Login to Access Video or Poster Abstract: MP83-08
Sources of Funding: - Flinders Centre for Innovation in Cancer and Faculty Heath Science, Flinders University._x000D_ - Flinders Faculty of Health Sciences Seeding grant._x000D_

Introduction

The anti-diabetic drug metformin (MET) and the anti-epileptic drug sodium valproate (VPA), when used alone, have shown anti-cancer effects in prostate cancer (PCa). However high doses are required which results in unacceptable toxicity. Here, we aimed to determine if the combination of MET and VPA (MET+VPA) at clinically relevant doses would (1) induce a synergistic anti-tumor effect in human PCa cell lines and patient-derived PCa explants, (2) cause minimal toxicity to normal tissues in vivo, (3) identify prognostic molecular markers for MET+VPA responses and (4) lead to rapid clinical application.

Methods

Human PCa cell lines (PC-3 and LNCaP) and radical prostatectomy explants from 8 patients were analyzed for response to MET+VPA. Ki67, cleaved caspase-3, the androgen receptor (AR), and p53 expression in explants were analyzed using immunohistochemistry. The combinatorial effects of MET+VPA were calculated using the Drug Combination Index (CI). The role of p53 and AR in response to MET+VPA was determined using TP53 gene knock-down in LNCaP and TP53 ectopic expression in PC3, and AR was chemically inhibited using Enzalutamide in LNCaP. The toxicity of MET+VPA was determined using histological scoring systems for kidney and liver toxicity in nude mice.

Results

MET+VPA synergistically inhibited proliferation in both PC-3 and LNCaP and synergistically induced apoptosis in LNCaP cells (CI<0.9). All PCa explants (pathological stage pT2C-pT3A and Gleason score 7-9) demonstrated a significant reduction (90%, p<0.001) in proliferation and a significant dose-dependent increase in apoptosis (300%, p<0.001) compared to vehicle. The p53 protein plays a role in MET+VPA as depletion of TP53 in LNCaP significantly reduced the apoptotic response by 58% (p=0.001) and the ectopic expression of TP53 in PC3 significantly increased the apoptotic response by 15% (p=0.047). The AR signaling pathway was also confirmed to play an important role in the apoptotic response to MET+VPA as Enzalutamide significantly reduced apoptosis by 28.5% (p=0.029) in LNCaP cells. No kidney or liver toxicity was detected in nude mice after 8 weeks administration of MET+VPA. These results support evaluation in a Phase I clinical trial which will start early in 2017 (Trial ID: ACTRN12616001021460p).

Conclusions

Our study has only taken 2 years from the first experiment to a phase I clinical trial. Although MET+VPA with an AR inhibitor may not show benefit, MET+VPA has potential to control clinically localized or metastatic PCa, particularly in tumors with functional p53 and/or AR signaling.

Funding

- Flinders Centre for Innovation in Cancer and Faculty Heath Science, Flinders University._x000D_ - Flinders Faculty of Health Sciences Seeding grant._x000D_