Aurora kinase A as a rational target for therapy in glioblastoma.
OBJECTIVE
Despite advances in the knowledge of tumor biology, the outcome of glioblastoma tumors remains poor. The design of many molecularly targeted therapies in glioblastoma has focused on inhibiting molecular abnormalities present in tumor cells compared with normal tissue rather than patient outcome-associated factors. As an alternative approach, the present study identified genes associated with shorter survival as potential therapeutic targets. It was hypothesized that inhibition of a molecular target associated with poor outcome would impact glioblastoma cell proliferation.


METHODS
The present study correlated patient survival data with tumor gene expression profiling and gene ontology analysis. Genes associated with shorter survival were identified and one of these was selected for therapeutic targeting in an in vitro system. Glioblastoma cell growth suppression was measured by H(3)-thymidine uptake, colony formation, and flow cytometry.


RESULTS
The gene expression microarray and ontology analysis revealed that genes involved in mitotic processes, including AURKA, were associated with poor prognosis in glioblastoma. Inhibition of AURKA suppressed glioblastoma cell growth. Moreover, inhibition of AURKA was synergistic with radiation in glioblastoma cells at high radiation doses.


CONCLUSIONS
Relative expression of AURKA may be of prognostic value and warrants further investigation with larger, prospective studies. Pharmacological inhibition of AURKA is a potentially promising therapy for glioblastoma.
Barton
Valerie N
VN
Department of Pediatrics, Anschutz Medical Campus, University of Colorado Denver, Colorado 80045, USA. valerie.barton@ucdenver.edu
Foreman
Nicholas K
NK
Donson
Andrew M
AM
Birks
Diane K
DK
Handler
Michael H
MH
Vibhakar
Rajeev
R
D000813:Anilides / Q000494:pharmacology*; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000235:genetics / Q000528:radiation effects; D012189:Retrospective Studies; D016019:Survival Analysis
D000813:Anilides; C550259:C 1368; D011743:Pyrimidines; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases