Efficacy of trastuzumab treatment in a metastatic mouse model of HER2 overexpressing human esophageal adenocarcinoma

Abstract

One of the main challenges of cancer therapy is the prevention of severe side effects often observed during conventional chemotherapies that affect non-malignant cells also. Therefore, a range of targeted therapies have been developed utilizing unique tumor cell characteristics for the mode of pharmacological action. One prominent example of targeted therapy is the treatment of human epidermal growth factor receptor (HER)2-positive breast cancer patients with the humanized monoclonal antibody trastuzumab (Herceptin ®). HER2 activates several downstream signalling pathways involved in tumor cell proliferation, migration and angiogenesis, all important steps of metastasis formation. Trastuzumab directly targets the extracellular domain of HER2 and shows a remarkable therapeutic efficacy in a subset of breast cancer patients. Interestingly, an overexpression of HER2 has meanwhile also been described in 10 – 40% of patients with esophageal adenocarcinoma. We have therefore investigated the effects of trastuzumab on proliferation, neoangiogenesis and metastatic spread of an esophageal adenocarcinoma cell line (PT1590) in vitro and in vivo. PT1590 revealed an amplified copy number of the HER2 encoding gene c-erbB2. HER2 overexpression occurred in xenograft tumors and spontaneous lung metastases. PT1590 proliferation was significantly inhibited by trastuzumab in vitro. In vivo, tumor weight, tumor volume, microvessel density and the number of spontaneous lung metastases significantly decreased after three weeks of treatment. Our findings demonstrate anti-proliferative, anti-metastatic and anti-angiogenic effects of trastuzumab in a xenograft tumor model of esophageal adenocarcinoma encouraging its clinical use for targeted therapy in cancers other than breast.