Abstract 3453: Effect of a histone DNA demethylase on castration resistant prostate cancer cell lines, a potential therapeutic application

Abstract

Abstract INTRODUCTION AND OBJECTIVES: Androgen receptor signaling is the key driving force in prostate cancer progression, even in castration-resistant prostate cancer (CRPC). SD70, a competitive inhibitor of KDM4 class of histone demethylases, was demonstrated to have significant inhibitory effect on AR transactivation function in LNCaP cells and androgen-insensitive basal activity in CWR22Rv1. In-vitro assessment of efficacy in CWR22Rv1 cells demonstrated cytotoxity at 5 μM. We aimed to demonstrate the efficacy of SD70 in CRPC cell lines, determine its effect in conjunction with currently approved therapies, and identify a useful biomarker for this novel drug. MATERIALS AND METHODS: Using MTT viability assays, we first assessed SD70 dosing against two CRPC lines (C42B and GRP), then against C42B drug-resistant strains (abiratarone, enzalutamide, abi+enza, docetaxel). For the resistant lines, cells were then treated with 1 μM SD70 in combination with 10 μM abiratarone, 10 μM enzalutamide or 1 nM docetaxel. In vivo drug study was conducted with mouse xenograft models (3 million CWR22Rv1 cells via s.c. injection) in athymic nude mice. When the tumor volume reached 100 mm3, animals were randomly assigned to receive 10 mg/kg SD70 or vehicle via i.p. injection daily. Tumor monitoring was continued until tumor burden exceeded humane endpoint limits indicated by IACUC. RESULTS: SD70 demonstrated complete cytotoxic response at 5 μM against C42B and GRP cell lines; IC50 was 2.1 μM and 2.9 μM, respectively. All drug-resistant C42B cell lines were responsive to SD70 treatment; IC50 ranged from 0.90-1.57 μM. SD70 was found to be synergistic with abiratarone, enzalutamide, and docetaxel against drug-resistant C42B and GRP cell lines. In the CWR22Rv1 mouse xenograft model, SD70-treated mice demonstrated significantly lower tumor volume at the end of treatment period (SD70: 507.31±203.72 mm3, control: 2388.01±543.58 mm3); no significant drug toxicity was observed. Expression of AR surrogate markers (PSA, KLK2, TMPRSS2) were diminished in C42B and enzalutamide-resistant C42B lines treated with SD70. No changes in autophagy reporter LC-3 or activation of Akt was observed. CONCLUSIONS: SD70 demonstrates promising cytotoxic efficacy against CRPC cells lines in vitro, and appears to have a synergistic effect with currently approved CRPC medications (docetaxel, enzalutamide, and abiratarone) in drug-resistant CRPC lines. Initial in vivo trial demonstrated excellent efficacy against CWR22Rv1 without significant toxicity. Ongoing evaluation into identifying biomarkers will allow for further evaluation of this promising new agent. Citation Format: Thenappan Chandrasekar, Joy C. Yang, Min Xie, Sheng Ding, Michael G. Rosenfeld, Christopher P. Evans. Effect of a histone DNA demethylase on castration resistant prostate cancer cell lines, a potential therapeutic application. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3453. doi:10.1158/1538-7445.AM2015-3453