title: Pediatric high-grade glioma: identification of poly(ADP-ribose) polymerase as a potential therapeutic target.
abstract: Pediatric high-grade gliomas (World Health Organization grades III and IV astrocytomas) remain tumors with a very poor prognosis for which novel therapeutic strategies are needed. Poly(ADP-ribose) polymerase (PARP) is known to have multiple functions in tumors, including single-strand DNA repair and induction of caspase-independent apoptosis. PARP has been suggested as a therapeutic target in adult malignancies, and this study examines whether it could also be a potential target in pediatric high-grade glioma. Tissue microarrays containing 150 formalin-fixed pediatric high-grade gliomas were examined by immunohistochemistry for levels of PARP and expression of apoptosis inducing factor (AIF). Full retrospective clinical and survival data were available for this cohort. Stratification and statistical analysis was performed to assess the effect of PARP status on prognosis. The level of PARP immunopositivity had a statistically significant inverse correlation (P = .019) with survival in supratentorial pediatric high-grade glioma. AIF staining was notable for its absence in the majority of tumors but with moderate levels of expression in surrounding normal brain. PARP is expressed at high levels in many pediatric high-grade gliomas, and in these tumors, the ability of PARP to activate AIF appears to have been lost. PARP may therefore represent a promising therapeutic target for these lesions and warrants evaluation in clinical trials.
authors.affiliation: Children's Brain Tumor Research Centre, University of Nottingham, Nottingham, UK.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Smith
authors.forename: Angela
authors.initials: A
authors.lastname: Long
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Barrow
authors.forename: Donald C
authors.initials: DC
authors.lastname: Macarthur
authors.forename: Beth
authors.initials: B
authors.lastname: Coyle
authors.forename: Richard G
authors.initials: RG
authors.lastname: Grundy
mesh_terms: D000293:Adolescent; D000328:Adult; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001932:Brain Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005910:Glioma / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D060787:Neoplasm Grading; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D046888:Tissue Array Analysis; D055815:Young Adult
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D011065:Poly(ADP-ribose) Polymerases