Faculty Collaboration Database

Pathway-specific analysis of gene expression data identifies the PI3K/Akt pathway as a novel therapeutic target in cervical cancer. Clin Cancer Res 2012 Mar 01;18(5):1464-71

Date

01/12/2012

Pubmed ID

22235101

Pubmed Central ID

PMC3627483

DOI

10.1158/1078-0432.CCR-11-2485

Scopus ID

2-s2.0-84857734203 (requires institutional sign-in at Scopus site)   94 Citations

Abstract

PURPOSE: 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.

EXPERIMENTAL DESIGN: 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.

Author List

Schwarz JK, Payton JE, Rashmi R, Xiang T, Jia Y, Huettner P, Rogers BE, Yang Q, Watson M, Rader JS, Grigsby PW

Author

Janet Sue Rader MD Chair, Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Animals
Deoxyglucose
Female
Gene Expression Profiling
Humans
Mice
Middle Aged
Phosphatidylinositol 3-Kinases
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt
Signal Transduction
Survival Analysis
Uterine Cervical Neoplasms