Herding clonal evolution to overcome drug resistance in high-grade serous ovarian cancer

Abstract

Ovarian cancer (OC) is one of the most common malignancies responsible for cancer-related deaths in women, and finding new treatment strategies is an area of unmet clinical need. To investigate how the concepts of cancer evolution could be applied to OC care, we hypothesised that the understanding of the clonal dynamics of high-grade serous OC barcoded models under the selection pressure of anticancer drug therapy would allow the development of new sequences of drug treatment, changing current paradigms.

The core of this thesis centred on exploring cancer evolution in OC, emphasising how commonly used drugs to treat this disease (carboplatin, paclitaxel and olaparib) influence its course, employing an advanced state-of-the-art DNA barcode methodology. My experiments showed a tangible correlation between barcoded cell populations pre- and post-drug exposure and barcodes detectable in culture medium. This pivotal observation suggests that liquid biopsies hold promise for real-time tracking evolution in OC.

Further, my experiments revealed consistent cell population profiles post-drug exposure across triplicate experiments, suggesting the presence of pre-existing persistent clones prior to drug exposure. Notably, my experiments also revealed significant differences between paclitaxel and DNA damaging/DNA repair-targeting drugs (carboplatin and olaparib) in barcoded populations. Specifically, carboplatin and paclitaxel caused less heterogeneous cell populations, while olaparib-exposed cells exhibited more pronounced heterogeneity. Furthermore, cells that emerged or persisted post carboplatin and olaparib exposure shared more similar evolutionary phenotypic patterns compared to OC cells exposed to paclitaxel.

Additional findings revealed intricate patterns of cancer evolution trade-offs in terms of proliferation and development of collateral sensitivity. Through single-cell RNA sequencing, gene expression patterns were elucidated, demonstrating distinct differences between paclitaxel-persistent and carboplatin/olaparib-persistent populations. In conclusion, this thesis provides an in-depth exploration of drug resistance/tolerance in OC. Such insights could impact treatment strategies and lead to further research, refining therapeutic approaches for OC.