Reduced Cytokine Release in Ex Vivo Response to Cilengitide and Cetuximab Is a Marker for Improved Survival of Head and Neck Cancer Patients

Susan Cedra; Susanne Wiegand; Marlen Kolb; Andreas Dietz; Gunnar Wichmann

doi:10.3390/cancers9090117

Reduced Cytokine Release in Ex Vivo Response to Cilengitide and Cetuximab Is a Marker for Improved Survival of Head and Neck Cancer Patients

Cancers (Basel). 2017 Sep 5;9(9):117. doi: 10.3390/cancers9090117.

Authors

Susan Cedra¹, Susanne Wiegand², Marlen Kolb³, Andreas Dietz⁴, Gunnar Wichmann⁵

Affiliations

¹ Department of Otolaryngology, Head and Neck Surgery, University of Leipzig, 04103 Leipzig, Germany. scedra@gmx.net.
² Department of Otolaryngology, Head and Neck Surgery, University of Leipzig, 04103 Leipzig, Germany. Susanne.Wiegand@medizin.uni-leipzig.de.
³ Department of Otolaryngology, Head and Neck Surgery, University of Leipzig, 04103 Leipzig, Germany. Marlen.Kolb@medizin.uni-leipzig.de.
⁴ Department of Otolaryngology, Head and Neck Surgery, University of Leipzig, 04103 Leipzig, Germany. andreas.dietz@medizin.uni-leipzig.de.
⁵ Department of Otolaryngology, Head and Neck Surgery, University of Leipzig, 04103 Leipzig, Germany. gunnar.wichmann@medizin.uni-leipzig.de.

Abstract

Targeting of α_Vβ3 and α_Vβ5 integrins by cilengitide may reduce growth of solid tumors including head and neck squamous cell carcinoma (HNSCC). Preclinical investigations suggest increased activity of cilengitide in combination with other treatment modalities. The only published trial in HNSCC (ADVANTAGE) investigated cisplatin, 5-fluorouracil, and cetuximab (PFE) without or with once (PFE+CIL1W) or twice weekly cilengitide (PFE+CIL2W) in recurrent/metastatic HNSCC. ADVANTAGE showed good tolerability of the cilengitide arms and even lower adverse events (AEs) compared to PFE but not the benefit in overall survival expected based on preclinical data. As we found in the FLAVINO assay, a short-time ex vivo assay for prediction of chemosensitivity, only a subgroup of HNSCC had an increased suppressive effect of cilengitide containing combination therapies on colony formation of epithelial cells (CF_ec) and release of pro-angiogenetic and pro-inflammatory cytokines, whereas other HNSCC failed to respond. Response to α_Vβ3 and α_Vβ5 integrin targeting by cilengitide classifies HNSCC regarding outcome. We present FLAVINO data arguing for further development of cilengitide plus cetuximab in treatment of a subgroup of HNSCC potentially identified by the FLAVINO assay using a set of biomarkers for response evaluation.

Keywords: biomarker; chemoresponse ex vivo; cilengitide; head and neck cancer; head and neck squamous cell carcinoma (HNSCC); integrin; interleukin 6; monocyte chemotactic protein-1; predictive assay; targeted therapy; αVβ3.