title: Pathway-specific analysis of gene expression data identifies the PI3K/Akt pathway as a novel therapeutic target in cervical cancer.
abstract: OBJECTIVE
  Cervical tumor response on posttherapy 2[(18)F]fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) is predictive of survival outcome. The purpose of this study was to use gene expression profiling to identify pathways associated with tumor metabolic response.
  
  
  METHODS
  This was a prospective tissue collection study for gene expression profiling of 62 pretreatment biopsies from patients with advanced cervical cancer. Patients were treated with definitive radiation. Fifty-three patients received concurrent chemotherapy. All patients underwent a pretreatment and a 3-month posttherapy FDG-PET/computed tomography (CT). Tumor RNA was harvested from fresh frozen tissue and hybridized to Affymetrix U133Plus2 GeneChips. Gene set enrichment analysis (GSEA) was used to identify signaling pathways associated with tumor metabolic response. Immunohistochemistry and in vitro FDG uptake assays were used to confirm our results.
  
  
  RESULTS
  There were 40 biopsies from patients with a complete metabolic response (PET-negative group) and 22 biopsies from patients with incomplete metabolic response (PET-positive group). The 3-year cause-specific survival estimates were 98% for the PET-negative group and 39% for the PET-positive group (P < 0.0001). GSEA identified alterations in expression of genes associated with the PI3K/Akt signaling pathway in patients with a positive follow-up PET. Immunohistochemistry using a tissue microarray of 174 pretreatment biopsies confirmed p-Akt as a biomarker for poor prognosis in cervical cancer. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 inhibited FDG uptake in vitro in cervical cancer cell lines.
  
  
  CONCLUSIONS
  Activation of the PI3K/Akt pathway is associated with incomplete metabolic response in cervical cancer. Targeted inhibition of PI3K/Akt may improve response to chemoradiation.
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. jschwarz@radonc.wustl.edu
authors.forename: Julie K
authors.initials: JK
authors.lastname: Schwarz
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Payton
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Rashmi
authors.forename: Tao
authors.initials: T
authors.lastname: Xiang
authors.forename: Yunhe
authors.initials: Y
authors.lastname: Jia
authors.forename: Phyllis
authors.initials: P
authors.lastname: Huettner
authors.forename: Buck E
authors.initials: BE
authors.lastname: Rogers
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
authors.forename: Mark
authors.initials: M
authors.lastname: Watson
authors.forename: Janet S
authors.initials: JS
authors.lastname: Rader
authors.forename: Perry W
authors.initials: PW
authors.lastname: Grigsby
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D003847:Deoxyglucose / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality
chemical_list: D003847:Deoxyglucose; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt