Publication Date




Embargo Period


Degree Type


Degree Name

Doctor of Philosophy (PHD)


Molecular and Cellular Pharmacology (Medicine)

Date of Defense


First Committee Member

Kerry Burnstein

Second Committee Member

Vladlen Slepak

Third Committee Member

Charles Luetje

Fourth Committee Member

Zafar Nawaz


Prostate cancer is the most commonly diagnosed non-cutaneous malignancy in U.S. men. While tumors initially respond to androgen-deprivation therapy, the standard care for advanced or metastatic disease, tumors eventually recur as castration-resistant prostate cancer. Upregulation of the insulin-like growth factor signaling axis drives growth and progression of prostate cancer by promoting proliferation, survival, and angiogenesis. Ganitumab (formerly AMG 479) is a fully human antibody that inhibits binding of IGF-1 and IGF-2 to IGF-1R. Ganitumab decreased IGF-1 induced phosphorylation of the downstream effector AKT and reduced proliferation of multiple androgen-dependent and castration-resistant human prostate cancer cell lines in vitro albeit to varying extents. We evaluated the therapeutic value of ganitumab in several pre-clinical settings including androgen-dependent prostate cancer, castration-resistant (recurrent) prostate cancer, and in combination with androgen-deprivation therapy. Ganitumab inhibited androgen-dependent human VCaP prostate cancer xenograft growth and increased tumor doubling time from 2.3±0.4 weeks to 6.4±0.4 weeks. Ganitumab inhibited growth of castration-resistant VCaP xenografts for over 11.5 weeks of treatment. In contrast, ganitumab did not have appreciable effects on the castration-resistant CWR-22Rv1 xenograft model. Ganitumab was most potent against VCaP xenografts when combined with androgen-deprivation therapy (castration). Tumor volume was reduced by 72% after 4 weeks of treatment and growth suppression was maintained over 16 weeks of treatment. However, a significant proportion of these tumors acquired resistance to ganitumab. To address mechanisms of resistance, we developed an in vitro model of ganitumab resistance, which we termed VCaP/GanR, by prolonged culture of the VCaP human prostate cancer cell in ganitumab. Acquired resistance to ganitumab in VCaP/GanR was a reproducible and stable phenotype. Unlike parental VCaP cells, VCaP/GanR did not undergo apoptosis following ganitumab treatment or serum deprivation. VCaP/GanR did not express increased levels of IGF-1R, insulin receptor, or phospho-AKT compared to parental VCaP. Increased IGF-1R, insulin receptor and phospho-AKT are associated with acquired resistance to IGF-1R inhibition in other cancers. VCaP/GanR exhibited increased levels of phosphorylated S6 indicative of high mTOR activity. However, acquired resistance to ganitumab was not dependent on increased mTOR activity in VCaP/GanR as mTOR inhibitor rapamycin failed to restore sensitivity to ganitumab. Phospho-proteomic arrays revealed alterations in several signaling cascades in VCaP/GanR compared to parental VCaP cells. Inhibitors were identified that restored the antiproliferative effects of ganitumab in VCaP/GanR. These data implicate a new mechanism of resistance to IGF-1R inhibition and support the judicious use of ganitumab in the treatment of prostate cancer.


prostate cancer; IGF-1R; antibody therapy; resistance; castration-resistant prostate cancer; cancer therapy