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Therapeutic Response To The Angiogenesis Inhibitor Sunitinib In Ovarian Clear Cell Cancer

Posted by Paul Cacciatore on March 25, 2011

A group of international researchers reported sustained responses in two ovarian clear cell cancer (OCCC) patients with chemotherapy-resistant disease, who were treated with the anti-angiogenesis inhibitor sunitinib (Sutent®). The researchers emphasize the growing realization that OCCC is molecularly and clinically distinct as compared to other forms of ovarian cancer, and note significant common scientific characteristics possessed by both OCCC and renal clear cell cancer.

Clear Cell Carcinoma of the Ovary

Ovarian clear cell cancer (OCCC) is a rare form or subtype of epithelial ovarian cancer that is generally refractory to platinum-based chemotherapy. A group of international researchers from the United Kingdom, Australia, Japan, Canada and the United States recently reported results from comprehensive OCCC tumor gene expression and copy number testing, which was designed to identify potential therapeutic targets of OCCC.

Gene expression and DNA copy number testing was performed using primary human OCCC tumor samples, and the test findings were confirmed by immunohistochemistry (IHC) on tissue microarrays. Based on this testing, the researchers identified specific over-expression of the IL6 (interleukin-6)-STAT3 (signal transducer and activator of transcription 3)-HIF (hypoxia-inducible factors) cellular pathway in OCCC tumors, as compared with high-grade serous ovarian cancers. Expression of PTHLH (parathyroid hormone-like hormone) and high levels of circulating IL6 were also found in OCCC patients, and the researchers believe that this finding may explain the frequent occurrence of hypercalcemia and thromboembolic events in OCCC. Notably, the study results set forth a description of amplification of several RTKs (receptor tyrosine kinases), most notably MET (met proto-oncogene [hepatocyte growth factor receptor]), which certainly suggests other potential therapeutic targets for this hard-to-treat subtype of ovarian cancer.

Circulating IL6 levels were measured in the blood serum from patients with OCCC or high-grade serous ovarian cancers and corresponded to progression-free and overall survival. Two OCCC patients were treated with sunitinib and their therapeutic responses were measured clinically and by positron emission tomography (PET). The researchers reported sustained clinical and functional imaging responses in two OCCC patients with chemotherapy-resistant disease who were treated with sunitinib, thereby showing  significant scientific parallels with renal clear cell cancer.

Based upon the findings above, the researchers highlighted the importance of specific therapeutic targets in the treatment of OCCC, and suggested that more extensive clinical trials with sunitinib in OCCC patients are warranted.  The overarching findings of this study provide significant impetus to the growing realization that OCCC is molecularly and clinically distinct as compared to other forms of ovarian cancer.

Source: Anglesio MS, George J, Kulbe H, et. al. IL6-STAT3-HIF Signalling and Therapeutic Response To The Angiogenesis Inhibitor, Sunitinib, In Ovarian Clear Cell Cancer. Clin Cancer Res. 2011 Feb 22. [Epub ahead of print] PubMed PMID: 21343371.

Additional Information:

  • Dedicated Ovarian Clear Cell Cancer Clinical Trials (currently recruiting as of 3/25/11).

A Phase II Evaluation of SU11248 (Sunitinib Malate) (IND #74019, NSC #736511) in the Treatment of Persistent or Recurrent Clear Cell Ovarian Carcinoma, Clinical Trial Summary, NCT00979992, ClinicalTrials.gov.

A Phase II Evaluation of Temsirolimus (CCI-779) [Torisel®] (NCI Supplied Agent: NSC# 683864, IND# 61010) in Combination With Carboplatin and Paclitaxel Followed by Temsirolimus (CCI-779) Consolidation as First-Line Therapy in the Treatment of Stage III-IV Clear Cell Carcinoma of the Ovary, Clinical Trial Summary, NCT01196429, ClinicalTrials.gov.

  • Open Ovarian Cancer and Solid Tumor Clinical Trials Testing MET Inhibitors (as of 3/25/11)

We provide below a list of MET inhibitors that are currently available through open ovarian cancer and solid tumor clinical trials.  A few caveats are noteworthy.

First, the association between MET inhibiton and ovarian clear cell cancer inhibition has NOT been established as a form of treatment in large randomized, prospective clinical trials.

Second, most of the clinical trials listed below are phase I studies designed to test the biological activity and safety of the drug — not the effectiveness.  Patients enrolled in a phase I trial are generally the first humans to receive the study drug.

Third, all patients should seek advice from their doctor in advance of deciding to enroll in a clinical trial. Many of the clinical drugs listed below inhibit one or more cellular functions in addition to MET.

List of open solid tumor clinical trials testing AMG 208.

List of open solid tumor clinical trials testing MGCD-265.

List of open solid tumor clinical trials testing PF-2341066 (crizotinib)(NCT01121588NCT00585195).

List of open ovarian cancer clinical trials testing sunitinib (SU11274)/Sutent®.

List of open solid tumor clinical trials testing sunitinib (SU11274)/Sutent®.

List of open solid tumor clinical trials testing cabozantinib (a/k/a XL184 or BMS-907351).

List of open solid tumor clinical trials testing ARQ197.

List of open solid tumor clinical trials testing INCB28060.

List of open solid tumor clinical trials testing E7050.

List of open solid tumor clinical trials testing MGCD265.

  • Genetic Similarity Between Ovarian Clear Cell Cancer & Renal Clear Cell Cancer

Yoshida S, Furukawa N, Haruta S, et. al. Theoretical model of treatment strategies for clear cell carcinoma of the ovary: focus on perspectives. Cancer Treat Rev. 2009 Nov;35(7):608-15. Epub 2009 Aug 8. Review. PubMed PMID: 19665848.

Rauh-Hain JA, Penson RT. Potential benefit of Sunitinib in recurrent and refractory ovarian clear cell adenocarcinoma. Int J Gynecol Cancer. 2008 Sep-Oct;18(5):934-6. Epub 2007 Dec 13. PubMed PMID: 18081793.

Zorn KK, Bonome T, Gangi L, et. al. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res. 2005 Sep 15;11(18):6422-30. PubMed PMID: 16166416.

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