title: Cediranib enhances control of wild type EGFR and EGFRvIII-expressing gliomas through potentiating temozolomide, but not through radiosensitization: implications for the clinic.
abstract: Glioblastomas (GBM) frequently overexpress the epidermal growth factor receptor (wtEGFR) or its mutant, EGFRvIII, contributing to chemo- and radioresistance. The current standard of care is surgery followed by radiation therapy with concurrent temozolomide (TMZ) followed by adjuvant TMZ. New treatment strategies for GBM include blockade of EGFR signaling and angiogenesis. Cediranib is a highly potent receptor tyrosine kinase inhibitor that inhibits all three VEGF receptors. This study investigated the radiosensitizing potential of cediranib in combination with TMZ in U87 GBM xenografts expressing wtEGFR or EGFRvIII. U87 GBM cells stably transfected with either wtEGFR or EGFRvIII were injected into the hind limbs of nude mice. Cediranib was dosed at 3 mg/kg daily five times a week orally for 2 weeks. TMZ was dosed at 10 mg/kg once only on day 0. Radiotherapy (RT) consisted of 3 fractions of 5 Gy (days 0-2). Cediranib did not radiosensitize either tumor type; however, cediranib did enhance the effectiveness of TMZ in both transfectants. Our results suggest that combining cediranib with temozolomide in the clinic will lead to improved tumor control.
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107, USA. Phyllis.wachsberger@jeffersonhospital.org
authors.forename: Phyllis R
authors.initials: PR
authors.lastname: Wachsberger
authors.forename: Richard Yaacov
authors.initials: RY
authors.lastname: Lawrence
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Xu
authors.initials: X
authors.lastname: Xia
authors.forename: Barbara
authors.initials: B
authors.lastname: Andersen
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000378:metabolism*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D011799:Quinazolines / Q000627:therapeutic use*; D011836:Radiation Tolerance / Q000187:drug effects*; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014965:X-Rays; D007211:Indoles
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D066246:ErbB Receptors; D011799:Quinazolines; D000077204:Temozolomide; D042461:Vascular Endothelial Growth Factor A; C467484:VEGFA protein, human; C410723:epidermal growth factor receptor VIII; C512478:EGFR protein, human; C500926:cediranib; D007211:Indoles