Enhancing radiosensitization in EphB4 receptor-expressing Head and Neck Squamous Cell Carcinomas

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作者
Shilpa Bhatia
Kellen Hirsch
Jaspreet Sharma
Ayman Oweida
Anastacia Griego
Stephen Keysar
Antonio Jimeno
David Raben
Valery Krasnoperov
Parkash S. Gill
Elena B. Pasquale
Xiao-Jing Wang
Sana D. Karam
机构
[1] University of Colorado Denver,Department of Radiation Oncology
[2] Anschutz Medical Campus,Division of Medical Oncology
[3] School of Medicine,Division of Hematology and Pathology
[4] University of Colorado Denver,Department of Pathology
[5] Anschutz Medical Campus,undefined
[6] VasGene Therapeutics Inc,undefined
[7] University of Southern California,undefined
[8] Sanford Burnham Prebys Medical Discovery Institute,undefined
[9] University of Colorado Denver,undefined
[10] Anschutz Medical Campus,undefined
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Scientific Reports | / 6卷
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摘要
Members of the Eph family of receptor tyrosine kinases have been implicated in a wide array of human cancers. The EphB4 receptor is ubiquitously expressed in head and neck squamous cell carcinoma (HNSCC) and has been shown to impart tumorigenic and invasive characteristics to these cancers. In this study, we investigated whether EphB4 receptor targeting can enhance the radiosensitization of HNSCC. Our data show that EphB4 is expressed at high to moderate levels in HNSCC cell lines and patient-derived xenograft (PDX) tumors. We observed decreased survival fractions in HNSCC cells following EphB4 knockdown in clonogenic assays. An enhanced G2 cell cycle arrest with activation of DNA damage response pathway and increased apoptosis was evident in HNSCC cells following combined EphB4 downregulation and radiation compared to EphB4 knockdown and radiation alone. Data using HNSCC PDX models showed significant reduction in tumor volume and enhanced delay in tumor regrowth following sEphB4-HSA administration with radiation compared to single agent treatment. sEphB4-HSA is a protein known to block the interaction between the EphB4 receptor and its ephrin-B2 ligand. Overall, our findings emphasize the therapeutic relevance of EphB4 targeting as a radiosensitizer that can be exploited for the treatment of human head and neck carcinomas.
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