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New class of cancer-killing drugs identified

Published on 18/06/21 at 08:25am

Scientists have announced the identification of a new class of cancer drugs, known as POLQ inhibitors, that specifically kill cancer cells with mutations in the BRCA genes while leaving healthy cells unharmed.

Most crucially, these drugs are able to kill cancer cells that have become resistant PARP inhibitors – an existing treatment for patients with BRCA mutations.

Researchers are already planning to test the new drug class in upcoming clinical trials. If the trials are successful, POLQ inhibitors could enter the clinic as a new approach to treating a range of cancers with BRCA mutations, such as breast, ovarian, pancreatic, and prostate cancer.

The announcement comes from The Institute of Cancer Research, London, and the pharmaceutical company Artios, whose study findings were published in The Lancet on Thursday.

For some time now, scientists have known that genetically removing a protein known as POLQ killed cells with BRCA gene defects, although drugs that prevent POLQ from working had not been identified.

In this new work, the researchers identified prototype drugs that not only stop POLQ from working, but which also kill cancer cells with BRCA gene mutations.

Both BRCA genes and POLQ are involved in repairing DNA. Cancer cells can survive without one or other of them, but if both are blocked or their genes switched off, cancer cells can no longer repair their DNA and they die.

Study co-leader, Professor Chris Lord, Professor of Cancer Genomics at The Institute of Cancer Research, and Deputy Director of the Breast Cancer Now, said: “All cells have to be able to repair damage to their DNA to stay healthy – otherwise mutations build up and eventually kill them. We have identified a new class of precision medicine that strips cancers of their ability to repair their DNA.

“This new type of treatment has the potential to be effective against cancers which already have weaknesses in their ability to repair their DNA, through defects in their BRCA genes. And excitingly, the new drugs also seem to work against cancer cells that have stopped responding to an existing treatment called PARP inhibitors – potentially opening up a new way of overcoming drug resistance. I’m very keen to see how they perform in clinical trials.”

Researchers found that when cells were treated with POLQ inhibitors, cancer cells with BRCA gene mutations were stripped of their ability to repair their DNA and died, but normal cells did not. By killing cancer cells with BRCA gene mutations, while leaving normal cells unharmed, POLQ inhibitors could offer a treatment for cancer with relatively few side effects.

Researchers also found that POLQ inhibitors work very well when used together in combination with PARP inhibitors.

The addition of POLQ inhibitors meant that PARP inhibitors were effective when used at a lower dose. And in laboratory tests in rats and in organoids – three-dimensional mini-tumours grown in the lab – POLQ inhibitors were able to shrink BRCA-mutant cancers that had stopped responding to PARP inhibitors because of a defect in a set of genes known as the ‘Shieldins’.

This suggests that POLQ inhibitors could offer an alternative treatment where PARP inhibitors are no longer working. Researchers believe that using a POLQ inhibitor in combination with a PARP inhibitor in patients with cancers that have faulty BRCA genes could prevent resistance from emerging in the first place.

Michelle Mitchell, Chief Executive at Cancer Research UK, said: “More than 25 years ago we helped discover the BRCA gene, which spurred on our scientists to work with others to develop PARP inhibitors, which are now benefiting many patients. But we are always trying to find newer and better ways to outstep cancer, especially when it stops responding to current treatments.

“By revisiting weaknesses in the BRCA repair pathway, researchers have not only found a way to make PARP inhibitors more effective, but they may have also identified an entirely new class of targeted drugs for BRCA cancers, which could include pancreatic cancer which has limited treated options. We look forward to seeing if these promising results in the lab transfer into benefits for patients when tested in trials.”

The study was funded by Breast Cancer Now and Cancer Research UK with The Royal Marsden NHS Foundation Trust helping to run clinical trials.

Artios will now run clinical trials investigating POLQ inhibitors, it was stated in a release.

Study Co-Leader, Dr Graeme Smith, Chief Scientific Officer at Artios Pharma, said: “These exciting preclinical results provide a clear rationale for future clinical studies with a POLQ inhibitor. At Artios, we are on track to initiate our POLQ clinical programme before the year end to explore POLQ inhibition in the sensitive cancer types that this study has uncovered. Our planned POLQ inhibitor clinical studies will leverage these results, exploring combination treatment with PARP inhibitors and different types of DNA damaging agents.”

Kat Jenkins

 

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