Working towards an optimized therapy for abnormal endometrial proliferation: treatment approaches and disease modeling

With the steadily increasing prevalence of endometrial hyperplasia (EH) and endometrial cancer (EC) among premenopausal women, the pursuit of improved conservative therapeutics is vitally important. Work in this dissertation attempts to optimize treatments for EH and EC through three different approaches: 1) formulating an enhanced progesterone (P4) vaginal formulation, 2) providing a new in vivo tool (animal model) for EH, and 3) testing the potential of imiquimod (IQ) as a treatment for primary EC. In the first approach, glycol chitin, a polymer with thermosensitive properties, was used as the delivery vehicle for the new progesterone (P4) formulation (GC-P4). Thermogelling, mechanical, and dynamic studies using rheology showed that GC-P4 gelled and maintained suitable physical characteristics in the vaginal environment. The formulation was capable of releasing the drug in a controlled manner with no effect on the drug's bioactivity. GC-P4 was safe to the vaginal environment as the in vitro studies depicted. Local safety was confirmed in mice, as well is the ability of GC-P4 to inhibit EH disease progression. The induction of EH after implantation of subcutaneous estrogen (E2) pellets in mice was the second approach explored. The main motive for this innovative approach was the lack of an in vivo model that effectively represents EH as seen in human. Analysis of endometrial tissues using H&E and several immunohistochemistry stains reflected different stages of disease development, hormonal receptors status, and common genetic abrasions as seen in the human disease. In order to widen the treatments options for patients with low grade EC who do not respond well to conventional treatments yet desire a conservative therapy, the potential role of IQ in the management of EC was evaluated. In vitro studies using Ishikawa and HEC-1A cells showed that IQ is capable of inducing apoptosis in cells, possibly through inhibiting expression of the BCL-2 family of proteins. Moreover, IQ was able to inhibit EC progression in a mouse xenograft model. The endeavor described in this dissertation aims to address some of unmet needs in researching and treating abnormal endometrial proliferations, i.e. EH and EC. The studies and tools developed here lay the foundation for future studies aiming at understanding and advancing therapies for EH and EC.