Elucidating recurrent ovarian cancer
Epithelial ovarian cancer accounts for 4 % of gynaecological cancer-related deaths in developed countries. Although the majority of patients initially respond well to surgery and chemotherapy, the five-year survival is only about 30 %. This suggests the presence of a small resistant cell population in the primary tumour that may be responsible for the ultimate relapse. The EU-funded OCTIPS (Ovarian cancer therapy – Innovative models prolong survival) project wished to analyse recurrent and resistant ovarian cancer at the molecular level. Researchers collected data from patients in two online databases and samples from paired tumours (primary and relapsed) of nearly 150 patients. Genomic analysis identified unstable chromosomal regions following platinum therapy, and a platinum score was devised predictive of resistance that included 13 copy number regions, including MECOM, CCNE1 and ERBB2. To address tumour resistance, they performed molecular analysis and identified mTOR signalling among the deregulated pathways that could be targeted for therapy. Scientists discovered two microRNAs to be highly expressed in recurrent HGSOC as well as a nuclear DNA-dependent protein kinase (DNA-PK), an enzyme implicated in DNA repair. Considerable effort went towards the development of innovative models that closely mimicked the relapse process, including xenografts and cell lines that presented platinum resistance. A computational molecular model of HGSOC relapse facilitated the identification of biomarker candidates and evaluation of promising therapy candidates. It also helped researchers identify synthetic lethal interactions and drug combinations and how these could be addressed by different drugs that are already in clinical use in the field of oncology. Furthermore, the consortium performed a number of clinical trials to demonstrate the use of validated molecular targets and test new combinations of drugs. Overall, the OCTIPS project provided new knowledge on the functional pathways and molecules that may be implicated in recurrent ovarian cancer. The molecular heterogeneity indicates that personalised analysis will be required to achieve efficient therapy design.
Keywords
Ovarian cancer, drug resistance, platinum therapy, mTOR, microRNA, DNA-PK, clinical trial
