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


METHODS
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.
Plymate
Stephen R
SR
Department of Medicine, University of Washington, Seattle, Washington 98104, USA. splymate@u.washington.edu
Haugk
Kathy
K
Coleman
Ilsa
I
Woodke
Lillie
L
Vessella
Robert
R
Nelson
Peter
P
Montgomery
R Bruce
RB
Ludwig
Dale L
DL
Wu
Jennifer D
JD
D000728:Androgens / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D003600:Cytosol / Q000378:metabolism; D013196:Dihydrotestosterone / Q000097:blood; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology*; D017526:Receptor, IGF Type 1 / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D013739:Testosterone / Q000097:blood
D000728:Androgens; D000911:Antibodies, Monoclonal; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone; D017526:Receptor, IGF Type 1