Uterine leiomyoma arise from the uterine smooth muscle compartment (myometrium) and are the most common gynecologic tumor in premenopausal women, occurring in up to 77% of all women. They are all significant cause of pelvic pain, menorrhagia, infertility, and pregnancy-related complications. These estrogen-dependent tumors are the leading indication for hysterectomy in reproductive age women. Currently, no medicinal therapy exists. Prolonged use of GnRH agonists, which can shrink tumors but induce a chemical menopause, is restricted due to serious side effects. The hormone-dependent phenotype of uterine leiomyoma suggests that interventions targeting the estrogen receptor (ER)-signaling pathway may have therapeutic efficacy. Proof-of-principal experiments have now established that treatment with anti-estrogen medications (e.g., tamoxifen and raloxifene) can significantly reduce tumor incidence, size, and proliferative index in the Eker rat, the only animal model known to acquire spontaneous uterine leiomyoma. Adenovirus-mediated delivery of a mutated dominant-negative ER (Ad-ER-DN) inhibited cell proliferation and induced apoptosis in human and rat leiomyoma cell lines. In a pilot experiment, Ad-ER-DN injected directly intratumor in nude mice with pre- existing fibroids induced immediate arrest and regression of tumor growth due to extensive apoptosis. explants in nude In this project, we will (Specific Aim 1) determine if Ad-ER-DN transduction inhibits endogenous ER signaling in estrogen-responsive rat and human leiomyoma cells, (Specific Aim 2) expand pilot results and evaluate the ability of Ad-ER-DN to ablate pre-established subcutaneous leiomyoma mice, and (Specific lira 3) conduct a pre-clinical trial to assess the ability of Ad-ER-DN to ablate uterine leiomyoma when delivered by direct intratumor injection in the immune-competent Eker rat. Tumor response will be correlated to proliferative and apoptotic indices, to markers of tumor angiogenesis, and to several estrogen-regulated genes. We will examine immune response and the safety of single vs. repeated recombinant adenovirus treatment alone or in combination with SERM (Raloxifene). Evident therapeutic potential aside, this project will add to our understanding of the molecular mechanisms of estrogen-dependence in this common uterine tumor. It will also show, in a well-characterized natural rat model, the effects of specific perturbing of ER signaling on several cellular functions (i.e., angiogenesis, apoptosis, and cell cycle). This knowledge will impact many other estrogen-related conditions (e.g., breast and endometrial cancer, cardiovascular disease, osteoporosis).
Showing the most recent 10 out of 64 publications
