Discovery enables more targeted treatment for ovarian cancer

Australian scientists have revealed a better way to identify which ovarian cancer patients should respond to powerful drugs called PARP inhibitors (PARPi), resolving an important question about why some patients respond to these drugs while others do not.

Professor Clare Scott, a co-leader on the study from the Walter and Eliza Hall Institute (WEHI), said it had been well documented that PARPi could only work when the cancer’s DNA repair process isn’t functioning as it should.

“For the past two decades, it was thought that ovarian cancer patients whose cancer’s BRCA1 genes are ‘silenced’ — or methylated — have faulty DNA repair and therefore were good candidates for PARPi treatment,” she said.

“Yet the puzzling thing was we were unable to predict the patients for which the drugs would work.”

WEHI’s Dr Olga Kondrashova, another study co-leader, said the ‘Eureka moment’ came when the researchers discovered subtle differences in some BRCA1 methylated cancers. These subtle yet significant epigenetic differences explained why some patients would respond to the drug while others would not.

“It was suddenly clear that all patients in the group could not be treated the same way,” Dr Kondrashova said. “We discovered that some of the patients had what could be described as ‘incomplete’ BRCA1 methylation where not every gene copy was ‘switched off’.

“As it turns out, incomplete methylation isn’t enough to cause faulty DNA repair in cancer cells, which meant PARPi wasn’t going to be effective for them.

“At the same time, those in the group who had ‘complete’ BRCA1 methylation in their cancer were responsive to PARPi confirming to us that the treatment should not be discounted.”

Prof Scott said the findings — published in the journal Nature Communications — were a result of methodologies developed by Associate Professor Alexander Dobrovic at the Olivia Newton-John Cancer Research Institute that could accurately determine the degree of BRCA1 methylation, quality datasets and sophisticated laboratory models called patient derived xenografts (PDX models).

“PDX models are powerful because they mimic the complexity of human tumours at key stages as the cancer progresses,” Prof Scott said. “Our models are developed with cancerous tissue donated by patients from The Royal Women’s Hospital, The Royal Melbourne Hospital and the Peter Mac at the time of their cancer diagnosis, or prior to and after treatment with PARPi.

“Like snapshots in time, PDX models allow us to accurately track how each patient’s cancer is changing or responding to treatment. The success of this approach shows that a long-term, detailed analysis is invaluable for providing better patient care.”

Prof Scott said understanding the various reasons for PARPi resistance is an invaluable approach for developing better, more personalised patient care, improving patient survival rates that have seen little change over the past 30 years.

“There is no ‘one size fits all’ approach for ovarian cancer care,” she said. “We need to keep making these strides in understanding so we can better match patients with the right treatment for their cancer.”

Image caption: Professor Clare Scott. Image credit: The Walter and Eliza Hall Institute.