PDGFR-α as a potential therapeutic target in uterine sarcomas

• Published in: Gynecologic oncology 2007-03, Vol.104 (3), p.524-528
• Main Authors: Adams, S.F, Hickson, J.A, Hutto, J.Y, Montag, A.G, Lengyel, E, Yamada, S.D
• Format: Article
• Language: English
• Subjects: c-kit; Female; Hematology, Oncology and Palliative Medicine; Humans; Imatinib mesylate; Obstetrics and Gynecology; PDGFR-α; PDGFR-β; Proto-Oncogene Proteins c-kit - biosynthesis; Receptor, Platelet-Derived Growth Factor alpha - biosynthesis; Receptor, Platelet-Derived Growth Factor beta - biosynthesis; Sarcoma - enzymology; Sarcoma - pathology; Tyrosine kinase inhibitors; Uterine Neoplasms - enzymology; Uterine Neoplasms - pathology; Uterine sarcomas
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2006.09.013

Abstract Objective. Uterine sarcomas are a heterogeneous group of tumors with a propensity for metastasis and resistance to conventional therapy. Recent success in the treatment of other solid tumors with the targeted tyrosine kinase inhibitor imatinib mesylate offers new avenues for investigation. The primary target of imatinib is c-kit, but the drug also inhibits PDGFR-α and PDGFR-β. Given the lack of identified molecular targets in endometrial stromal sarcomas, leiomyosarcomas, and carcinosarcomas, the purpose of this study was to determine the protein expression of c-kit, PDGFR-α, and PDGFR-β in these tumors as a preliminary step to determining their susceptibility to directed therapy. A secondary goal was to identify specific gene mutations that might be associated with activation of these proteins in uterine sarcomas. Methods. Archived tissue from 42 cases of uterine sarcomas was stained for c-kit, PDGFR-α, and PDGFR-β using immunohistochemistry. Laser-capture microdissected samples of uterine carcinosarcomas, or homogeneous areas of leiomyosarcomas or endometrial stromal sarcomas, were subjected to genetic analysis of PDGFR-α exons 12 and 18. Results. The majority (38/42, 90%) of uterine sarcomas lacked c-kit expression and 90% (38/42) demonstrated negative or weak staining for PDGFR-β. In contrast, 70% (30/42) of cases had strong staining for PDGFR-α in the tumor but not in normal myometrium or endometrium. Sequencing results revealed no mutations in exons 12 or 18 of PDGFR-α. Conclusion. c-kit and PDGFR-β are unlikely to represent primary treatment targets in uterine sarcomas. The strong expression of PDGFR-α in uterine sarcoma specimens suggests a role for this receptor in tumor development, although its potential as a therapeutic target requires further investigation.