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

Abstract

Purpose: 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. Experimental Design: 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. Results: Monotherapy ED 50 values for tumor growth inhibition ranged from1.8 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 hypoxiainducible factor 1apotentially acting as molecular links between EGFR and VEGFR2 inhibition. Conclusions: Results show antitumor synergy for combined EGFR and VEGFR2 targeted therapy, supporting the significant therapeutic potential of this combination strategy.

Current role of antibody therapy in patients with metastatic colorectal cancer

“…Preclinical studies confirmed a synergistic growth inhibition (Morelli et al, 2006;Tonra et al, 2006) and preliminary clinical data have already verified efficacy of the combination . The BOND II trial was a randomized phase II trial (combination of Cx and Bv with or without irinotecan), but it was sadly preliminary stopped due to poor accrual after inclusion of only 74 patients with irinotecanresistent mCRC (Table 3).…”

A human IgG-like bispecific antibody co-targeting epidermal growth factor receptor and the vascular endothelial growth factor receptor 2 for enhanced antitumor activity

“…23,26 In addition, the combination of EGFR and VEGFR2 antagonists enhanced anti-tumor effect, which suggests EGFR and VEGFR2 co-targeted therapy has therapeutic potential in colon tumors. [27][28] In this article, we designed a bispecific antibody based on a known EGFR antibody and our VEGFR2 antibody. Its efficacy was evaluated both in vitro assays and nude mice tumor xenograft models, indicating co-targeting EGFR and VEGFR2 may be of clinical relevance in treating EGFR and/or VEGFR2 overexpressing malignant.…”

Regulation of Angiogenesis in Human Cancer via Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2)

“…Tonra et al used anti-EGFR (cetuximab) and VEGFR-2 (DC101) antibodies in pancreatic (BxPc-3) and colon cancer (GEO) cell lines. The dose response of the combined treatment revealed synergism for both cell lines (CI=0.1, P<0.01 for BxPC-3 and CI=0.1, P<0.01 for GEO) (Tonra et al 2006). Several studies have been conducted using VEGFR-2 inhibitors for treatment highlighting the role of this pathway in the pathogenesis, proliferation and survival of PCa.…”