onapristone and Uterine-Neoplasms

Although progesterone receptor (PR)-targeted therapies are modestly active in patients with uterine cancer, their underlying molecular mechanisms are not well understood. The clinical use of such therapies is limited because of the lack of biomarkers that predict response to PR agonists (progestins) or PR antagonists (onapristone). Thus, understanding the underlying molecular mechanisms of action will provide an advance in developing novel combination therapies for cancer patients. Nuclear translocation of PR has been reported to be ligand-dependent or -independent. Here, we identified that onapristone, a PR antagonist, inhibited nuclear translocation of ligand-dependent or -independent (EGF) phospho-PR (S294), whereas trametinib inhibited nuclear translocation of EGF-induced phospho-PR (S294). Using orthotopic mouse models of uterine cancer, we demonstrated that the combination of onapristone and trametinib results in superior antitumor effects in uterine cancer models compared with either monotherapy. These synergistic effects are, in part, mediated through inhibiting the nuclear translocation of EGF-induced PR phosphorylation in uterine cancer cells. Targeting MAPK-dependent PR activation with onapristone and trametinib significantly inhibited tumor growth in preclinical uterine cancer models and is worthy of further clinical investigation.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Female; Gonanes; Humans; Mice; Mice, Nude; Receptors, Progesterone; Uterine Neoplasms

To assess the action of onapristone, a type I antiprogestin, on prolactin (PRL) production by explant cultures of leiomyoma and myometrium.. Explant cultures of myometrium and leiomyomas from 3 premenopausal women undergoing hysterectomy in the proliferative phase of the menstrual cycle.. PRL secretion measured by radioimmunoassay.. PRL secretion was decreased in leiomyomas by onapristone. There was no effect in the myometrium. There was no additional effect with the addition of the type II antiprogestin mifepristone (RU 486).. PRL production is suppressed in leiomyomas but not in myometrium after treatment with onapristone in vitro. This suppression may serve as a marker for the clinical effectiveness of agents used in the treatment of leiomyomas.

Topics: Culture Techniques; Dose-Response Relationship, Drug; Female; Gonanes; Hormone Antagonists; Humans; Hysterectomy; Leiomyoma; Myometrium; Premenopause; Progestins; Prolactin; Uterine Neoplasms