title: Approaches to sensitizing glioblastoma to radiotherapy: use of lentiviral vectors.
abstract: Glioblastoma multiforme (GBM) is the most common primary brain tumour and             extirpation followed by radio- and chemotherapy has had minimal impact on the             median survival of patients which is still less than one year. Hence, a novel             therapeutic modality is required if the survival of patients with this disease             is to be improved. ATM, mutated in the human genetic disorder ataxia-telangiectasia             (A-T), plays a central role in the response to DNA double strand breaks and patients             with this disorder are characterised by extreme sensitivity to radiation, increased             risk of cancer and neurodegeneration. Thus, ATM represents a potential target             for radiosensitization of brain tumour cells. A safe, non-replicating lentivirus             is used to abrogate ATM in GBM through the antisense and RNAi approaches for radiosensitization.             With either techniques, ATM protein was reduced by >90% and there was a 3‑fold             sensitization of GBM cells to radiation. ATM protein activation as well as ATM             pS1981 foci formation were defective and downstream signalling determined by Ser15             phosphorylation on p53 was reduced. Success in the approaches provides a novel             and exciting strategy for the treatment of GBM and thus improving the survival             of patients with these tumours.
authors.affiliation: Department of Surgery, University of Queensland, St. Lucia, Queensland,                     Australia.
authors.forename: Teong Lip
authors.initials: TL
authors.lastname: Chuah
authors.forename: David Gregory
authors.initials: DG
authors.lastname: Walker
authors.forename: Ming
authors.initials: M
authors.lastname: Wei
authors.forename: Shaun
authors.initials: S
authors.lastname: Scott
authors.forename: Martin Francis
authors.initials: MF
authors.lastname: Lavin
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D001932:Brain Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors; D005909:Glioblastoma / Q000378:metabolism / Q000532:radiotherapy*; D057809:HEK293 Cells; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011836:Radiation Tolerance / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases