title: Prioritization of EGFR/IGF-IR/VEGFR2 combination targeted therapies utilizing cancer models.
abstract: BACKGROUND
  Rational strategies utilizing anticancer efficacy and biological principles are needed for the prioritization of specific combination targeted therapy approaches for clinical development, from among the many with experimental support.
  
  
  METHODS
  Antibodies targeting epidermal growth factor receptor (EGFR) (cetuximab), insulin-like growth factor-1 receptor (IGF-IR) (IMC-A12) or vascular endothelial growth factor receptor 2 (VEGFR2) (DC101), were dosed alone or in combination, in 11 human tumor xenograft models established in mice. Efficacy readouts included the tumor burden and incidence of metastasis, as well as tumor active hypoxia inducible factor-1 (HIF-1), human VEGF and blood vessel density.
  
  
  RESULTS
  Cetuximab and DC101 contributed potent and non-overlapping benefits to the combination approach. Moreover, DC101 prevented escape from IMC-A12 + cetuximab in a colorectal cancer model and cetuximab prevented escape from DC101 therapy in a pancreatic cancer model.
  
  
  CONCLUSIONS
  Targeting VEGFR2 + EGFR was prioritized over other treatment strategies utilizing EGFR, IGF-IR and VEGFR2 antibodies. The criteria that proved to be valuable were a non-overlapping spectrum of anticancer activity and the prevention of resistance to another therapy in the combination.
authors.affiliation: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY10014, U.S.A. James.Tonra@imclone.com
authors.forename: James R
authors.initials: JR
authors.lastname: Tonra
authors.forename: Erik
authors.initials: E
authors.lastname: Corcoran
authors.forename: Dhanvanthri S
authors.initials: DS
authors.lastname: Deevi
authors.forename: Philipp
authors.initials: P
authors.lastname: Steiner
authors.forename: Jessica
authors.initials: J
authors.lastname: Kearney
authors.forename: Huiling
authors.initials: H
authors.lastname: Li
authors.forename: Dale L
authors.initials: DL
authors.lastname: Ludwig
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Zhu
authors.forename: Larry
authors.initials: L
authors.lastname: Witte
authors.forename: David
authors.initials: D
authors.lastname: Surguladze
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C511761:DC101 monoclonal antibody; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000068818:Cetuximab