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 1 week 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 post-castration. 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.
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 immunodeficientmice. 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 1 week 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 post-castration. 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.
Authors: Evan Y Yu; Hongli Li; Celestia S Higano; Neeraj Agarwal; Sumanta K Pal; Ajjai Alva; Elisabeth I Heath; Elaine T Lam; Shilpa Gupta; Michael B Lilly; Yoshio Inoue; Kim N Chi; Nicholas J Vogelzang; David I Quinn; Heather H Cheng; Stephen R Plymate; Maha Hussain; Catherine M Tangen; Ian M Thompson Journal: J Clin Oncol Date: 2015-04-06 Impact factor: 44.544
Authors: Cynthia C T Sprenger; Kathleen Haugk; Shihua Sun; Ilsa Coleman; Peter S Nelson; Robert L Vessella; Dale L Ludwig; Jennifer D Wu; Stephen R Plymate Journal: Clin Cancer Res Date: 2009-12-15 Impact factor: 12.531
Authors: Cale D Fahrenholtz; Ferenc G Rick; Maria I Garcia; Marta Zarandi; Ren-Zhi Cai; Norman L Block; Andrew V Schally; Kerry L Burnstein Journal: Proc Natl Acad Sci U S A Date: 2014-01-06 Impact factor: 11.205
Authors: James P Dean; Cynthia C Sprenger; Junxiang Wan; Kathleen Haugk; William J Ellis; Daniel W Lin; John M Corman; Bruce L Dalkin; Elahe Mostaghel; Peter S Nelson; Pinchas Cohen; Bruce Montgomery; Stephen R Plymate Journal: J Clin Endocrinol Metab Date: 2013-03-26 Impact factor: 5.958