Elucidating recurrent ovarian cancer

EOC patients initially respond well to first-line surgery and chemotherapy, but most relapse and acquire platinum resistance resulting in their death. The OCTIPS (Ovarian cancer therapy – Innovative models prolong survival) project is studying the molecular mechanisms involved in the development of recurrent EOC to improve therapeutic efficacy.

To begin with, researchers established two online databases and delivered paired tumour tissues at initial prognosis as well as relapse. Impressively, OCTIPS constructed a tissue microarray set that contains paired samples from around 70 HGSOC patients.

Genomic and transcriptional comparison of paired primary and relapsed tumour samples revealed biological processes contributing to resistance and recurrent disease. Some of these genes and microRNAs were selected for further validation. Using biological network interference modelling, compounds interfering with these processes were successfully identified.

OCTIPS generated several cell lines representing primary ovarian cancer and ovarian cancer relapse as well as patient-derived xenografts (PDX) from HGSOC. They also characterised 39 ovarian cancer cell lines generally used in research.

Experiments on HGSOC-PDX showed good correlation with patient samples. They also established a molecular model of platinum-based resistance in ovarian cancer. Along with the avian egg models, these model systems should prove extremely useful for studying HGSOC resistance and assessing drug efficacy.

Project members evaluated currently used drug combinations as well as those in phase III/IV clinical trials. A key finding is that pre-treatment measurement of the AKT pathway signature could predict treatment response for drugs such as GSK2141795. Researchers are also setting up an early-phase clinical trial to assess CYC065, a cyclin-dependent kinase inhibitor in CCNE1 amplified ovarian cancer.

By the end of the project, OCTIPS deliverables will provide new knowledge on cancer progression and mechanism of drug resistance, as well as help identify potentially effective therapeutic strategies.

EOC treatment has significant side-effects, a low success rate and a very high burden on health care budgets. OCTIPS activities could improve patient outcomes as well as their quality of life. Their knowledge repository on ovarian cancer relapse as well as disease models will be invaluable to any researchers working on EOC.