Ganitumab (AMG 479) inhibits IGF-II-dependent ovarian cancer growth and potentiates platinum-based chemotherapy

Pedro J. Beltran, Frank J. Calzone, Petia Mitchell, Young Ah Chung, Elaina Cajulis, Gordon Moody, Brian Belmontes, Chi Ming Li, Steven Vonderfecht, Victor E. Velculescu, Guorong Yang, Jingwei Qi, Dennis J. Slamon, Gottfried E. Konecny

Research output: Contribution to journalArticle

Abstract

Purpose: Insulin-like growth factor 1 receptor (IGF-IR) has been implicated in the pathogenesis of ovarian cancer. Ganitumab is an investigational, fully human monoclonal antibody against IGF-IR. Here, we explore the therapeutic potential of ganitumab for the treatment of ovarian cancer. Experimental Design: The effects of ganitumab were tested in vitro against a panel of 23 established ovarian cancer cell lines. The ability of ganitumab to inhibit IGF-I-, IGF-II-, and insulin-mediated signaling was examined in vitro and in tumor xenografts using ovarian cancer models displaying IGF-IR/PI3K/AKT pathway activation by two distinct mechanisms, PTEN loss and IGF-II overexpression. Drug interactions between ganitumab and cisplatin, carboplatin, or paclitaxel were studied in vitro and in vivo. Results: In vitro, growth inhibition varied significantly among individual ovarian cancer cell lines. IGF-II mRNA and phospho-IGF-IR protein expression were quantitatively correlated with response to ganitumab, and PTEN mutations conferred resistance to ganitumab. Ganitumab potently inhibited baseline and IGF-I-, IGF-II-, and insulin-induced IGF-IR and IGF-IR/insulin hybrid receptor signaling in vitro and in vivo. Synergistic and additive drug interactions were seen for ganitumab and carboplatin or paclitaxel in vitro. Furthermore, ganitumab significantly increased the efficacy of cisplatin in ovarian cancer xenograft models in vivo. Conclusions: These observations provide a biologic rationale to test ganitumab as a single agent or in combination with carboplatin/cisplatin and paclitaxel in patients with ovarian cancer. Moreover, assessment of tumor expression of IGF-II, phospho-IGF-IR, or PTEN status may help select patients with ovarian cancer who are most likely to benefit from ganitumab.

Original languageEnglish (US)
Pages (from-to)2947-2958
Number of pages12
JournalClinical Cancer Research
Volume20
Issue number11
DOIs
StatePublished - Jun 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Beltran, P. J., Calzone, F. J., Mitchell, P., Chung, Y. A., Cajulis, E., Moody, G., Belmontes, B., Li, C. M., Vonderfecht, S., Velculescu, V. E., Yang, G., Qi, J., Slamon, D. J., & Konecny, G. E. (2014). Ganitumab (AMG 479) inhibits IGF-II-dependent ovarian cancer growth and potentiates platinum-based chemotherapy. Clinical Cancer Research, 20(11), 2947-2958. https://doi.org/10.1158/1078-0432.CCR-13-3448