A Multifaceted Approach to Biomarker Discovery for BRCA-Associated Fallopian Carcinoma
Abstract
The Central Problem: Survival from a diagnosis of ovarian cancer continues to be significantly affected by the frequent late stage of diagnosis of the disease. When ovarian cancers are detected early enough, the chances of survival in patients with the disease increase dramatically—5-year survival rates are more than 90% for patients at this stage. However, there are currently no clinical biomarkers that can detect the disease at the earliest, most treatable stages. Addressing FY22 OCRP Areas of Emphasis: This proposal focuses on two FY22 OCRP priorities, specifically understanding the basic biology and etiology of ovarian cancer initiation and progression and identifying and developing new strategies for screening, early-stage detection, prevention, accurate diagnosis and prognosis. Using our experimental approaches, we expect to identify high-probability biomarkers for early-stage ovarian cancer detection based on unique cell types of normal fallopian tubes (FTs) and serous tubal intraepithelial carcinomas (STIC) precursors of ovarian cancer. In this study, we hypothesize that the development and characterization of human avatars of FT created from induced pluripotent stem cell (iPSC) models of women carrying germline mutations in genes known to cause ovarian cancer (BRCA1 and BRCA2) can identify biomarkers of early-stage pathogenesis of ovarian cancers. This will be further complemented using innovative single cell profiling of normal FT and STIC tissues from subjects with and without BRCA1/BRCA2 mutations. Single cell methods allow us to resolve cell-specific heterogeneity in tissues and help us find both cell types and specific molecular markers that are particularly associated with early-stage disease. Finally, one of the main reasons for the lack of success in this area in the past has been our inability to develop accurate and successful screening strategies for the detection of early-stage ovarian cancer. To address this challenge, we have developed tissue-informed methods for the analysis of cell free DNA to diagnose cancers in the blood (liquid biopsies). This validated method represents a novel approach to detect early- stage cancers in women before they can develop advanced ovarian cancer, which is without a doubt a more effective way to prevent deaths from ovarian cancer. Patient Cohort: The research described in the proposal is based on a unique, clinically annotated biorepository of specimens collected over more than 30 years from subjects at high risk of ovarian cancers (the Gilda Radner Hereditary Cancer Program, or GRHCP). Specimens and clinical and epidemiological data have been collected for ~2,000 subjects screened for mutations in high and moderate penetrant susceptibility genes, including BRCA1 and BRCA2. More than 900 BRCA1/BRCA2 carriers have been identified and more than 60,000 liquid biopsy samples have been collected from these subjects following annual visits both prior to any diagnosis of ovarian cancer and in other subjects following a disease diagnosis. This biorepository is ideal for the identification of putative clinical biomarkers in BRCA1/BRCA2 carriers and non-carriers associated with early-stage diagnosis of ovarian cancer. Clinical Implications: We expect this work to identify hundreds to thousands of previously unknown biomarkers that are associated with the development of ovarian cancer in patients with and without BRCA1 and BRCA2 mutations. Because of the novelty of the methods we are using, none of which have been used before in this context, we anticipate we will find several novel biomarkers that can detect ovarian cancers at their earliest and most treatable stages. If the project is successful, it is likely that these strategies and/or the biomarkers we identify will be effectively used in clinical practice to screen for early-stage ovarian cancer as a prevention measure against further development to late-stage disease when outcomes are so poor.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310362
Entities
People
- Simon A Gayther
Organizations
- Cedars-Sinai Medical Center
- United States Army