Prostate Cancer: Basic Research IIModerated Poster1320 ALTERED EXPRESSION OF FARNESYL PYROPHOSPHATE SYNTHASE IN PROSTATE CANCER – EVIDENCE FOR A ROLE OF THE MEVALONATE PATHWAY FOR DISEASE PROGRESSION
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INTRODUCTION AND OBJECTIVES
Preclinical studies demonstrated direct and indirect effects of drugs inhibiting the mevalonate pathway, such as nitrogen-containing bisphosphonates (NBPs) and statins, on tumor growth and cancer progression. However, the exact role of this pathway in prostate cancer (PC) progression has not been identified yet. Aim of the study was to evaluate the expression of the enzyme farnesyl pyrophosphate synthase (FPPS), the molecular target of NBPs and key enzyme of the mevalonate pathway, in PC tissue.
METHODS
PC and corresponding benign prostatic tissue samples of 114 consecutive men who underwent radical prostatectomy were constructed to a tissue microarray (median Age 65, median PSA 9 ng/ml, median Gleason 6). FPPS staining was performed using a polyclonal antibody and expression was quantified by the Remmele/Stegner immunoreactivity score (IRS) including both percentage of positive cells and staining intensity (1-12). Patients' clinical follow-up was assessed with a median follow-up of 69 months.
RESULTS
Mean IRS for FPPS in PC and benign tissue areas were 5.7 (95% CI 5.0-6.5) and 2.6 (2.1-3.0, p<0.0001). In PC tissue of patients with locally advanced disease (pT≥3), mean IRS were 6.87 (5.57-8.17) vs. 5.09 (4.22-5.96) in patients with organ-confined disease (p=0.035). IRS of PC tissue significantly correlated with Gleason score (p=0.007). No significant correlation was observed between preoperative PSA and FPPS expression of PC tissue (p=0.13). Patients with moderate or strong FPPS expression
CONCLUSIONS
This is the first study investigating the expression of FPPS in PC specimens. The association of FPPS with established histopathological risk parameters indicates a potential contribution of the mevalonate pathway to the progression of PC. Inhibition of this pathway in PC patients might have an effect on tumor progression beyond inhibition of PC-related bone disease. Moreover, FPPS expression might be a prognostic indicator for potential antitumor effects of mevalonate pathway-inhibiting drugs.
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Source of Funding: Novartis Oncology