Back to Search
Start Over
IL6-STAT3-HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2011 Apr 15; Vol. 17 (8), pp. 2538-48. Date of Electronic Publication: 2011 Feb 22. - Publication Year :
- 2011
-
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.<br />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.<br />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.<br />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.<br /> (©2011 AACR.)
- Subjects :
- 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
Immunohistochemistry
Interleukin-6 blood
Interleukin-6 genetics
Middle Aged
Oligonucleotide Array Sequence Analysis
Ovarian Neoplasms genetics
Ovarian Neoplasms metabolism
STAT3 Transcription Factor genetics
Signal Transduction drug effects
Sunitinib
Tissue Array Analysis
Treatment Outcome
Adenocarcinoma, Clear Cell drug therapy
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Indoles therapeutic use
Interleukin-6 metabolism
Ovarian Neoplasms drug therapy
Pyrroles therapeutic use
STAT3 Transcription Factor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 17
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 21343371
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-10-3314