Disorders 1 Division of Reproductive Endocrinology, Women's Health and Musculoskeletal Biology, Wyeth Research, Collegeville, Pennsylvania, 2 and 3 translational Biological Research Technologies, Wyeth Research, Cambridge, Massachusetts, 4 Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, 5 Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, and 6 detection and Chemistry, Wyeth Research, Pearl River, New York, Applications br reprints: Scott A. Jelinsky, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140. Phone: 6176655366, Fax 6176655320, Email: sjelinsky (a) wyeth.com. br uterine leiomyomas or fibroids are benign tumors of the uterine myometrium significantly affect up to 30% of women of reproductive age. Despite being the leading cause of hysterectomy in the United States, representing up to 200,000 procedures per year, the etiology of leiomyoma remains largely unknown. As a basis for understanding the pathogenesis of leiomyoma and identification of the objectives of drug treatment was performed transcriptional profiling of leiomyoma and unaffected myometrium of Eker rats and humans, the best characterized preclinical model for leiomyomas. A global comparison of mRNA versus human leiomyoma and myometrium of rat identified a large significant overlap of gene expression deregulation in leiomyomas. A pathway analysis using a fair method of enrichment geneset algorithm based on the detected target sigPathway mammalian rapamycin (mTOR) pathway as one of the most regulated pathways in both human and rat tumors. To validate this pathway as a therapeutic target for uterine leiomyomas, were conducted preclinical studies in rats Acar. These rats develop uterine leiomyomas, following the loss of TSC2 function and regulation of mTOR signaling. Inhibition of mTOR in female rats with rapamycin Eker similarly129327 for 2 weeks decreased mTOR signaling and cell proliferation in tumors, and treatment for 4 months significantly reduced tumor incidence, multiplicity and size. These results identify the deregulation of mTOR signaling as a component of the etiology leiomyoma among species and shows directly the dependence of uterine leiomyomas with the mTOR signaling pathway active in this growth. [Cancer Res 2009; 69 (15): 61,718] br br br br
