IL6-STAT3-HIF Signaling and Therapeutic Response to the Angiogenesis Inhibitor Sunitinib in Ovarian Clear Cell Cancer
Clinical Cancer Research
Purpose: Ovarian clear cell adenocarcinoma (OCCA) is an uncommon histotype that is generally refractory to platinum-based chemotherapy. We analyse here the most comprehensive gene expression and copy number datasets to date, to identify potential therapeutic targets of OCCA. Experimental Design: Gene expression and DNA copy number were performed using primary human OCCA tumour samples, and findings confirmed by immunohistochemistry on tissue microarrays. Circulating IL6 levels were measured in
... erum 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 measured clinically and by positron emission tomography. Results: We find specific over-expression of the IL6, STAT3 and HIF pathway in OCCA tumours 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 RTK, 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, showing significant parallels with renal clear cell cancer. Conclusion: 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 realisation that OCCA is molecularly and clinically distinct to other forms of ovarian cancer.