Australian researchers have discovered an epigenetic biomarker that may help identify more women with ovarian cancer who will be susceptible to PARP inhibitor therapy.A team at the Walter and Eliza Hall Institute (WEHI) in Melbourne have found that epigenetic marks for RAD51C gene silencing are required to avoid ovarian cancer cells developing resistance to PARP inhibitor therapy.
PARP inhibitors are currently indicated for the treatment of women with BRCA1/2 mutated DNA repair genes that make cancer cells susceptible to PARP inhibitors.
If confirmed, the new finding suggests that PARP inhibitors should also be made available to women who have the marker for RAD51C gene silencing, as this will denote they are susceptible to treatment, the researchers said.
Their findings showing that acquired RAD51C promoter methylation loss causes PARP inhibitor resistance in high grade serous ovarian carcinoma is published in the journal Cancer Research,
The work was done by WEHI researchers Dr Ksenija Nesic and and Professor Clare Scott, in conjunction with researchers from QIMR Berghofer researcher and US collaborators.
Preclinical models called PDX (patient-derived xenografts) were used with tumour samples from 13 women with high-grade serous cancer. About half the cells had ‘epigenetic marks’ that silenced the RAD51C gene, and were susceptible to PARP inhibitor therapy.
“We showed that RAD51C silencing has to be absolute for the PARP inhibitors to work. If the cancer has any residual DNA repair capabilities, or if these epigenetic marks are lost during treatment, it became resistant to the therapy,” Dr Nesic said.
“This builds on previous work from the Scott laboratory that PARP inhibitors become ineffective if the BRCA1 gene is not completely silenced – the first time that incomplete gene silencing had been linked to PARP inhibitor resistance.”
Professor Scott is joint head of clinical translation at WEHI and a medical oncologist at the Royal Melbourne and Royal Women’s Hospitals and Peter MacCallum Cancer Centre.
She noted that PARP inhibitors such as olaparib and niraparib were currently approved in Australia as maintenance treatment for women with BRCA-mutated high grade epithelial ovarian cancer, in whom there had been little improvement in survival rates with other treatments in the past 30 years.
With PARP inhibitors, first cancer recurrence was delayed by 3.5 years and, in advanced disease, progression free survival was extended, she said.
“In 2017, we showed that PARP inhibitors need to be more widely available to women who have genetic mutations that inactivate RAD51C. This new study suggests they should also be made available to women who have epigenetic marks that inactivate or silence RAD51C, expanding the number of women who could benefit from these therapies,” said professor Scott
Dr Nesic said knowledge of the epigenetic marks would also allow more personalised treatment by indicating whether resistance to therapy would develop over time.
“In the future, we propose that women undergoing treatment for ovarian cancer should have their tumours monitored over time. If their cancers lose their gene silencing, then women should be offered alternative therapies, as PARP inhibitors will no longer be effective,” she said.