Testing Chemoprevention Strategies in a Genetically Engineered Mouse Model of High-Grade Serous Carcinoma
Abstract
Rationale/Objective: In the United States, the overall 5-year survival rate of women with ovarian cancer is only 30-40%, and increases in survival since 1995 have been very modest (2-4%), despite significant efforts aimed at improving therapies for advanced-stage disease and screening for early detection. Ovarian cancer is a heterogeneous disease comprised of multiple different subtypes. High-grade serous carcinoma (HGSC) is the most common type of ovarian cancer and the one responsible for most ovarian cancer-related deaths. Importantly, most HGSCs are now thought to arise from cells in the fallopian tube, not the ovary. Early HGSC and its precursor, known as serous tubal intraepithelial carcinoma (STIC), are microscopic and cannot be detected with currently available imaging or other methods. Moreover, most women with HGSC are diagnosed after the cancer has already widely metastasized and cannot be cured by surgery and/or with existing chemotherapies. Given the many challenges associated with detecting microscopic tubal HGSCs before they have metastasized, as well as effecting cures for women with widely metastatic HGSC, an enhanced focus on preventing the development of HGSC is warranted. Ovarian cancer prevention studies are difficult to execute in humans, since very large numbers of women are typically needed to show the effect of a given intervention; other variables that may impact cancer development are difficult to control; and the time needed to see an effect is lengthy (usually many years). Genetically engineered mouse models (GEMMs) of cancer have the potential to provide tractable and relatively rapid systems with which to test cancer prevention strategies and inform cancer prevention trials in humans. Mice have a much shorter life span than humans (approximately 2 years), and other variables that might impact cancer development can be more carefully controlled. We have recently developed a GEMM of HGSC in which we can induce HGSC development in the mouse fallopian tubes (oviducts) and then monitor tumor progression over many months. The mouse HGSCs are based on many of the same genetic defects that characterize human HGSCs, and they recapitulate many of the same features, including cell of origin, acquisition of additional genetic changes, appearance under the microscope, and ability to metastasize in a distribution that closely mimics human HGSC. The earliest tubal lesions are not typically seen until ~6-8 months after induction, and mice develop more advanced tubal tumors and then metastatic disease over the ensuing several months. We believe these features, including the lengthy latency of tumor development, render our GEMM ideally suited to test potential chemopreventive agents for their ability to prevent or delay HGSC development, which is the goal of this project. What is the Central Problem? Because most women with HGSC present with advanced stage disease, most ovarian cancer research has been aimed at extending their survival and improving early diagnosis. Relatively few studies have focused on how to prevent these tumors from developing in the first place. Unfortunately, robust preclinical model systems for testing ovarian cancer prevention strategies have been lacking. Our new HGSC GEMM provides such a model system. Recent data in the published literature suggest that selected drugs already approved for use in humans may help prevent ovarian cancer. For example, PARP inhibitors have emerged as effective chemotherapeutic agents for women with ovarian cancer, and three have already received Food and Drug Administration approval. These drugs can be delivered orally, and importantly, are generally well tolerated. It is possible that low dose or intermittent treatment with PARP inhibitors will prevent or delay ovarian cancer onset in women at risk of developing the disease. Statins are widely used to lower blood cholesterol levels in an attempt to reduce risk of heart attack and st
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910162
Entities
People
- Kathleen Cho
Organizations
- United States Army
- University of Michigan