An antibody targeting the type I insulin-like growth factor receptor enhances the castration-induced response in androgen-dependent prostate cancer

Stephen R. Plymate*, Kathy Haugk, Ilsa Coleman, Lillie Woodke, Robert Vessella, Peter Nelson, R. Bruce Montgomery, Dale L. Ludwig, Jennifer D. Wu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Purpose: To determine the effect of inhibition of insulin-like growth factor-IR (IGF-IR) signaling with an antibody to the IGF-IR, A12, in conjunction with androgen withdrawal on prostate cancer progression in a human prostate xenograft model, LuCaP 35. Experimental Design: LuCaP 35 was implanted s.c. in severe combined immunodeficient mice. At the time of castration, mice were randomized to one of three groups. Group 1 was castrate only; group 2 received A12 40 mg/kg i.p. for 2 weeks beginning 1week after castration; and group 3 received A12 40 mg/kg i.p. for 2 weeks beginning 2 weeks after castration. Results: In group 1, tumor volume decreased to 60% of the starting volume 4 weeks postcastration. In groups 2 and 3, tumor volumes nadired 6 weeks after castration at <10% of the volume at time of castration (P < 0.01). Tumor regrowth was not seen in groups 2 or 3 until 15 weeks after castration. Androgen receptor (AR) localization in tumors showed a decrease in nuclear staining in groups 2 and 3 compared with group 1 (P < 0.001). Tumor volume correlated with nuclear AR intensity. AR-regulated genes increased early in group 1, but did not increase in groups 2 and 3. Thus, tumor-specific survival was prolonged by the addition of A12 to castration. Conclusions: This study shows that the inhibition of IGF-IR enhances the effects of castration in prostate cancer. These effects are associated with a decrease in AR signaling and nuclear AR localization, and recurrence is associated with an increase in AR-regulated gene expression.

Original languageEnglish (US)
Pages (from-to)6429-6439
Number of pages11
JournalClinical Cancer Research
Volume13
Issue number21
DOIs
StatePublished - Nov 1 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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