Abstract C55: Ganitumab (AMG 479) inhibits the development and progression of castration-resistant VCaP human prostate cancer xenografts.
Authors: Fahrenholtz Cale D. , Beltran Pedro J. , Calzone Frank J. , Burnstein Kerry L. 
Published: June 2012

Abstract
Prostate tumors are initially dependent on androgens for growth; thus the standard of care for advanced or metastatic prostate cancer is androgen deprivation therapy. While this treatment strategy diminishes tumor burden and growth, prostate cancer invariably recurs in a castration-resistant form for which therapeutic options are extremely limited. Therefore, new therapeutic regimens are needed that are effective against castration-resistant prostate cancer (CRPC) and its development. The insulin-like growth factor 1 (IGF-1) signaling axis drives both anti-apoptotic and proliferative signals and is dysregulated in prostate cancer. Ganitumab (AMG 479), a fully human monoclonal antibody (IgG1) against the type 1 insulin-like growth factor receptor (IGF-1R), is currently in a phase III clinical trial for treatment of metastatic pancreatic cancer. Since the IGF-1 signaling axis is thought to be instrumental in prostate cancer growth and development, we evaluated the therapeutic potential of ganitumab in a human model of prostate cancer, alone and in combination with androgen deprivation therapy. We used the human prostate cancer cell line, VCaP, which expresses wild type PTEN and grows readily as xenografts that are initially androgen-dependent but progress to castration-resistance in vivo. VCaP is unique among prostate cancer cell lines in that they express the TMPRSS-ERG fusion protein characteristic of a substantial proportion of clinical prostate cancer specimens. In vitro, we found that IGF-1 stimulated phosphorylation of AKT and cell proliferation in VCaP cells, and ganitumab treatment effectively inhibited both. Ganitumab treatment of androgen-dependent VCaP xenografts (300 μg/dose, 2×/week, ip) increased the mean tumor doubling time from 2.9 to 6.3 weeks resulting in significant (p&lt;0.005) tumor growth inhibition of 85% after 4 weeks of treatment. When castration-resistant VCaP xenografts were treated with ganitumab, stasis was achieved over an 11 week treatment period. Most importantly, when ganitumab treatment was combined with androgen deprivation therapy (castration), tumor regression occurred and progression to CRPC was significantly (p&lt;0.0001) delayed in all mice. After 2 weeks of treatment, tumor volume was reduced by 72% in ganitumab-treated as compared to control (androgen deprivation only)-treated mice. After 16 weeks of ganitumab treatment, 60% of tumors had not recurred in the combination arm. Serum levels of the clinically relevant biomarker, prostate specific antigen (PSA), followed similar trends as tumor volumes in all experiments. Together, these studies suggest that ganitumab could be an important therapeutic strategy for many stages of prostate cancer, especially when combined with androgen deprivation therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C55.