Abstract
BackgroundchA21 is a novel tumor-inhibitory antibody which recognized subdomain I of HER2 extracellular domain with an epitope distinct from other HER2 antibodies. Previously, we demonstrated that chA21 inhibits human ovarian carcinoma cell line SKOV-3 growth in vitro and in vivo study. In this study, we further investigated the anti-angiogenic efficacy combination of chA21 with trastuzumab in SKOV-3 xenograft model.MethodsNude mice were s.c. challenged with SKOV-3 cells and received treatment of chA21 alone, trastuzumab alone or both antibodies together twice a week for 21 days. Tumor volume and microvessel density (MVD) were evaluated. The effect of chA21 plus trastuzumab treament on vascular endothelial growth factor (VEGF) secretion, endothelial cells proliferation and migration, and the status of HER2 downstream pathway AKT/phosphorylated AKT (pAKT) were evaluated in vitro.ResultsIn vivo study combination of chA21 with trastuzumab resulted in reduce tumor growth and angiogenesis than each monotherapy. In vitro study, the combination of chA21 with trastuzumab inhibits VEGF secretion, endothelial cells proliferation and migration. Furthermore, the combination treatment inhibits pAKT expression.ConclusionOur findings suggested that the combination of chA21 with trastuzumab can cause augmented inhibition of angiogenesis in SKOV-3 xenograft model. Inhibition of agniogenesis may through suppression of AKT pathway. The therapeutic benefits of combination chA21 with trastuzumab warrant further study in an attempt to make the translation into the clinic.
Highlights
Epithelial ovarian carcinoma is the most lethal gynecologic malignancy and resulting in high mortality rates among women patients [1]
We further investigated if more effective inhibition of angiogenesis is one of the underlying causes of the better therapeutic efficacy of the chA21 with trastuzumab combination in SKOV-3 xenograft model
Enhanced tumor growth inhibition by combination of chA21 with trastuzumab Initially, we evaluated whether the chA21 plus trastuzumab treatment leads to better tumor inhibition in SKOV-3 xenografts
Summary
Epithelial ovarian carcinoma is the most lethal gynecologic malignancy and resulting in high mortality rates among women patients [1]. Despite the advances in surgery, chemotherapy and radiotherapy, the average time of clinical remission is 2.5 years and approximately 20% of patients never achieve remission [2]. It underscores the need for new therapeutic strategies that can be translated to the clinical treatment. HER2 overexpression has been reported to in 15% to 30% of ovarian carcinoma patients [4,5]. We demonstrated that chA21 inhibits human ovarian carcinoma cell line SKOV-3 growth in vitro and in vivo study. We further investigated the anti-angiogenic efficacy combination of chA21 with trastuzumab in SKOV-3 xenograft model
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