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News & Trends - Pharmaceuticals

Could PARP inhibitors benefit more ovarian cancer patients?

Health Industry Hub | August 6, 2021 |
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Pharma News: Researchers have made a discovery that could help more Australian women with ovarian cancer gain access to game-changing cancer treatments called PARP inhibitors.

The research team found tumours from some ovarian cancer patients had changes that silenced a gene involved in DNA repair and showed that this made tumours sensitive to PARP inhibitors such as AstraZeneca’s Lynparza  (olaparib), GSK’s Zejula (niraparib) and Pfizer’s Talzenna (talazoparib).

The discovery identifies a new group of patients who are likely to benefit from the therapy and should be included in trials of PARP inhibitors. It also indicates these women should be closely monitored for changes that affect gene silencing, which could render their cancers resistant to therapy.

The research, published in the journal Cancer Research, was led by WEHI researchers Dr Ksenija Nesic, Dr Matthew Wakefield and Professor Clare Scott, QIMR Berghofer researcher Dr Olga Kondrashova and Associate Professor Alexander Dobrovic from the University of Melbourne Department of Surgery, together with Australian and US collaborators.

Dr Nesic said the cancer cells that were susceptible to PARP inhibitors shared a unique characteristic. “We observed that ovarian cancers with ‘epigenetic marks’ which silenced the RAD51C gene were susceptible to PARP inhibitor therapy,” Dr Nesic said.

Epigenetic marks are ‘notations’ on DNA that can, among other things, instruct the genes to be switched on (expressed) or switched off (silenced). RAD51C is also associated with DNA repair in cells.

“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.”

A game-changer for ovarian cancer

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 said PARP inhibitors have had a profound impact in treating BRCA1/2 mutated ovarian cancers.

“Ovarian cancer is often diagnosed at an advanced stage and many women relapse after treatment,” Professor Scott said. “PARP inhibitors are currently approved in Australia for treating women with BRCA1/2 mutated cancers, with unprecedented success. In these women, first cancer recurrence is delayed by 3.5 years and, in advanced disease, progression free survival is extended. This is significant for women with ovarian cancer, considering we have seen little improvement in survival rates in the past 30 years.

“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.”

Dr Nesic said the studies highlighted how medical research provided much needed guidance about personalised treatment options, and improved patient outcomes.

“This research has identified more women who would benefit from PARP inhibitor therapy and showed us that the best therapy for a patient can change over time,” Dr Nesic said.

“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.”

The research was supported by the Australian National Health and Medical Research Council, ACRF, Cancer Council Victoria, the National Breast Cancer Foundation, the Stafford Fox Medical Research Foundation, the Victorian Cancer Agency and the Victorian Government.


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