Abstract
The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis is an essential regulator of angiogenesis and important therapeutic target in cancer. Ramucirumab is an anti-VEGFR2 monoclonal antibody used for the treatment of several cancers. Increased circulating VEGF-A levels after ramucirumab administration are associated with a worse prognosis, suggesting that excess VEGF-A induced by ramucirumab negatively affects treatment efficacy and that neutralizing VEGF-A may improve treatment outcomes. Here, we evaluated the effect of combination treatment with an anti-VEGFR2 antibody and anti-VEGF-A antibody on gastric tumor progression and normal tissues using a preclinical BALB/c-nu/nu mouse xenograft model. After anti-VEGFR2 antibody treatment in mice, a significant increase in plasma VEGF-A levels was observed, mirroring the clinical response. The elevated VEGF-A was host-derived. Anti-VEGF-A antibody co-administration enhanced the anti-tumor effect of the anti-VEGFR2-antibody without exacerbating the toxicity. Mechanistically, the combination treatment induced intra-tumor molecular changes closely related to angiogenesis inhibition and abolished the gene expression changes specifically induced by anti-VEGFR2 antibody treatment alone. We particularly identified the dual treatment-selective downregulation of ZEB1 expression, which was critical for gastric cancer cell proliferation. These data indicate that the dual blockade of VEGF-A and VEGFR2 is a rational strategy to ensure the anti-tumor effect of angiogenesis-targeting therapy.
Highlights
Gastric cancer is the seventh most commonly diagnosed cancer and the third leading cause of cancer-related deaths worldwide[1]
Targeted therapy, we used a mouse xenograft model inoculated with human gastric cancer cells according to previous preclinical evaluations of VEGF receptor 2 (VEGFR2)-targeted agents[13], which were based on the evidence that there is minimal species-specificity in the effect of vascular endothelial growth factor (VEGF) on V EGFR25
We examined whether the levels of Vascular endothelial growth factor-A (VEGF-A) and other soluble factors in the blood were induced after anti-VEGFR2 antibody administration, as observed in clinical patients[14]
Summary
Gastric cancer is the seventh most commonly diagnosed cancer and the third leading cause of cancer-related deaths worldwide[1]. Systemic chemotherapy with fluoropyrimidine plus a platinum agent is the standard of care worldwide[2,3] Several biologics, such as anti-angiogenic agents and immune checkpoint inhibitors, have been widely used for gastric cancer[4,5]. Study comparing paclitaxel plus ramucirumab and paclitaxel plus placebo showed a significantly prolonged overall survival from 7.4 months in the placebo group to 9.6 months in the ramucirumab group Based on these data, ramucirumab was approved and is currently widely used as a second-line treatment in gastric c ancer[4]. In our previous clinical study[15], the elevation of VEGF-A after ramucirumab treatment was predominantly associated with worse outcome among the VEGF members that we analyzed. We examined the therapeutic significance of anti-VEGF-A antibody co-administration in VEGFR2-targeted therapy using a preclinical mouse xenograft model
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