Developing adaptive therapy to suppress the evolution of treatment resistance in high-gradeserous ovarian cancer


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Helen Hockings, Huang W, Lakatos E, Graham T, Lockley M

Abstract

Background

Survival in high grade serous ovarian cancer (HGSOC) is impacted by the emergence of resistance to platinum chemotherapy. The traditional ethos of killing the greatest number of cancer cells with the maximum tolerated dose of chemotherapy may be flawed in evolutionary terms. Adaptive therapy exploits the competitive interactions between drug-sensitive and resistant subclones, keeping a sufficient population of sensitive cells which suppress the proliferation of the ‘less fit’ resistant cells. Our lab has generated unique panels of carboplatin- and cisplatin-resistant OVCAR4 HGSOC cell lines to model acquired resistance to chemotherapy. We have demonstrated competition between platinum-sensitive and resistant cells in vitro. Flow cytometry for propidium iodide and annexin V revealed that resistant cells undergo cell cycle arrest in sub-G0 and apoptosis when cultured with sensitive cells, increasing in proportion to the size of the sensitive population. 

In the absence of chemotherapy, sensitive cells outgrow resistant cells in subcutaneous and
intraperitoneal co-cultures in female CD1 nude mice. Using a subcutaneous tumour model, adaptive therapy has shown a benefit over standard therapy in vivo, with prolonged time to tumour re-growth.

Method

A challenge in bringing adaptive therapy to the clinical setting is quantifying the proportions of
therapy-sensitive and resistant disease. We have developed a method using low pass whole genome sequencing to calculate relative quantities of copy number aberrations found in sensitive and resistant disease. We are applying this to circulating tumour DNA isolated from serial plasma and tissue samples collected from 19 HGSOC patients, using the copy number profile from a diagnostic biopsy as a baseline for sensitive disease. This technique will enable real-time tracking of tumour composition and guide personalised treatment scheduling.

Results


Conclusion

Based on our research, a clinic trial is being set up to test adaptive therapy in HGSOC patients in the platinum-sensitive relapsed disease setting.

Impact statement