RRC ID 38421
Author Anglesio MS, George J, Kulbe H, Friedlander M, Rischin D, Lemech C, Power J, Coward J, Cowin PA, House CM, Chakravarty P, Gorringe KL, Campbell IG, Australian Ovarian Cancer Study Group, Okamoto A, Birrer MJ, Huntsman DG, de Fazio A, Kalloger SE, Balkwill F, Gilks CB, Bowtell DD.
Title IL6-STAT3-HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer.
Journal Clin Cancer Res
Abstract PURPOSE:Ovarian clear cell adenocarcinoma (OCCA) is an uncommon histotype that is generally refractory to platinum-based chemotherapy. We analyze here the most comprehensive gene expression and copy number data sets, to date, to identify potential therapeutic targets of OCCA.
EXPERIMENTAL DESIGN:Gene expression and DNA copy number were carried out using primary human OCCA tumor samples, and findings were confirmed by immunohistochemistry on tissue microarrays. Circulating interleukin (IL) 6 levels were measured in serum from patients with OCCA or high-grade serous cancers and related to progression-free and overall survival. Two patients were treated with sunitinib, and their therapeutic responses were measured clinically and by positron emission tomography.
RESULTS:We find specific overexpression of the IL6-STAT3-HIF (interleukin 6-signal transducer and activator of transcription 3-hypoxia induced factor) pathway in OCCA tumors compared with high-grade serous cancers. Expression of PTHLH and high levels of circulating IL6 in OCCA patients may explain the frequent occurrence of hypercalcemia of malignancy and thromboembolic events in OCCA. We describe amplification of several receptor tyrosine kinases, most notably MET, suggesting other potential therapeutic targets. We report sustained clinical and functional imaging responses in two OCCA patients with chemotherapy-resistant disease who were treated with sunitinib, thus showing significant parallels with renal clear cell cancer.
CONCLUSIONS:Our findings highlight important therapeutic targets in OCCA, suggest that more extensive clinical trials with sunitinib in OCCA are warranted, and provide significant impetus to the growing realization that OCCA is molecularly and clinically distinct to other forms of ovarian cancer.
Volume 17(8)
Pages 2538-48
Published 2011-4-15
DOI 10.1158/1078-0432.CCR-10-3314
PII 1078-0432.CCR-10-3314
PMID 21343371
MeSH Adenocarcinoma, Clear Cell / drug therapy* Adenocarcinoma, Clear Cell / genetics Adenocarcinoma, Clear Cell / metabolism Adult Aged Angiogenesis Inhibitors / therapeutic use Cell Line, Tumor Cluster Analysis Drug Resistance, Neoplasm Female Gene Expression Profiling Gene Expression Regulation, Neoplastic / drug effects Humans Hypoxia-Inducible Factor 1, alpha Subunit / genetics Hypoxia-Inducible Factor 1, alpha Subunit / metabolism* Immunohistochemistry Indoles / therapeutic use* Interleukin-6 / blood Interleukin-6 / genetics Interleukin-6 / metabolism* Middle Aged Oligonucleotide Array Sequence Analysis Ovarian Neoplasms / drug therapy* Ovarian Neoplasms / genetics Ovarian Neoplasms / metabolism Pyrroles / therapeutic use* STAT3 Transcription Factor / genetics STAT3 Transcription Factor / metabolism* Signal Transduction / drug effects Sunitinib Tissue Array Analysis Treatment Outcome
IF 8.911
Times Cited 153
Human and Animal Cells