Targeting IGF-IR with ganitumab inhibits tumorigenesis and increases durability of response to androgen-deprivation therapy in VCaP prostate cancer xenografts

Cale D. Fahrenholtz, Pedro J. Beltran, Kerry L Burnstein

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Prostate cancer is the most commonly diagnosed malignancy in 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 (CRPC). Upregulation of the insulin-like growth factor receptor type I (IGF-IR) signaling axis drives growth and progression of prostate cancer by promoting proliferation, survival, and angiogenesis. Ganitumab (formerlyAMG479) is a fully human antibody that inhibits binding of IGF-I and IGF-II to IGF-IR. We evaluated the therapeutic value of ganitumab in several preclinical settings including androgen-dependent prostate cancer, CRPC, and in combination with androgen-deprivation therapy. Ganitumab inhibited IGF-I-induced phosphorylation of the downstream effector AKT and reduced proliferation of multiple androgen-dependent and castration-resistant human prostate cancer cell lines in vitro. Ganitumab inhibited androgen-dependent VCaP xenograft growth and increased tumor-doubling time from 2.3 - 0.4 weeks to 6.4 - 0.4 weeks. Ganitumab blocked 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 complete 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. These data suggest that judicious use of ganitumab particularly in conjunction with androgen-deprivation therapymaybe beneficial in the treatment of prostate cancer.

Original languageEnglish
Pages (from-to)394-404
Number of pages11
JournalMolecular Cancer Therapeutics
Volume12
Issue number4
DOIs
StatePublished - Apr 1 2013

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Heterografts
Androgens
Castration
Prostatic Neoplasms
Carcinogenesis
Therapeutics
Growth
Insulin-Like Growth Factor I
Neoplasms
IGF Type 1 Receptor
Insulin-Like Growth Factor II
AMG 479
Tumor Burden
Up-Regulation
Phosphorylation
Cell Line
Survival
Antibodies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Targeting IGF-IR with ganitumab inhibits tumorigenesis and increases durability of response to androgen-deprivation therapy in VCaP prostate cancer xenografts. / Fahrenholtz, Cale D.; Beltran, Pedro J.; Burnstein, Kerry L.

In: Molecular Cancer Therapeutics, Vol. 12, No. 4, 01.04.2013, p. 394-404.

Research output: Contribution to journalArticle

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abstract = "Prostate cancer is the most commonly diagnosed malignancy in 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 (CRPC). Upregulation of the insulin-like growth factor receptor type I (IGF-IR) signaling axis drives growth and progression of prostate cancer by promoting proliferation, survival, and angiogenesis. Ganitumab (formerlyAMG479) is a fully human antibody that inhibits binding of IGF-I and IGF-II to IGF-IR. We evaluated the therapeutic value of ganitumab in several preclinical settings including androgen-dependent prostate cancer, CRPC, and in combination with androgen-deprivation therapy. Ganitumab inhibited IGF-I-induced phosphorylation of the downstream effector AKT and reduced proliferation of multiple androgen-dependent and castration-resistant human prostate cancer cell lines in vitro. Ganitumab inhibited androgen-dependent VCaP xenograft growth and increased tumor-doubling time from 2.3 - 0.4 weeks to 6.4 - 0.4 weeks. Ganitumab blocked 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 complete 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. These data suggest that judicious use of ganitumab particularly in conjunction with androgen-deprivation therapymaybe beneficial in the treatment of prostate cancer.",
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