Abstract 5603: Response of human prostate cancer xenografts to IGF-IR inhibition correlates with PTEN and androgen receptor splice variant status
Authors: Sprenger Cynthia C. , Nguyen Holly , Vessella Robert , Coleman Ilsa , Nelson Peter , Montgomery Robert , Plymate Stephen 
Published: August 2012

Clinical studies with agents targeting the insulin-like growth factor receptor (IGF-IR) in prostate cancer have shown promise but as with most single agent trials only a portion of patients that enter into a targeted agent trial respond, e.g. activating mutations in the EGF-receptor in patients with lung cancer. We have shown in human tumor xenografts that the combination of IGF-IR inhibition with the human mab IMC-A12 in combination with androgen deprivation (ADT) was more efficacious than ADT alone. In a subsequent neoadjuvant study with IMC-A12, responses were at least as efficacious in hi-grade disease (Gleason 7 (4+3), 8, and 9) when compared to ADT alone. In order to determine predictors of response to IMC-A12 plus ADT (surgical castration) in human prostate cancer, we examined the response of 21 human prostate cancer xenografts (LuCaP series) grown in SCID mice for responses to castration, IMC-A12 40mg/kg ip 3x a week for four weeks, or castration followed by four weeks of IMC-A12. At the end of the IMC-A12 treatment animals were followed until tumor recurrence. When all animals were completed tumor growth was analyzed. The main differences in growth rates, as expected based on previous studies, occurred in mice receiving IMC-A12 plus castration compared to castration alone. Responses were segregated into three groups: Major Response - slope of tumor growth was negative in the IMC-A12 + Castration group compared to castration alone; Moderate Response - slope of combined treatment is flat and castration alone is positive; No-response - no differences in slope between castration and castration plus IMC-A12. We then examined the association of response to IMC-A12 to potential effectors of IGF-IR expression and signaling in the prostate including AR and AR splice variants and PTEN status. Tumor transcript profiles were generated on all xenografts prior to treatment and gene sets predictive of response determined. None of the PTEN null tumors showed a strong response to IMC-A12 and all PTEN null tumors expressed the AR-splice variant ARv567es. Of the 3 xenografts with one copy of PTEN, non- or partial responders either expressed no AR (neuroendocrine tumor) or expressed ARv567es. Of xenografts with 2 or more copies of PTEN, non- or moderate responders expressed AR-variants. Finally, transcript profiles provided a gene signature that was highly predictive of response to IMC-A12. These data indicate that PTEN insufficiency or the presence of an AR-splice variant that cannot increase IGF-IR via non-genomic activity are associated with resistance to IMC-A12. Further, a gene signature has been developed from the 21 xenografts that is predictive of response to IMC-A12 and castration.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5603. doi:1538-7445.AM2012-5603