Abstract 5376: Antisense oligonucleotide targeting insulin-like growth factor-1 receptor (IGF-1R) enhances paclitaxel sensitivity in a castrate-resistant and paclitaxel-resistant prostate cancer model

While prostate cancer (PCa) initially responds to androgen deprivation therapy (ADT), castrate-resistant disease (CRPC) relapse is inevitable. Altered expression of insulin-like growth factor (IGF) axis components have been consistently found in PCa and associated with adaptive growth and survival signaling implicated in CRPC progression. These activities are mediated by activation of the IGF-I receptor (IGF-IR). While CRPC patients treated with taxanes (paclitaxel or docetaxel) alone or in combination with estramustine phosphate or predonisone show a survival benefit, development of chemotherapeutic resistance eventually occurs. Therefore novel strategies targeting the molecular basis of ADT and chemotherapy resistance are required. In this study, we assess the potency and anti-cancer activity of a 2′-MOE-modified antisense oligonucleotide (ASO) targeting human IGF-IR, ATL1101, on the CRPC cell line, PC3 and a paclitaxel-resistant androgen-independent PC3-derived cell line, PtxR PC3, in vitro and in vivo. PtxR PC3 cells were established by culturing in step-wise increased drug concentrations. IGF-IR mRNA and protein expression in ATL1101- and control oligonucleotides (ODN)-treated PtxR PC3 cells were measured by QT-PCR and immunoblotting. The effect of IGF-1R ASO and paclitaxel combination therapy on parental and PtxR PC3 cell growth and apoptosis in vitro was examined by crystal violet assay and flow cytometry. In vitro combination index (CI) was calculated by Calcusyn® softoware. For xenograft studies, parental and PtxR PC-3 cells were inoculated s.c. in the flanks of athymic male nude mice and tumor volume kinetics were compared for mice treated with paclitaxel injected i.v. and either ATL1101 or control ODN injected i.p. In vitro, the IC₅₀ for paclitaxel in PtxR PC3 was 20-fold higher than that in parental cells. PtxR PC3 also show significant cross-resistance to docetaxel and mitoxantrone. We observed equivalent dose- and sequence-specific suppression of IGF-IR mRNA and protein expression, and comparable decreased proliferation and increased apoptosis in ATL1101-treated parental and PtxR PC3 cells in vitro. Combination of ATL1101 with paclitaxel showed CI values below 1 at the IC50, IC75, IC90, suggesting the drug interactions resulted in synergy. In vivo, ATL1101 significantly increased sensitivity of PtxR PC3 tumors to combination therapy with paclitaxel as compared to control ODN in murine xenografts. This study reports the first preclinical proof-of-principle data that this novel IGF-IR ASO suppresses growth of paclitaxel resistant PC tumors, synergistically enhancing paclitaxel sensitivity in vitro and in vivo.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5376.