title: Axitinib sensitization of high Single Dose Radiotherapy.
abstract: OBJECTIVE
  Single Dose Radiation Therapy (SDRT) provides remarkably high rates of control even for tumors resistant to fractionated radiotherapy. SDRT tumor control depends on acute acid sphingomyelinase-mediated endothelial cell injury and monoclonal antibodies targeting Vascular Endothelial Cell Growth Factor (VEGF) signaling radiosensitized tumor endothelium when delivered immediately prior to irradiation. Here we evaluate the ability of the oral VEGF receptor inhibitor, axitinib, to sensitize tumor endothelium and increase tumor control with SDRT.
  
  
  METHODS
  Axitinib was added to primary cultured endothelial cells, or administered orally to Sv129/BL6 mice bearing radiosensitive MCA/129 sarcoma or radioresistant B16F1 melanoma flank tumors, followed by SDRT. Endothelial apoptosis was assessed by TUNEL assay or bis-benzamide staining. Mice with irradiated tumors were followed for 90days to evaluate the impact of axitinib on SDRT tumor control.
  
  
  RESULTS
  Pre-treatment with axitinib increased acute endothelial cell apoptosis following SDRT in vitro, and in vivo for both MCA/129 and B16F1 tumors. Axitinib correspondingly increased SDRT tumor growth delay and complete response rate (by 40%) for both tumors. Administration precisely 1h before SDRT was critical for radiosensitization.
  
  
  CONCLUSIONS
  Axitinib radiosensitizes tumor endothelial cells and enhances tumor cure with SDRT, which may permit dose de-escalation and significantly expand the range of clinical indications for SDRT.
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, USA. Electronic address: shyam.rao@ucdmc.ucdavis.edu.
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Rao
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Thompson
authors.affiliation: Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Haimovitz-Friedman
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, USA.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Powell
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, USA.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Fuks
authors.affiliation: Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, USA.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Kolesnick
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D000077784:Axitinib; D042783:Endothelial Cells / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000532:radiotherapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011879:Radiotherapy Dosage; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D000077784:Axitinib; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Acid sphingomyelinase; Anti-angiogenic; Ceramide; Radiosurgery; Stereotactic body radiation therapy; Vascular endothelial growth factor