title: ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation.
abstract: OBJECTIVE
  Glioblastoma multiforme (GBM) is the most lethal form of brain cancer with a median survival of only 12 to 15 months. Current standard treatment consists of surgery followed by chemoradiation. The poor survival of patients with GBM is due to aggressive tumor invasiveness, an inability to remove all tumor tissue, and an innate tumor chemo- and radioresistance. Ataxia-telangiectasia mutated (ATM) is an excellent target for radiosensitizing GBM because of its critical role in regulating the DNA damage response and p53, among other cellular processes. As a first step toward this goal, we recently showed that the novel ATM kinase inhibitor KU-60019 reduced migration, invasion, and growth, and potently radiosensitized human glioma cells in vitro.
  
  
  METHODS
  Using orthotopic xenograft models of GBM, we now show that KU-60019 is also an effective radiosensitizer in vivo. Human glioma cells expressing reporter genes for monitoring tumor growth and dispersal were grown intracranially, and KU-60019 was administered intratumorally by convection-enhanced delivery or osmotic pump.
  
  
  RESULTS
  Our results show that the combined effect of KU-60019 and radiation significantly increased survival of mice 2- to 3-fold over controls. Importantly, we show that glioma with mutant p53 is much more sensitive to KU-60019 radiosensitization than genetically matched wild-type glioma.
  
  
  CONCLUSIONS
  Taken together, our results suggest that an ATM kinase inhibitor may be an effective radiosensitizer and adjuvant therapy for patients with mutant p53 brain cancers.
authors.affiliation: Department of Radiation Oncology, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23112, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Biddlestone-Thorpe
authors.forename: Muhammad
authors.initials: M
authors.lastname: Sajjad
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rosenberg
authors.forename: Jason M
authors.initials: JM
authors.lastname: Beckta
authors.forename: Nicholas C K
authors.initials: NC
authors.lastname: Valerie
authors.forename: Mary
authors.initials: M
authors.lastname: Tokarz
authors.forename: Bret R
authors.initials: BR
authors.lastname: Adams
authors.forename: Alison F
authors.initials: AF
authors.lastname: Wagner
authors.forename: Ashraf
authors.initials: A
authors.lastname: Khalil
authors.forename: Donna
authors.initials: D
authors.lastname: Gilfor
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Golding
authors.forename: Sumitra
authors.initials: S
authors.lastname: Deb
authors.forename: David G
authors.initials: DG
authors.lastname: Temesi
authors.forename: Alan
authors.initials: A
authors.lastname: Lau
authors.forename: Mark J
authors.initials: MJ
authors.lastname: O'Connor
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Choe
authors.forename: Luis F
authors.initials: LF
authors.lastname: Parada
authors.forename: Sang Kyun
authors.initials: SK
authors.lastname: Lim
authors.forename: Nitai D
authors.initials: ND
authors.lastname: Mukhopadhyay
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Valerie
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage*; D009154:Mutation; D011836:Radiation Tolerance / Q000187:drug effects; D011839:Radiation, Ionizing; D013892:Thioxanthenes / Q000008:administration & dosage*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C546193:2-(2,6-dimethylmorpholin-4-yl)-N-(5-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl)acetamide; D009025:Morpholines; C495901:TP53 protein, human; D013892:Thioxanthenes; D016159:Tumor Suppressor Protein p53; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins