Novel NSAID Derivatives for the Chemoprevention of Ovarian Cancer in the Spontaneous Hen Model
Abstract
Rationale/Objective: Epithelial ovarian cancer (EOC) is the most lethal of the gynecological 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 results in immediate menopause. Therefore, less invasive, yet equally effective prevention strategies for EOC that do not severely impact quality of life are needed. As we are in the early phases of understanding the beginnings of EOC development, studying prevention approaches in a model that develops disease spontaneously and under similar conditions to women is vital as anything less oversimplifies a poorly understood process, which can make clinical interpretation of results difficult. This proposal will work to develop a non-invasive drug-prevention strategy for EOC that has an acceptable side effect profile. Critical Problem: Inflammation is common in the fallopian tube and ovary especially around the time of ovulation. The repetition of such an inflammatory event during monthly cycles over the course of years is implicated as a major contributor to the development of disease. Therefore, minimizing or preventing inflammation in the tube and ovary should reduce disease development. This has been observed in women who take non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin or Celebrex. Unfortunately, the daily doses required to effect disease prevention also result in unacceptable side effects. This has been a major limitation in the development of drugs to prevent EOC. An effective medication for cancer prevention must not have significant side effects; otherwise, the risk of the drug outweighs the benefit of reducing the risk of cancer. Our group has developed an anti-inflammatory compound, MCI-030, that blocks a different enzyme than more traditional NSAIDs and in effect, minimizes side effects. Despite the difference in mechanism, MCI-030 has resulted in more potent reductions in tumor cell growth than traditional NSAIDs. Therefore, we are proposing a study whereby we will assess the ability of MCI-030 to prevent ovarian cancer in the egg-laying hen, the only animal other than humans to spontaneously develop ovarian cancer. The hen model is vital to truly investigate the clinical impact of any intervention on EOC risk reduction, as it is the only model that will develop disease spontaneously without having to manipulate it genetically or alter its immune system. We will study the side effects and activity of MCI-030 in the hen with the expectation that the low doses necessary to prevent disease will minimize any side effects. We will then study the ability of this medication to prevent EOC. Investigating MCI-030 in the hen will potentially advance our understanding of how EOC develops and will produce a method to interrupt this process in a manner that is non-invasive and has few side effects, thereby addressing the major limitation to effective drug prevention for ovarian cancer. Vision and Mission: This project aligns closely with the vision and mission of the Ovarian Cancer Research Program as effective prevention strategies are desperately needed to reduce the incidence of disease. A byproduct of studying such efforts is a more clear view of the culmination of events resulting in the initiation of disease. To prevent a disease, one must understand the cause. We aim to not only explore the cause, but also to target it with a medication that is well tolerated with few side effects. If successful, the impact of this study will be felt broadly. Currently, the most effective prevention strategy for EOC is invasive and reserved for women felt to be a highest risk for disease. Our approach, if effective, is minimally invasive, c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710229
Entities
People
- Jennifer Scalici
Organizations
- United States Army
- University of South Alabama