Augmented inhibition of angiogenesis by combination of HER2 antibody chA21 and trastuzumab in human ovarian carcinoma xenograft

Zhang, Anli; Shen, Guodong; Zhao, Ting; Zhang, Guihong; Liu, Jing; Song, Lijun; Wei, Wei; Ling, Bing; Wu, Zhengsheng; Wu, Qiang

doi:10.1186/1757-2215-3-20

Cited by 16 publications

(15 citation statements)

References 28 publications

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“…For example, the combination of trastuzumab with chA21 significantly reduced tumor size in mice with SKOV3 xenografts compared with antibody monotherapy (p<0.05) (A. Zhang et al, 2010). Similar results were observed with pertuzumab-trastuzumab combinations (Faratian et al, 2011) that have shown promise in the clinic (see Section 3.1) .…”

Section: The Future Of the Her Family As Targets In Oncologysupporting

confidence: 70%

HER2 as a Therapeutic Target in Ovarian Cancer

Amler¹,

Wang²

2012

Ovarian Cancer - Clinical and Therapeutic Perspectives

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Section: The Future Of the Her Family As Targets In Oncologysupporting

confidence: 70%

HER2 as a Therapeutic Target in Ovarian Cancer

Amler¹,

Wang²

2012

Ovarian Cancer - Clinical and Therapeutic Perspectives

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“…A secondary mechanism of action is through inhibition of angiogenic factors, creating an indirect anti-angiogenic treatment. This is thought to be due to down-regulation of vascular endothelial growth factor (VEGF) expression induced by trastuzumab, although the exact pathway has yet to be established [9–11]. Trastuzumab has been established as an effective therapy in the treatment of HER2+ breast cancers [12, 13], and is currently included in the standard-of-care treatment for patients with this disease.…”

Section: Introductionmentioning

confidence: 99%

Trastuzumab improves tumor perfusion and vascular delivery of cytotoxic therapy in a murine model of HER2+ breast cancer: preliminary results

Sorace

Quarles

Whisenant

et al. 2016

Breast Cancer Res Treat

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To employ in vivo imaging and histological techniques to identify and quantify vascular changes early in the course of treatment with trastuzumab in a murine model of HER2+ breast cancer. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantitatively characterize vessel perfusion/permeability (via the parameter Ktrans) and the extravascular extracellular volume fraction (ve) in the BT474 mouse model of HER2+ breast cancer (N = 20) at baseline, day one, and day four following trastuzumab treatment (10 mg/kg). Additional cohorts of mice were used to quantify proliferation (Ki67), microvessel density (CD31), pericyte coverage (α-SMA) by immunohistochemistry (N = 44), and to quantify human VEGF-A expression (N = 29) throughout the course of therapy. Longitudinal assessment of combination doxorubicin ± trastuzumab (N = 42) tested the hypothesis that prior treatment with trastuzumab will increase the efficacy of subsequent doxorubicin therapy. Compared to control tumors, trastuzumab-treated tumors exhibited a significant increase in Ktrans (P = 0.035) on day four, indicating increased perfusion and/or vessel permeability and a simultaneous significant increase in ve (P = 0.01), indicating increased cell death. Immunohistochemical and ELISA analyses revealed that by day four the trastuzumab-treated tumors had a significant increase in vessel maturation index (i.e., the ratio of α-SMA to CD31 staining) compared to controls (P < 0.001) and a significant decrease in VEGF-A (P = 0.03). Additionally, trastuzumab dosing prior to doxorubicin improved the overall effectiveness of the therapies (P < 0.001). This study identifies and validates improved perfusion characteristics following trastuzumab therapy, resulting in an improvement in trastuzumab-doxorubicin combination therapy in a murine model of HER2+ breast cancer. This data suggests properties of vessel maturation. In particular, the use of DCE-MRI, a clinically available imaging method, following treatment with trastuzumab may provide an opportunity to optimize the scheduling and improve delivery of subsequent cytotoxic therapy.

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“…Development of new antibody drugs or combinations of ectodomain binding monoclonal antibodies is a reasonable approach to limit the emergence of resistance or even to treat the single antibody-resistant tumor (8,20). The antip185 her2/neu antibody chA21 mediates specific inhibitory effects on p185 her2/neu -overexpressed cancer cells (21,22), as well as human breast and ovarian cancer xenograft (23,24). Our previous data revealed that chA21 is a potent down-regulator of p185 her2/neu (22).…”

Section: P185mentioning

confidence: 99%

Structural Insights into the Down-regulation of Overexpressed p185 Protein of Transformed Cells by the Antibody chA21

Zhou

Zha

Liu

et al. 2011

Journal of Biological Chemistry

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p185her2/neu belongs to the ErbB receptor tyrosine kinase family, which has been associated with human breast, ovarian, and lung cancers. Targeted therapies employing ectodomain-specific p185 her2/neu monoclonal antibodies (mAbs) have demonstrated clinical efficacy for breast cancer. Our previous studies have shown that p185 her2/neu mAbs are able to disable the kinase activity of homomeric and heteromeric kinase complexes and induce the conversion of the malignant to normal phenotype. We previously developed a chimeric antibody chA21 that specifically inhibits the growth of p185 her2/neu -overexpressing cancer cells in vitro and in vivo. Herein, we report the crystal structure of the single-chain Fv of chA21 in complex with an N-terminal fragment of p185 her2/neu , which reveals that chA21 binds a region opposite to the dimerization interface, indicating that chA21 does not directly disrupt the dimerization. In contrast, the bivalent chA21 leads to internalization and down-regulation of p185 her2/neu . We propose a structure-based model in which chA21 cross-links two p185 her2/neu molecules on separate homo-or heterodimers to form a large oligomer in the cell membrane. This model reveals a mechanism for mAbs to drive the receptors into the internalization/degradation path from the inactive hypophosphorylated tetramers formed dynamically by active dimers during a "physiologic process." p185 her2/neu is one of the four receptor tyrosine kinases of the ErbB family. We initially found that both homodimerization and heterodimerization with other ErbB receptors will induce transphosphorylation of the intracellular domains and result in the downstream signaling for cell proliferation and transformation. Moreover our studies have established that heterodimerization leads to increased signaling and transforming activity (1, 2). Significant overexpression of p185 her2/neu results in abnormalities in cell signaling and can cause cell transformation. Early studies from several laboratories found that her2/neu gene was amplified and overexpressed in 20 -30% of breast and ovarian cancers. Breast cancers that have p185 her2/neu overexpressed have a more aggressive course associated with higher relapse rates (3). p185her2/neu represents the first oncoprotein target amenable for drug intervention and immunotherapy in which disabling the kinase reverses the malignant properties of the transformed cell and renders the tumor sensitive to chemotherapy and radiation therapy (4 -8).The p185 her2/neu protein possesses a similar architecture to the other three ErbB members of this family. These kinases are type 1 transmembrane proteins and comprise an extracellular domain (ECD) 4 with four subdomains (I/L1, II/S1, III/L2, IV/S2), a single transmembrane helix, an intracellular tyrosine kinase domain, and a C-terminal tail (9). Recent crystallographic studies revealed that the subdomains II and IV contribute to dimerization events of the ErbB receptors (10, 11). Monoclonal antibodies that bind the ectodomains of these ErbB proteins hav...

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Augmented inhibition of angiogenesis by combination of HER2 antibody chA21 and trastuzumab in human ovarian carcinoma xenograft

Cited by 16 publications

References 28 publications

HER2 as a Therapeutic Target in Ovarian Cancer

HER2 as a Therapeutic Target in Ovarian Cancer

Trastuzumab improves tumor perfusion and vascular delivery of cytotoxic therapy in a murine model of HER2+ breast cancer: preliminary results

Structural Insights into the Down-regulation of Overexpressed p185 Protein of Transformed Cells by the Antibody chA21

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