Antisense oligonucleotide targeting of insulin-like growth factor-1 receptor (IGF-1R) in prostate cancer.

摘要

OBJECTIVE: Altered expression of insulin-like growth factor receptor (IGF-1R) is associated with castrate-resistant prostate cancer (CRPC) progression. We hypothesize that increased expression and/or responsiveness of IGF-IR may promote disease progression. This study assesses ATL1101, a 2'-MOE-modified antisense oligonucleotide (ASO) targeting human IGF-IR, with regard to potency and anti-cancer activity in androgen-responsive (LNCaP) and -independent (PC3) prostate cancer cells in vitro and in vivo. METHODS: IGF-IR mRNA and protein expression was assessed in ATL1101- and control oligonucleotides (ODN)-treated prostate cancer cells by QT-PCR and immunoblotting. The effect of IGF-1R ASO on cell growth and apoptosis in vitro was examined by crystal violet assay, flow cytometry, and expression and activation state of downstream signaling targets was examined by immunoblotting. In vivo growth of subcutaneous xenografts was performed in nude mice treated with intraperitoneally administered ATL1101 or control ODN by measuring tumor volume of PC3 xenografts in intact mice, and tumor volume and serum prostate-specific antigen levels in castrated mice harboring LNCaP xenografts. RESULTS: We observed dose- and sequence-specific suppression of IGF-IR mRNA and protein expression in ATL1101-treated cells in vitro. Suppressed IGF-IR expression correlated with decreased proliferation and increased apoptosis of PC3 cells under standard culture conditions and of LNCaP cells under androgen-deprived culture conditions. ATL1101 suppressed PC3 tumor growth as a monotherapy and delayed CRPC progression of LNCaP xenografts. CONCLUSIONS: This study reports the first preclinical proof-of-principle data that this novel IGF-IR ASO selectively suppresses IGF-1R expression, suppresses growth of CRPC tumors, and delays CRPC progression in vitro and in vivo.