title: IL6-STAT3-HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Anglesio
authors.forename: Joshy
authors.initials: J
authors.lastname: George
authors.forename: Hagen
authors.initials: H
authors.lastname: Kulbe
authors.forename: Michael
authors.initials: M
authors.lastname: Friedlander
authors.forename: Danny
authors.initials: D
authors.lastname: Rischin
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lemech
authors.forename: Jeremy
authors.initials: J
authors.lastname: Power
authors.forename: Jermaine
authors.initials: J
authors.lastname: Coward
authors.forename: Prue A
authors.initials: PA
authors.lastname: Cowin
authors.forename: Colin M
authors.initials: CM
authors.lastname: House
authors.forename: Probir
authors.initials: P
authors.lastname: Chakravarty
authors.forename: Kylie L
authors.initials: KL
authors.lastname: Gorringe
authors.forename: Ian G
authors.initials: IG
authors.lastname: Campbell
authors.forename: Aikou
authors.initials: A
authors.lastname: Okamoto
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: Anna
authors.initials: A
authors.lastname: de Fazio
authors.forename: Steve E
authors.initials: SE
authors.lastname: Kalloger
authors.forename: Frances
authors.initials: F
authors.lastname: Balkwill
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.forename: David D
authors.initials: DD
authors.lastname: Bowtell
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007211:Indoles / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D046888:Tissue Array Analysis; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D015850:Interleukin-6; D011758:Pyrroles; D050796:STAT3 Transcription Factor; D000077210:Sunitinib