title: Enhancing radiosensitization in EphB4 receptor-expressing Head and Neck Squamous Cell Carcinomas.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Bhatia
authors.affiliation: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Kellen
authors.initials: K
authors.lastname: Hirsch
authors.affiliation: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Jaspreet
authors.initials: J
authors.lastname: Sharma
authors.affiliation: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Ayman
authors.initials: A
authors.lastname: Oweida
authors.affiliation: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Anastacia
authors.initials: A
authors.lastname: Griego
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Keysar
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.affiliation: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: David
authors.initials: D
authors.lastname: Raben
authors.affiliation: VasGene Therapeutics Inc, Los Angeles, CA 90033, USA.
authors.forename: Valery
authors.initials: V
authors.lastname: Krasnoperov
authors.affiliation: Division of Hematology and Pathology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Parkash S
authors.initials: PS
authors.lastname: Gill
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Elena B
authors.initials: EB
authors.lastname: Pasquale
authors.affiliation: Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Sana D
authors.initials: SD
authors.lastname: Karam
mesh_terms: D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor / Q000528:radiation effects; D004260:DNA Repair; D059565:G2 Phase Cell Cycle Checkpoints; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology; D051379:Mice; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000172:deficiency / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance; D036224:Receptor, EphB4 / Q000172:deficiency / Q000502:physiology*; D047368:Tumor Burden; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D036224:Receptor, EphB4