stromal Cell Lines." In Vivo 28(4):457-465.

8. Adam, C., A. Baeurle, J. L. Brodsky, P. Wipf, D.Schrama, J. C. Becker and R. Houben (2014)."The HSP70 modulator MAL3-101 inhibitsMerkel cell carcinoma." PLoS One 9(4): e92041.