Effective inhibition of metastases and primary tumor growth with CTCE-9908 in esophageal cancer

• Published in: The Journal of surgical research Vol. 182; no. 2; pp. 250 - 256
• Main Authors: Drenckhan, Astrid, PhD, Kurschat, Nina, PhD, Dohrmann, Thorsten, MD, Raabe, Nina, MD, Koenig, Alexandra M., MD, Reichelt, Uta, MD, Kaifi, Jussuf T., MD, Izbicki, Jakob R., MD, Gros, Stephanie J., MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.06.2013
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; CTCE-9908; CXCR4; Esophageal carcinoma; Esophageal Neoplasms - chemistry; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - pathology; Homing; Humans; Liver Neoplasms - secondary; Lung Neoplasms - secondary; Magnetic Resonance Imaging; Metastases; Mice; Orthotopic model; Peptides - pharmacology; Peptides - therapeutic use; Receptors, CXCR4 - analysis; Receptors, CXCR4 - antagonists & inhibitors; Surgery; Homing; Esophageal carcinoma; CTCE-9908; Magnetic resonance imaging; Orthotopic model; CXCR4; Metastases
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2012.09.035

Abstract Background In spite of multimodular treatment, the therapeutic options for esophageal carcinoma are limited, and metastases remain the leading cause of tumor-related mortality. Expression of the chemokine receptor CXCR4 significantly correlates with poor survival rates in patients with esophageal carcinoma and is associated with lymph node and bone marrow metastases. The aim of this study was to evaluate the effect of the CXCR4 antagonist CTCE-9908 on metastatic homing and primary tumor growth in vitro and in vivo in an orthotopic xenograft model of esophageal cancer. Materials and methods OE19 cells were examined for stromal cell–derived factor 1 alpha–mediated migration under CTCE-9908 treatment. The CTCE-9908 treatment was further evaluated in an in vitro proliferation assay and orthotopic esophageal model, accompanied by magnetic resonance imaging. Tumor and metastases were immunohistochemically examined for CXCR4 expression. Results CTCE-9908 has an inhibitory effect on stromal cell–derived factor 1 alpha–mediated migration and proliferation of OE19 cells. Treatment with CTCE-9908 in the orthotopic esophageal model leads to a reduction of metastatic spread and primary tumor growth. This was confirmed by magnetic resonsance imaging. Treatment with CTCE-9908 results in altered CXCR4 expression pattern exhibiting a high degree of variability. Conclusion CTCE-9908 effectively inhibits OE19 cell migration and proliferation in vitro , reduces metastases to lung, liver, and lymph nodes in vivo , and moreover leads to tumor growth reduction in an orthotopic model of esophageal carcinoma.