Abstract 2698: Improved therapeutic activity of Isoflavone-G2535 and Docetaxel combination in hormone refractory prostate cancer

Abstract

Abstract The emergence of Castrate Resistant Prostate Cancer (CRPC) and its subsequent metastasis to the bone is in part driven by Androgen Receptor (AR) signaling, and contributes to overall poor survival of prostate cancer patients. Here, we present in vitro and in vivo preclinical evidence of chemo-sensitization of CRPC cells to the most clinically useful therapeutic agent, Docetaxel (Taxotere) by G2535, an isoflavone that attenuates AR signaling. In vitro studies were done using AR+ prostate cancer (PCa) cell lines (LNCaP and C4-2B) to understand the molecular basis of combination therapy. We found that the combination was significantly more effective in inhibiting cell growth and induction of apoptosis (p<0.01), down-regulation of AR and its target, prostate specific antigen (PSA) (p<0.01) with suboptimal concentrations of Docetaxel (1nmole/L) compared to monotherapy. It is known that resistance to chemotherapy in CRPC is partly associated with constitutively activated NF-κB/Akt signaling pathways, which becomes further activated by chemotherapeutic drugs, and these molecular targets were found to be down-regulated by G2535 treatment. Of greater significance were the results from in vivo tumor growth inhibition studies conducted in a SCID-hu model of experimental bone metastasis induced by C4-2B cells. Tumor volume, AR and serum PSA was used as response markers to evaluate therapeutic activity of the combination therapy relative to a single regimen and untreated control. At termination, we found 75% reduction in tumor volume elicited by the combination treatment relative to the untreated control group. Most importantly, the anti-tumor activity was associated with the down-regulation of molecular markers in tumor tissue remnants that were similar to those observed in vitro (down regulation of NF-κB, Bcl-2 and survivin) accompanied by a significant reduction in serum PSA. Using qPCR, we found that the level of miR-34a, which target AR, was increased by 1.5 fold after G2535 treatment alone whereas this increase was found to be 3-fold in the combination group. Increased expression of miR-34a resulted in the down regulation of AR and PSA in this in vivo model. Based on our findings, we conclude that the combination of G2535 and Taxotere could be an alternative promising regimen for the treatment of CRPC and its metastases for which curative treatment is urgently needed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2698. doi:1538-7445.AM2012-2698