Abstract 20: Xentuzumab, a humanized IGF-1 and IGF-2 ligand neutralizing antibody, improves the antitumor efficacy of enzalutamide in preclinical models of prostate cancer

Abstract

Abstract Background: The proliferative and pro-survival signals driven by the insulin-like growth factor (IGF) ligands, IGF-1 and IGF-2, are transmitted through their binding to the IGF-1 receptor (IGF-1R). In addition, IGF-2 activates the insulin receptor variant A (IR-A) that is expressed during embryonic development as well as in many cancers. A large body of preclinical evidence suggests that IGF signaling plays a key role in cancer by driving therapy resistance, due to cross-talk with other signaling networks such as androgen receptor signaling. The aim of this study was to explore the potential of the IGF-1/-2 ligand blocking antibody, xentuzumab (BI 836845[1]), to enhance the anti-tumor activity of enzalutamide in prostate cancer cell lines and in a patient-derived prostate cancer xenograft model. Methods: Effects of enzalutamide, xentuzumab and combinations thereof on in vitro proliferation, survival, cell cycle and signaling were evaluated using the prostate cancer cell lines VCaP, DuCaP, MDA PCa 2b, and LNCaP. The in vivo efficacy of enzalutamide, alone and in combination with xentuzumab was investigated using LuCaP 96CR, a patient-derived xenograft model of castration-resistant prostate cancer. Tumors were implanted s.c. into castrate SCID mice. When tumors exceeded 150mm3 animals were randomized into groups: 1) Control; 2) enzalutamide (50 mg/kg QD po), 3) xentuzumab (BI 836845[1], 200 mg/kg QW ip) in combination with enzalutamide. Results: Cell viability was more effectively reduced by the combination of enzalutamide and xentuzumab than either drug alone in three of four cell lines expressing the IGF-1R and the androgen receptor (AR). In VCaP cells, prolonged inhibition of IGF pathway signaling and enhanced blockade of proliferation as well as induction of apoptosis was observed after combination treatment. In vivo, enzalutamide monotherapy did not show significant antitumor efficacy in the LuCaP 96CR model, however, combined treatment with xentuzumab significantly inhibited progression of LuCaP 96CR tumor growth (p<0.001 vs. enzalutamide alone). Reduced serum PSA levels were observed after enzalutamide and combination treatment. Enzalutamide plus xentuzumab inhibited tumor growth at tolerated doses and resulted in significant improvements in survival. Conclusions: These studies demonstrated that addition of the IGF-1/-2 neutralizing antibody xentuzumab to enzalutamide results in improved anti-neoplastic activity in a subset of prostate cancer cell lines in vitro, and to re-sensitization to enzalutamide in a patient-derived xenograft model of CRPC. Reference: [1] Friedbichler K et al. (2014). Mol Cancer Ther 13(2):399-409. Citation Format: Ulrike Weyer-Czernilofsky, Marco H. Hofmann, Paul J. Adam, Flavio Solca, Katrin Friedbichler, Norbert Kraut, Eva Corey, Thomas Bogenrieder. Xentuzumab, a humanized IGF-1 and IGF-2 ligand neutralizing antibody, improves the antitumor efficacy of enzalutamide in preclinical models of 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 20. doi:10.1158/1538-7445.AM2017-20