Synergistic Antitumor Effects of Combined Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor-2 Targeted Therapy

James R Tonra,Huiling Li,Francine E Carrick,Daniel J Hicklin,Dhanvanthri S Deevi,Su Wang,Erik Corcoran

doi:10.1158/1078-0432.ccr-05-1682

Abstract

Combination therapies that target the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways, are being actively tested for the treatment of cancer. In evaluating combination strategies, the ideal combination would be one in which the treatments interact in a way that is synergistic with regard to antitumor effects. Here, we have evaluated the interaction between anti-EGFR antibody Erbitux (cetuximab) and anti-VEGFR2 antibody, DC101, in preclinical models of pancreatic (BxPC-3) and colon (GEO) cancer. Analysis of the interaction between cetuximab and DC101 in vivo used a novel method for establishing the upper 95% confidence limits for the combination index (CI) of isobologram analyses, where CI < 1 indicates synergy. Assessment of tumor cell proliferation, apoptosis, VEGF production, and hypoxia, as well as tumor vascularization, was performed to gain insights into the mechanistic basis for synergy between agents targeting different tumor compartments. Monotherapy ED(50) values for tumor growth inhibition ranged from 1.8 to 2.3 mg/kg and 10.5 to 16.6 mg/kg for cetuximab and DC101, respectively. From the dose response of the combination treatment, it was determined that cetuximab and DC101 are synergistic in the BxPC-3 (CI = 0.1, P < 0.01) and GEO (CI = 0.1, P < 0.01) models. Overlapping effects on the tumor cell and vascular compartments form a basis for the interaction, with VEGF production and hypoxia-inducible factor 1alpha potentially acting as molecular links between EGFR and VEGFR2 inhibition. Results show antitumor synergy for combined EGFR and VEGFR2 targeted therapy, supporting the significant therapeutic potential of this combination strategy.

Highlights

Combination therapies that target the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways, are being actively tested for the treatment of cancer
Cetuximab and DC101 antibody treatments were tested independently and in combination at a range of doses to characterize the interaction between the treatments with regard to tumor growth inhibition (Table 1)
Preclinical and clinical data support an increase in antitumor effect when combining an efficacious dose of an EGFR antagonist with a VEGFR antagonist [11, 16, 17, 19]

Summary

Introduction

Combination therapies that target the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways, are being actively tested for the treatment of cancer. The full potential of targeted therapies for the treatment of cancer is still being tested, combining these targeted therapies with the aim of increased efficacy and a reduced toxicity profile is rapidly emerging as a therapeutic strategy. One such approach that is showing promise is combined inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) signaling. Inhibiting EGFR signaling significantly inhibits tumor growth in numerous preclinical models including pancreatic (1 – 3), colon [4], and lung [5] cancer models These effects have been associated with reduced tumor cell proliferation and increased tumor cell apoptosis (1, 4 – 6).

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Results

Conclusion