Before the Chicken or the Egg: Modulating Ovarian Hormonal and Inflammatory Inputs to Interrupt Carcinogenesis in a Novel Murine Model of Spontaneous EOC
Abstract
Rational/Objective: Epithelial ovarian cancer (EOC) is the most lethal of the gynecologic malignancies and remains so despite advances in treatment. The approach to EOC that has shown to most dramatically improve survival is the preventive effort of removing the fallopian tube and ovaries in women at high risk of developing disease. Unfortunately, this requires an invasive procedure in which women must make permanent decisions regarding fertility and the impact of the ensuing immediate menopause. Therefore, less invasive, yet equally effective prevention strategies for EOC that do not severely impact quality of life are needed. The current thought in the development of EOC is that it is a result of incessant or uninterrupted ovulation that causes inflammation over the course in reproductive life which explains why pregnancy, oral contraceptive pills (OCPs), and non-steroidal-anti-inflammatory agents (NSAIDs) are thought to be protective. Egg-laying hens, like humans, develop ovarian cancer, but do so at a much higher rate, plausibly due to their every-28-hours ovulation cycle. In our prior OCRP pilot work, we used this natural spontaneous EOC hen model to conduct an evaluation of a novel compound (MCI-030), synthesized to be a more tolerable and efficacious alternative to a traditional NSAID, to determine whether it could prevent ovarian cancer. We observed a reduction in cancer incidence in hens and through our molecular work, identified an anti-inflammatory role for MCI-030 that may be specific to ovulatory inflammation through acting on a novel molecular target: phosphodiesterase 10 (PDE10). Furthermore, findings similar to ours in hens have been observed with Progesterone (P4) treatment. As PDE10 has been identified as a major gene in P4 signaling, we aim to investigate the impact of each agent in this current proposal, both alone and in combination. One limitation of the hen model is that there are limited tools to follow up our results. We aim to overcome this problem and further investigate MCI-030 as a cancer prevention agent and its relationship in P4 signaling by collaborating with the Zong laboratory that has developed a cutting-edge mouse model termed the Mosaic Analysis with Double Markers (MADM). This innovative system allows us to study changes in the fallopian tube far before the development of obvious invasive disease. The MADM mice have been engineered to exist, like BRCA mutation carriers, at high risk of developing disease. This model therefore provides an opportunity over the course of 40 weeks to study the early changes in the tube and ovary that lead to EOC. Relative to this proposal, the MADM mouse model is a powerful system to evaluate the ability of MCI-030 and P4 to prevent these changes as well as the relationship between the two, effectively halting the development of EOC. The goal of the current proposal is to evaluate two chemo-prevention agents, MCI-030 and P4, in a model system that can provide evidence that they can truly prevent ovarian carcinogenesis. At the same time this system allows us to understand how they are having an impact. Expansion of Prior Work: We initially proposed MCI-030 as a more tolerable and efficacious NSAID derivative with a novel target (PDE10) and hypothesized that by decreasing oncogenic signaling, this agent could reduce EOC in hens. In the course of conducting this study, we observed a trend towards a lower cancer incidence in the MCI-030 treated hens, but ovulatory irregularities were also improved. There is also evolving evidence in the literature that PDE10 is actively involved in Progesterone activity and that P4 is able to cleanse the fallopian tube of abnormal cells. We therefore hypothesize that MCI-030 works by modulating ovulatory inflammation in the context of P4 stimulation in the ovary and tube, and at the same time suppressing cancer-causing signaling which will reduce pre-cancerous disease. PDEs are enzymes that are re
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210509
Entities
People
- Jennifer Scalici
Organizations
- United States Army
- University of South Alabama