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Published on: September 12, 2019
A therapeutic model for advanced endometrial cancer: systemic progestin in combination with local adenoviral-mediated
Donghai Dai1, Lina Albitar, Tan Nguyen
1Reproductive Molecular Biology Laboratory, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center, MSC10 5580, 1 University of New Mexico, Albuquerque, NM 87131, USA.
Abstract:
Cancer of the uterine endometrium is a frequent gynecologic malignant disease for which few therapeutic options are available for advanced disease. Progesterone is the normal female hormone that limits growth and proliferation of endometrial cancers; however, progesterone receptors are frequently down-regulated, leading to treatment failures. The current studies explored the effectiveness of adenoviral-mediated progesterone receptor gene transduction in combination with progestin therapy in mouse xenograft models. Pretreatment of cells with progesterone receptor-encoding adenovirus and progestin inhibited the development of s.c. tumors in athymic mice. In the i.p. xenograft model, replacement of both isoforms of progesterone receptor, PRA and PRB, in combination with progestin treatment resulted in a significant 2.6-fold increase in overall survival time compared with control animals. These studies indicate that when progesterone receptor levels are maintained, progestin therapy is effective in limiting tumor growth. Future therapeutic regimens targeted at enhancing progesterone receptor expression have the potential to improve outcomes in women with endometrial cancer.
Insights
Restoring progesterone receptor (PR) expression via gene therapy, combined with progestin treatment, effectively limits endometrial cancer growth in mouse models. This approach significantly increased survival, offering a promising new strategy for advanced disease.
Area of Science:
- Gynecologic Oncology
- Molecular Medicine
- Gene Therapy
Background:
- Endometrial cancer is a common gynecologic malignancy with limited treatment options for advanced stages.
- Progesterone normally inhibits endometrial cancer growth, but receptor down-regulation causes treatment failure.
- Progesterone receptors (PRs) are crucial for progestin therapy efficacy in endometrial cancer.
Purpose of the Study:
- To investigate the efficacy of adenoviral-mediated progesterone receptor gene transduction combined with progestin therapy.
- To evaluate the impact of restoring PR expression on endometrial cancer growth in preclinical models.
Main Methods:
- Utilized mouse xenograft models (subcutaneous and intraperitoneal) of endometrial cancer.
- Employed adenoviral vectors for progesterone receptor gene delivery (PRA and PRB isoforms).
- Administered progestin therapy in conjunction with gene transduction.
Main Results:
- Combined PR gene transduction and progestin therapy inhibited subcutaneous tumor development.
- Restoration of both PRA and PRB isoforms significantly increased overall survival by 2.6-fold in the intraperitoneal model.
- Demonstrated that maintaining progesterone receptor levels enhances progestin therapy effectiveness.
Conclusions:
- Adenoviral-mediated PR gene transduction combined with progestin therapy is a viable strategy for endometrial cancer.
- Maintaining adequate progesterone receptor expression is critical for successful progestin treatment.
- Targeting PR expression holds potential for improving outcomes in women with advanced endometrial cancer.
