Circulating Exosomal Protein Expression for Early Prediction of Platinum Resistance in High-Grade Serous Ovarian Cancer
Abstract
Rationale and Objective: Ovarian cancer is the most lethal of all gynecologic cancers in the United States. High-grade serous ovarian carcinoma (HGSOC), the most common subtype, is associated with a particularly poor prognosis due to late diagnosis and a high rate of resistance to standard chemotherapy regimens. Only a quarter of patients with chemotherapy-resistant HGSOC survive longer than 12 months. In an effort to combat the development of chemotherapy resistance, it is important to evaluate potential predictive cancer biomarkers. CA125 is the only widely available biomarker for HGSOC; however, it is not able to detect early disease or predict response to treatment. 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 easier detection of cancer-specific proteins. The current study proposes to identify expression of unique exosomal proteins that may serve as biomarkers for HGSOC. This would allow clinicians to identify patients earlier in hopes of implementing targeted therapy to improve treatment response and survival. Problem to Be Addressed and How It Will Advance the Field: To date, no reliable predictive biomarkers have been recognized that are capable of identifying patients with chemotherapy-resistant HGSOC despite an urgent need to identify patients who are unlikely to benefit from standard chemotherapy. While many protein biomarkers for HGSOC have been studied, none has been found to be clinically relevant. Further, serum protein biomarkers are found in low concentration, making them difficult to reliably detect with existing methods. This is why exosomal proteins are an attractive source of biomarkers. This is the first study exploring the clinical implications of exosomal proteins identified in our preliminary studies as well as further screening of exosomal proteins in both our Principal Investigator’s and co-Investigator’s (Larry Maxwell, M.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 isolation is a critical step toward translating our findings to the clinical setting. Thus, the proposed research is completely novel, as we have identified a unique set of exosomal proteins that have yet to be validated as a predictive biomarker for chemotherapy resistance in patients with HGSOC. Potential Impacts and Translational Applicability: Overall, the proposed study will achieve the following short-term impacts: (1) Development of a novel microfluidics-based device for exosome isolation with greater purity and quality and decreased time and cost that can be directly applicable for clinical exosome-based biomarker screening in patient serum samples. We are currently using this approach to isolate exosomes from clinical samples in our laboratory and expect that it can be clinically translated with ease. (2) Identify and validate the expression of exosomal proteins that are elevated in patients with HGSOC that could serve as biomarkers for chemotherapy resistance. The proposed research is founded upon a strong collaboration between basic and clinical research teams that have substantial translational potential. Who Will Benefit: We hope to contribute research that will lead to improved detection of chemotherapy resistance in patients with HGSOC, which could then allow better, more targeted treatments for these patients. This research would benefit all patients with ovarian cancer and hopefully contribute to improved surviv
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110427
Entities
People
- Karuppaiyah Selvendiran
Organizations
- Ohio State University
- United States Army