Identifying Novel Biomarkers for Early Detection of Ovarian Cancer Using Exosomes
Abstract
Rationale and Objective: High-grade serous ovarian cancer (HGSOC) accounts for over 75% of all epithelial ovarian cancer, and the majority of patients with HGSOC are diagnosed with advanced-stage disease due to a lack of screening and early detection methods. Exosomes are nano-sized (30-120 nm) vesicles that are released by a variety of cells in the body. In contrast to serum proteins, such as CA125, exosomes are an attractive source of biomarkers as they carry cargo (proteins, microRNAs, and lipids) from their cells of origin, are highly stable, and can be obtained from any biological fluid using non-invasive procedures. Exosomes also have a less-complex collection of proteins compared to whole serum, thus allowing for easier detection of cancer-specific proteins. The rationale for the proposed study is that with the high mortality of advanced HGSOC there is an urgent need for high-quality screening and early detection methods. The overall objective of this proposal is to identify and validate clinically relevant exosomal protein signatures of early-stage HGSOC for use as biomarkers to screen for earlier diagnosis. Problem to be Addressed and How It Will Advance the Field: To date, no known biomarkers have proven to be effective for screening or early detection of ovarian cancer because most lack specificity and cannot be obtained using robust and reproducible technologies that are required for their validation. Despite its high variability in expression, CA125 remains the only widely used biomarker for HGSOC; however, it is not sensitive nor specific enough to detect HGSOC at early stages. While many proteomic biomarkers have been identified, they have not been confirmed in subsequent studies. This is why exosomal proteins are an attractive source of biomarkers. This is first study exploring the clinical implications of a set of exosomal proteins that we have identified in preliminary studies and plan to expand with further screening of exosomal proteins in both our Principal Investigator’s and collaborator’s (Larry Maxwell, M.D. and Jinxiong She, Ph.D.) laboratories. Our laboratory has developed a microfluidic-based device for isolating exosomes from patient serum that is more efficient and has greater purity and specificity than conventional methods. This superior method of isolation is a critical step toward translating our findings to the clinical setting. In our pilot studies, this set of candidate proteins (several of which are completely novel) had greater sensitivity and specificity for early-stage HGSOC disease than CA125. Potential Impacts and Translational Applicability: Our study proposes to explore the biology and clinical value of exosomes as a source of protein biomarkers that can be used for the early detection of HGSOC. The proposed study will achieve two major short-term impacts: (1) We have developed a cost-effective microfluidics device with translational potential for exosomal isolation in the clinical setting. In our pilot studies, this instrument yielded high purity exosomes in a significantly shorter period of time compared to traditional ultracentrifugation and commercially available kits. These factors are critical for moving forward in clinical translation. (2) We identified candidate exosomal proteins from patient serum samples that are differentially expressed in early-stage HGSOC compared to healthy controls or benign ovarian disease, as well as when comparing healthy controls with advanced-stage HGSOC. In our preliminary studies, these candidate proteins outperformed the current standard of care biomarker, CA125. Because of the novel microfluidics device, this work has the ability to be easily translated for widespread clinical use and therefore has the potential to significantly reduce the amount of women diagnosed with ovarian cancer at an advanced stage. Who Will Benefit: We hope to contribute research that will lead to the identification and valid
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210371
Entities
People
- Karuppaiyah Selvendiran
Organizations
- Ohio State University
- United States Army