title: Ganitumab (AMG 479) inhibits IGF-II-dependent ovarian cancer growth and potentiates platinum-based chemotherapy.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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. Clin Cancer Res; 20(11); 2947-58. ©2014 AACR.
authors.affiliation: Authors' Affiliations: Oncology Research Therapeutic Area, Genomics Analysis Unit, Department of Pathology, Amgen Inc., Thousand Oaks; Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and The Ludwig Center and the Howard Hughes Medical Institute, Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland pbeltran@amgen.com.
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Beltran
authors.affiliation: Authors' Affiliations: Oncology Research Therapeutic Area, Genomics Analysis Unit, Department of Pathology, Amgen Inc., Thousand Oaks; Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and The Ludwig Center and the Howard Hughes Medical Institute, Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Calzone
authors.affiliation: Authors' Affiliations: Oncology Research Therapeutic Area, Genomics Analysis Unit, Department of Pathology, Amgen Inc., Thousand Oaks; Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and The Ludwig Center and the Howard Hughes Medical Institute, Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Petia
authors.initials: P
authors.lastname: Mitchell
authors.affiliation: Authors' Affiliations: Oncology Research Therapeutic Area, Genomics Analysis Unit, Department of Pathology, Amgen Inc., Thousand Oaks; Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and The Ludwig Center and the Howard Hughes Medical Institute, Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Young-Ah
authors.initials: YA
authors.lastname: Chung
authors.affiliation: Authors' Affiliations: Oncology Research Therapeutic Area, Genomics Analysis Unit, Department of Pathology, Amgen Inc., Thousand Oaks; Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and The Ludwig Center and the Howard Hughes Medical Institute, Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Elaina
authors.initials: E
authors.lastname: Cajulis
authors.affiliation: Authors' Affiliations: Oncology Research Therapeutic Area, Genomics Analysis Unit, Department of Pathology, Amgen Inc., Thousand Oaks; Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and The Ludwig Center and the Howard Hughes Medical Institute, Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Gordon
authors.initials: G
authors.lastname: Moody
authors.affiliation: Authors' Affiliations: Oncology Research Therapeutic Area, Genomics Analysis Unit, Department of Pathology, Amgen Inc., Thousand Oaks; Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and The Ludwig Center and the Howard Hughes Medical Institute, Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Brian
authors.initials: B
authors.lastname: Belmontes
authors.affiliation: Authors' Affiliations: Oncology Research Therapeutic Area, Genomics Analysis Unit, Department of Pathology, Amgen Inc., Thousand Oaks; Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and The Ludwig Center and the Howard Hughes Medical Institute, Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Li
authors.affiliation: Authors' Affiliations: Oncology Research Therapeutic Area, Genomics Analysis Unit, Department of Pathology, Amgen Inc., Thousand Oaks; Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and The Ludwig Center and the Howard Hughes Medical Institute, Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Steven
authors.initials: S
authors.lastname: Vonderfecht
authors.affiliation: Authors' Affiliations: Oncology Research Therapeutic Area, Genomics Analysis Unit, Department of Pathology, Amgen Inc., Thousand Oaks; Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and The Ludwig Center and the Howard Hughes Medical Institute, Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.affiliation: Authors' Affiliations: Oncology Research Therapeutic Area, Genomics Analysis Unit, Department of Pathology, Amgen Inc., Thousand Oaks; Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and The Ludwig Center and the Howard Hughes Medical Institute, Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Guorong
authors.initials: G
authors.lastname: Yang
authors.affiliation: Authors' Affiliations: Oncology Research Therapeutic Area, Genomics Analysis Unit, Department of Pathology, Amgen Inc., Thousand Oaks; Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and The Ludwig Center and the Howard Hughes Medical Institute, Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Qi
authors.affiliation: Authors' Affiliations: Oncology Research Therapeutic Area, Genomics Analysis Unit, Department of Pathology, Amgen Inc., Thousand Oaks; Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and The Ludwig Center and the Howard Hughes Medical Institute, Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
authors.affiliation: Authors' Affiliations: Oncology Research Therapeutic Area, Genomics Analysis Unit, Department of Pathology, Amgen Inc., Thousand Oaks; Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and The Ludwig Center and the Howard Hughes Medical Institute, Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Gottfried E
authors.initials: GE
authors.lastname: Konecny
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D016190:Carboplatin / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D017239:Paclitaxel / Q000008:administration & dosage; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007335:Insulin-Like Growth Factor II; D016190:Carboplatin; C545764:ganitumab; D017526:Receptor, IGF Type 1; D051059:PTEN Phosphohydrolase; D017239:Paclitaxel; D002945:Cisplatin
references.citation: Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9267-71
references.pmid: 1409633
references.citation: Eur J Cancer. 2012 Jul;48(10):1570-80
references.pmid: 22033326
references.citation: J Clin Oncol. 2008 Apr 1;26(10):1626-34
references.pmid: 18316791
references.citation: Mol Cancer Ther. 2005 Nov;4(11):1764-71
references.pmid: 16275998
references.citation: Lancet. 2009 Oct 17;374(9698):1331-8
references.pmid: 19767092
references.citation: Assay Drug Dev Technol. 2007 Jun;5(3):391-401
references.pmid: 17638539
references.citation: Nat Rev Cancer. 2004 Jul;4(7):505-18
references.pmid: 15229476
references.citation: Gynecol Oncol. 2005 Feb;96(2):355-61
references.pmid: 15661221
references.citation: Semin Reprod Med. 2009 Jan;27(1):43-51
references.pmid: 19197804
references.citation: J Clin Oncol. 2009 Mar 20;27(9):1419-25
references.pmid: 19224846
references.citation: Cancer Res. 2000 Nov 1;60(21):5988-94
references.pmid: 11085518
references.citation: Nature. 1993 Apr 22;362(6422):747-9
references.pmid: 8385745
references.citation: Hum Mol Genet. 2011 Jun 1;20(11):2263-72
references.pmid: 21422097
references.citation: Nat Genet. 1999 Jan;21(1):99-102
references.pmid: 9916799
references.citation: Onkologie. 2009 Nov;32(11):638-44
references.pmid: 19887867
references.citation: Cancer Res. 2009 Nov 1;69(21):8275-83
references.pmid: 19843859
references.citation: Clin Cancer Res. 1998 Nov;4(11):2577-83
references.pmid: 9829719
references.citation: J Biol Chem. 2002 Sep 6;277(36):33490-500
references.pmid: 12087097
references.citation: Science. 2006 Oct 13;314(5797):268-74
references.pmid: 16959974
references.citation: J Natl Cancer Inst. 2004 May 19;96(10):739-49
references.pmid: 15150302
references.citation: Clin Cancer Res. 2010 Jun 1;16(11):2999-3010
references.pmid: 20404007
references.citation: Clin Cancer Res. 2006 Feb 15;12(4):1208-14
references.pmid: 16489075
references.citation: J Pharmacol Exp Ther. 2011 Jun;337(3):644-54
references.pmid: 21385891
references.citation: Expert Opin Ther Targets. 2013 Mar;17(3):307-20
references.pmid: 23294364
references.citation: Mol Cancer Res. 2006 Apr;4(4):283-92
references.pmid: 16603642
references.citation: CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
references.pmid: 20610543
references.citation: Mol Cancer Ther. 2012 Jul;11(7):1609-17
references.pmid: 22556379
references.citation: Cancer Res. 2006 Sep 1;66(17):8715-21
references.pmid: 16951187
references.citation: Mol Endocrinol. 1990 Dec;4(12):1914-20
references.pmid: 2082190
references.citation: Reprod Fertil Dev. 2011;24(1):19-28
references.pmid: 22394714
references.citation: PLoS Med. 2008 Dec 2;5(12):e232
references.pmid: 19053170
references.citation: Mol Cell Biol. 1999 May;19(5):3278-88
references.pmid: 10207053
references.citation: Mol Cancer Ther. 2009 May;8(5):1095-105
references.pmid: 19366899
references.citation: J Natl Cancer Inst. 2012 Jul 3;104(13):975-81
references.pmid: 22761272
references.citation: Mol Cancer Ther. 2010 Oct;9(10):2652-64
references.pmid: 20924128
references.citation: Clin Cancer Res. 2011 Mar 15;17(6):1591-602
references.pmid: 21278246
references.citation: Am J Surg. 2008 Jun;195(6):719-25
references.pmid: 18440486
references.citation: Nat Rev Genet. 2006 Aug;7(8):606-19
references.pmid: 16847462
references.citation: Cancer Res. 2009 Apr 1;69(7):2996-3003
references.pmid: 19318572