Anti-Tumor Activity of the IGF-1/IGF-2-Neutralizing Antibody Xentuzumab (BI 836845) in Combination with Enzalutamide in Prostate Cancer Models

Androgen deprivation therapy and second-generation androgen receptor signaling inhibitors such as enzalutamide (ENZA) are standard treatments for advanced/metastatic prostate cancer. Unfortunately, most men develop resistance and relapse; signaling via insulin-like growth factor (IGF) has been implicated in castration-resistant prostate cancer. We evaluated the anti-tumor activity of xentuzumab (XENT; IGF-ligand-neutralizing antibody), alone and in combination with ENZA, in prostate cancer cell lines (VCaP, DuCaP, MDA PCa 2b, LNCaP, PC-3) using established in vitro assays, and in vivo , using LuCaP 96CR, a prostate cancer patient-derived xenograft (PDX) model. XENT+ENZA reduced the viability of phosphatase and tensin homolog (PTEN)-expressing VCaP, DuCaP, and MDA PCa 2b cells more than either single agent, and increased anti-proliferative activity and apoptosis induction in VCaP. XENT or XENT+ENZA inhibited IGF type 1 receptor (IGF-1R) and AKT serine/threonine kinase (AKT) phosphorylation in VCaP, DuCaP, and MDA PCa 2b cells; XENT had no effect on AKT phosphorylation and proliferation in PTEN -null LNCaP or PC-3 cells. Knockdown of PTEN led to loss of anti-proliferative activity of XENT and reduced activity of XENT+ENZA in VCaP cells. XENT+ENZA inhibited the growth of castration-resistant LuCaP 96CR PDX with acquired resistance to ENZA, and improved survival in vivo . The data suggest that XENT+ENZA combination therapy may overcome castration resistance and could be effective in patients who are resistant to ENZA alone. PTEN status as a biomarker of responsiveness to combination therapy needs further investigation.