The efficacy of IGF-I receptor monoclonal antibody against human gastrointestinal carcinomas is independent of k-ras mutation status.

Abstract

PURPOSE:

Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal cancers. We have previously shown successful targeting therapy for colorectal, pancreatic, gastric, and esophageal carcinomas using recombinant adenoviruses expressing dominant negative IGF-IR. Mutation in k-ras is one of key factors in gastrointestinal cancers. In this study, we sought to evaluate the effect of a new monoclonal antibody for IGF-IR, figitumumab (CP-751,871), on the progression of human gastrointestinal carcinomas with/without k-ras mutation.

EXPERIMENTAL DESIGN:

We assessed the effect of figitumumab on signal transduction, proliferation, and survival in six gastrointestinal cancer cell lines with/without k-ras mutation, including colorectal and pancreatic adenocarcinoma, esophageal squamous cell carcinoma, and hepatoma. Combination effects of figitumumab and chemotherapy were also studied. Then figitumumab was evaluated in the treatment of xenografts in nude mice.

RESULTS:

Figitumumab blocked autophosphorylation of IGF-IR and its downstream signals. The antibody suppressed proliferation and tumorigenicity in all cell lines. Figitumumab inhibited survival by itself and up-regulated chemotherapy (5-FU and gemcitabine) induced apoptosis. Moreover, the combination of this agent and chemotherapy was effective against tumors in mice. The effect of figitumumab was not influenced by the mutation status of k-ras. Figitumumab reduced expression of IGF-IR but not insulin receptor in these xenografted tumors. The drug did not affect murine body weight or blood concentrations of glucose, insulin, IGF binding protein 3, and growth hormone.

CONCLUSIONS:

IGF-IR might be a good molecular therapeutic target and figitumumab may thus have therapeutic value in human gastrointestinal malignancies even in the presence of k-ras mutations.

• Authors: Masanori Ii, Hua Li, Yasushi Adachi, Hiroyuki Yamamoto, Hirokazu Ohashi, Hiroaki Taniguchi, Yoshiaki Arimura, David P Carbone, Kohzoh Imai, Yasuhisa Shinomura
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 15 Pg. 5048-59 (Aug 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21642381 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Antibodies, Monoclonal
• Immunoglobulins, Intravenous
• Receptor, IGF Type 1
• figitumumab

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Disease Progression
• Gastrointestinal Neoplasms (drug therapy, genetics)
• Genes, ras
• Humans
• Immunoglobulins, Intravenous
• Mice
• Mice, Nude
• Mutation
• Receptor, IGF Type 1 (immunology)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays