Background: Recent data from multiple investigators have shown that an increase in constitutively active androgen receptor (AR) variants such as AR-V7 is associated with more aggressive prostate cancer and a significantly shortened overall survival. Additionally, expression of AR-V7 in circulating tumor cells or increased expression in metastatic tissue is a biomarker for resistance to currently available anti-androgen therapies, including enzalutamide (ENZA) and abiraterone, resulting in castration resistant prostate cancer (CRPC). Insulin-like growth factor (IGF) signaling pathways have been incriminated as mechanisms of resistance but little is known about the potential role of IGFs in CRPC growth in relation to AR variants. In this preclinical study we examined the effects of IGF-I and -II inhibition in LuCaP 96CR, an ENZA resistant prostate cancer patient-derived xenograft.

Hypothesis: IGF-I and -II neutralization will block AR-V7 activity and inhibit castration-resistant prostate cancer growth.

Study procedures: LuCaP 96CR was implanted s.c. into castrate SCID mice (15 mice per group). When tumors exceeded 150mm3 animals were randomized into groups: 1) Control; 2) ENZA (50 mg/kg, QD, po), 3) xentuzumab (BI 836845[1], 200 mg/kg QW IP) in combination with ENZA. At the end of the study, tumors were collected for preparation of RNA and protein lysates and histology.

Results: ENZA did not show significant inhibitory effects on LuCaP 96CR, but the combination of xentuzumab and ENZA resulted in significant tumor inhibition (p<0.001) vs. ENZA alone. AR full length (AR-FL) mRNA and protein increased after ENZA treatment (p<0.001) but did not further rise significantly when xentuzumab was co-administered. In contrast, significantly elevated AR-V7 mRNA and protein levels were detected in tumors from mice treated with the xentuzumab and ENZA combination (p<0.001). Downstream markers of AR-V7 activity, UBE2C and UGT2B17 mRNA, increased after ENZA treatment when compared to vehicle (UGT2B17, p<0.01); no further significant increase of UGT2B17 was detected after combination treatment and UBCE2C significantly decreased (p<0.001).

Summary: These data show that addition of xentuzumab provides tumor inhibition of ENZA-resistant CRPC. Interestingly, associated with a significant decrease in tumor growth, this treatment resulted in increased AR-V7 mRNA and protein expression but no significant increases in downstream markers of AR-V7 activity, UBE2C and UGT2B17.

Conclusion: Our results suggest that the IGF-I and -II neutralizing antibody xentuzumab may reverse AR-V7-mediated ENZA resistance.

Citation Format: Gang Liu, Holly M. Nguyen, Kristine van Maltzan, Shihua Sun, Cynthia Sprenger, Ulrike Weyer-Czernilofsky, Eva Corey, Stephen R. Plymate. Neutralization of IGF-I and -II ligands with the fully humanized bispecific monoclonal antibody xentuzumab inhibits AR-V7-induced enzalutamide resistance in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1194. doi:10.1158/1538-7445.AM2017-1194