PRECLINICAL STUDIES ON HUMAN FIBROIDS IN IMMUNODEFICIENT MICE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Uterine fibroids (leiomyomata) are benign tumors of the uterine muscle or myometrium that affect 25-40% of women of reproductive age. Despite the high prevalence of fibroids in reproductive age women, there are few animal models for fibroid disease. To fill this gap we created a human xenograft model for preclinical studies of human fibroids. For this model, fibroids are collected from women undergoing hysterectomy and transplanted into immunodeficient SCID mice for study. Our goal was to test the effects of novel anti-fibroid therapies including androgens and androgen antagonists on growth of fibroid and myometrial grafts in these mice. Recent studies indicate that the hosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway may participate in steroid regulation of cell proliferation in fibroid cells. The mammalian target for rapamycin is a downstream mediator of PI3K/Akt. We tested the effect of rapamycin, and BEZ35 (a rapamycin analog) on fibroid graft growth. Fibroid tissues were collected from 10 women undergoing hysterectomy at the OHSU Hospital after IRB approval and informed consent and subcutaneous grafted into ovariectomized mice. The mice bearing the grafts were treated with implants releasing either estradiol (E2), progesterone (P), E2 + P, E2 + P + Rapamycin, or and E2 + P + BEZ235. Rapamycin significantly reduce fibroid growth in our mouse model. BEZ235 did not reduce graft size, but did reduced fibroid cell proliferation.