Prioritization of EGFR/IGF-IR/VEGFR2 combination targeted therapies utilizing cancer models.
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.
Tonra
James R
JR
ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY10014, U.S.A. James.Tonra@imclone.com
Corcoran
Erik
E
Deevi
Dhanvanthri S
DS
Steiner
Philipp
P
Kearney
Jessica
J
Li
Huiling
H
Ludwig
Dale L
DL
Zhu
Zhenping
Z
Witte
Larry
L
Surguladze
David
D
Hicklin
Daniel J
DJ
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
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