Abstract LB-31: Castration induces upregulation of intratumoral androgen biosynthesis and androgen receptor expression in orthotopic VCaP human prostate cancer xenograft model

Abstract

Androgens are key factors involved in the development and progression of prostate cancer (PCa), and the growth of PCa can be suppressed by androgen deprivation therapy (ADT). In a significant proportion of men receiving ADT, PCa progresses to castration-resistant prostate cancer (CRPC), which is a major challenge in the development of efficient therapies. The aim of the study was to characterize the cellular and molecular changes in tumors after ADT (castration), by using orthotopic VCaP human prostate cancer xenograft model. VCaP cells were inoculated in the dorsolateral prostate of immunodeficient mice, and tumor growth was followed by weekly serum PSA measurements. Mice with recurrent tumors after castration were randomized to treatment groups. Serum PSA concentrations showed significant correlation with the tumor volume, confirming that PSA is a reliable indicator of the tumor volume in the orthotopic VCaP xenograft model. Tumor and serum samples were collected and concentrations of androgens were measured by LC-MS/MS. Castration-resistant tumors retained their intratumoral androgen (androstenedione, testosterone, 5α-dihydrotestosterone) concentrations at levels similar to those in tumors growing in intact hosts. Accordingly, castration induced upregulation of enzymes involved in androgen biosynthesis (CYP17A1, AKR1C3 and HSD17B6), as well as expression of full-length androgen receptor (AR) and AR splice variants (AR-V1 and AR-V7). Furthermore, AR target gene expression was maintained in castration-resistant xenografts. AR antagonists, MDV3100 and ARN-509, suppressed the PSA production of castration-resistant tumors, confirming their androgen-dependency. In conclusion, we demonstrated that VCaP xenograft model exhibits the key characteristics of clinical CRPC, thus providing a valuable tool to identify druggable targets and for testing therapeutic strategies targeting AR signaling in CRPC.

Citation Format: Matias Knuuttila, Emrah Yatkin, Jenny Kallio, Saija Savolainen, Teemu Daniel Laajala, Tero Aittokallio, Riikka Oksala, Merja Häkkinen, Pekka Keski-Rahkonen, Seppo Auriola, Matti Poutanen, Sari Mäkelä. Castration induces upregulation of intratumoral androgen biosynthesis and androgen receptor expression in orthotopic VCaP human prostate cancer xenograft model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-31. doi:10.1158/1538-7445.AM2014-LB-31