Using Explant Technology to Discover Markers of Response to Hsp90 Inhibitors in Prostate Cancer

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 292-325-Breast & Prostate Cancer
Basic
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-325
Margaret M Centenera*1, Natalie K Ryan2, Shalini Jindal2, Florian Weiland2, Peter Hoffmann2, Wayne D Tilley3 and Lisa Maree Butler4
1University of Adelaide, Adelaide, Australia, 2University of Adelaide, 3Univ of Adelaide/Hanson Inst, Adelaide SA, Australia, 4Univ of Adelaide, Adelaide SA, Australia
Using explant technology to discover markers of response to Hsp90 inhibitors in prostate cancer

Margaret M. Centenera1, Natalie K. Ryan1, Shalini Jindal2, Florian Weiland2, Peter Hoffmann2, Wayne D. Tilley1 and Lisa M. Butler1

1Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, University of Adelaide and Hanson Institute, Adelaide, SA 5005, Australia.

2Adelaide Proteomics Centre, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia

Targeting heat shock protein 90 (Hsp90) chaperone activity holds significant promise for the treatment of prostate cancer. Hsp90 is overexpressed in prostate cancer cells, and several key signalling molecules implicated in prostate cancer growth require Hsp90 for their stability and activity. There are two Hsp90 inhibitors currently undergoing clinical evaluation in men with treatment resistant prostat cancer. In these trials, the biomarker used to detect Hsp90 inhibition is induction of the co-chaperone Hsp70, measured in peripheral blood mononuclear cells. However we recently demonstrated using our unique human prostate cancer explant model that induction of Hsp70 is not associated with changes in cancer cell proliferation and is therefore not suitable for assessing clinical activity or biological response to Hsp90 inhibition. In this study, we have performed mass spectrometry-based proteomic analysis of prostate cancer explant tissues treated with the Hsp90 inhibitor NVP-AUY922 to identify novel candidate markers of therapeutic response. The proteomic profile in treated versus untreated prostate tumours derived from 12 patients was determined using 2D Difference In-Gel Electrophoresis (2D-DIGE). Twenty eight protein spots were identified as differentially expressed between the treated and untreated groups (fold change ≥1.2, p<0.05) and were submitted for identification by LC-MS mass spectrometry. Treatment was largely associated with increased expression of keratin proteins. Following bioinformatic analysis, candidate markers were validated in an independent set of treated prostate explants. The results of this study will be clinically evaluated in two independent clinical trials designed to assess pharmacodynamic changes associated with Hsp90 inhibition. While the ultimate aim of this research is to advance the clinical development of Hsp90 inhibitors for prostate cancer, we have also demonstrated that our explant model provides a systemic method that can be incorporated into pre-clinical studies for the identification of therapeutic markers and therapeutic targets.

Nothing to Disclose: MMC, NKR, SJ, FW, PH, WDT, LMB

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

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