Small Extracellular Vesicles as Mediators and Biomarkers of Platinum-Resistant Epithelial Ovarian Cancer

Abstract

Platinum-based chemotherapy has been part of the standard-of-care treatment for ovarian cancer since 1978. However, one-third of patients do not respond to first-line chemotherapy, and most eventually develop platinum resistance with recurrence. To date, the only clinical marker used to evaluate response to chemotherapy is CA125, monitored during and after treatment. Identifying a biomarker of platinum-resistance in treatment-naïve patients would enable individualized therapy and improve outcomes.

In this thesis, we demonstrate that identifying a predictive biomarker for chemoresistance is a patient-centred research priority. Through a roundtable discussion with ovarian cancer patient panellists with lived experience of ovarian cancer, this research direction was identified as having meaningful potential benefit for future patients.

In two biomarker studies, we quantified plasma gelsolin (pGSN) from small extracellular vesicles (sEVs), which has been shown to be highly secreted by chemoresistant ovarian cancer cells, in blood samples from treatment-naïve patients. In the first study, we found that total circulating pGSN was significantly decreased in chemoresistant patients, while sEV-pGSN was significantly increased. The ratio of total pGSN to sEV-pGSN improved sensitivity and specificity compared to either marker alone. We extended these findings in the second study by incorporating MRI-based radiomics in a machine learning algorithm with total and sEV-pGSN to predict chemoresistance. Consistently, the combined markers improved predictive accuracy.

Finally, we investigated the role of sEVs in chemoresistance in vitro. We showed that elevated pGSN is not universal across chemoresistant cell lines. However, in resistant A2780cp cells with high pGSN expression relative to paired sensitive A2780s cells, inhibiting sEV biosynthesis improved chemosensitivity. This was not the case for PEO4 cells, which exhibited comparable pGSN expression to their paired chemosensitive PEO1 cells.

Altogether, our findings suggest that pGSN-associated chemoresistance is mediated by sEVs and reflected in patient circulation. Measuring sEV-pGSN offers a strategy to identify chemoresistance prior to treatment and guide personalized therapy.