Effective Therapeutic Targeting of the Overexpressed HER-2 Receptor in a Highly Metastatic Orthotopic Model of Esophageal Carcinoma

Abstract

This study aimed to determine the targeted efficacy of trastuzumab (Herceptin) on human epidermal growth factor receptor 2 (HER-2)-overexpressing metastatic esophageal cancer in an orthotopic mouse model. HER-2 overexpression and amplification of human esophageal primary and metastatic tumors were shown with HER-2-fluorescence in situ hybridization analysis and HER-2 immunostaining. Following orthotopic implantation with the HER-2-overexpressing OE19 human esophageal cancer cell line, mice were treated with trastuzumab. Sequential magnetic resonance imaging was used to monitor primary tumor and metastasis during treatment. After six weeks, a significant inhibition of primary tumor development was imaged in trastuzumab-treated animals in comparison with the control group. Trastuzumab treatment also led to a reduction of lymphatic metastasis. Thus, HER-2 targeted therapy with trastuzumab resulted in a significant primary tumor growth reduction as well as a decrease of lymph node metastases in the orthotopic model of metastatic esophageal carcinoma. The results of the present study suggest the clinical use of trastuzumab for HER-2-overexpressing esophageal cancer, which is a significant fraction of the patient population. Treatment of this highly treatmentresistant disease with trastuzumab in the adjuvant setting to prevent lymph node metastasis after primary tumor resection is suggested by the data in this report. Mol Cancer Ther; 9(7); 2037-45. ©2010 AACR.

Lapatinib acts on gastric cancer through both antiproliferative function and augmentation of trastuzumab-mediated antibody-dependent cellular cytotoxicity

“…As it is well known that MKN7, NCI-N87, and OE19 are HER2-overexpressing and HER2-gene-amplified gastric cancer cell lines [18,[35][36][37][38], we used MKN7, NCI-N87, and OE19 as HER2-overexpressing cell lines and the others as HER2-low-expressing cell lines in this study.…”

Establishment and characterization of esophageal squamous cell carcinoma patient-derived xenograft mouse models for preclinical drug discovery

“…25,36 Development of esophageal animal xenograft models has been especially difficult but some success has been achieved, 37 either by the inoculation of EC cell lines into immunodeficient rodents (mice and rats) or rabbits. 15,[38][39][40][41] Unfortunately, again, however, these cell lines also suffer from the same issues of long in vitro culture times and loss of original tumor characteristics. Another problem faced by the field of esophageal oncology research is that most of the commercially available EC cell lines were originally derived from esophageal adenocarcinoma, 15 45 the majority of PDECX models were of adenocarcinoma origin.…”

“…15,[38][39][40][41] Unfortunately, again, however, these cell lines also suffer from the same issues of long in vitro culture times and loss of original tumor characteristics. Another problem faced by the field of esophageal oncology research is that most of the commercially available EC cell lines were originally derived from esophageal adenocarcinoma, 15 45 the majority of PDECX models were of adenocarcinoma origin. Therefore, our present study aimed to establish a panel of Chinese patient-derived ESCC xenograft mouse models, harboring a variety of genetic aberrations and thereby constituting a pharmacologic platform for targeted drug efficacy evaluation.…”

“…12 Furthermore, the efficacy of new therapeutic drugs remains to be tested in ESCC as most of the previous trials have included predominantly esophageal adenocarcinoma patients. [13][14][15][16][17][18][19] Despite some successes in the treatment of cancers, 9 more novel rational therapies targeting specific cancer-related molecules are urgently needed. The increasing body of knowledge around molecular and genetic events involved in oncogenesis and tumor progression has led to the identification of new therapeutic targets and the synthesis of novel therapeutic agents.…”

Novel metastatic models of esophageal adenocarcinoma derived from FLO-1 cells highlight the importance of E-cadherin in cancer metastasis

“…Indeed, the reported postoperative mortality for Levrat's rodent surgical reflux model is at least 30% [13]. Secondly, the metastatic phenotype is not robust or reproducible, with the rate of metastasis varying between 0–78% across different studies [11, 13–16]. Thirdly, the duration from surgery or cancer cell inoculation to micro-metastasis is over 40 weeks in some models [13, 15].…”