Scientists have identified a new class of targeted cancer drugs that offer the potential to treat patients whose tumors have defective copies of the BRCA cancer genes.
The drugs, known as POLQ inhibitors, specifically kill cancer cells with mutations in BRCA genes while leaving healthy cells unharmed.
Most importantly, they can kill cancer cells that have become resistant to PARP inhibitors – an existing treatment for patients with BRCA mutations.
Researchers are already planning to test the new class of drugs in future clinical trials. If the trials are successful, POLQ inhibitors could enter the clinic as a new approach to treat a range of cancers with BRCA mutations, such as breast, ovarian, pancreatic and prostate cancer.
Scientists at the Institute of Cancer Research in London and the pharmaceutical company Artios explored the potential of using POLQ inhibitors in the treatment of cancer cells with defects in the BRCA genes.
Their study, published today (Thursday) in Nature Communication, was funded by Artios, Cancer Research UK and Breast Cancer Now.
For some time now, scientists have known that the genetic elimination of a protein known as POLQ kills cells with defects in the BRCA gene, although the drugs that prevent POLQ from working have not been identified. .
In this new work, researchers have identified prototypes of drugs that not only stop POLQ from working, but also kill cancer cells with mutations in the BRCA gene.
The BRCA and POLQ genes are both involved in DNA repair. Cancer cells can survive without either of them, but if both are blocked or their genes turned off, cancer cells can no longer repair their DNA and they die.
The researchers found that when cells were treated with POLQ inhibitors, cancer cells with mutations in the BRCA gene were deprived of their ability to repair their DNA and died, but normal cells were not. By killing cancer cells with mutations in the BRCA gene, while leaving normal cells unharmed, POLQ inhibitors could offer cancer treatment with relatively few side effects.
Researchers have also found that POLQ inhibitors work very well when used in combination with PARP inhibitors.
The addition of POLQ inhibitors meant that the PARP inhibitors were effective when used at a lower dose. And in lab tests on rats and organoids – three-dimensional mini-tumors grown in the lab – POLQ inhibitors were able to reduce BRCA mutant cancers that had stopped responding to PARP inhibitors due to a defect in one. set of genes known as ‘Shieldins’.
This suggests that POLQ inhibitors may offer an alternative treatment where PARP inhibitors no longer work. Researchers believe that using a POLQ inhibitor in combination with a PARP inhibitor in cancer patients who have defective BRCA genes could prevent the emergence of resistance in the first place.
Scientists at the Institute of Cancer Research (ICR), funded by Breast Cancer Now and Cancer Research UK, have discovered how to genetically target PARP inhibitors against BRCA mutant cancers and, with colleagues at the Royal Marsden NHS Foundation Trust, have helped conduct clinical trials leading to the first PARP inhibitor approved for use.
The next step will now be to test the POLQ inhibitors in clinical trials conducted by Artios.
Study co-lead Professor Chris Lord, professor of cancer genomics at the Institute of Cancer Research in London and deputy director of the Breast Cancer Now Toby Robins Research Center at ICR, said:
“All cells need to be able to repair DNA damage to stay healthy – otherwise mutations build up and eventually kill them. We have identified a new class of precision medicine that robs cancers of their ability. to repair their DNA. This new type of treatment has the potential to be effective against cancers that already have weaknesses in their ability to repair their DNA, through defects in their BRCA genes. And exciting, the new drugs also appear work against cancer cells that have stopped responding to an existing treatment called PARP inhibitors – potentially opening up a new avenue for overcoming drug resistance. I can’t wait to see how they perform in clinical trials. “
Professor Paul Workman, Managing Director of the Institute of Cancer Research in London, said:
âIt is exciting that the new POLQ inhibitors provide a different approach to treating cancers with BRCA gene defects – and in particular that this class of drugs retains their activity in cancers that have developed resistance to PARP inhibitors. Most exciting of all is the potential to combine drugs that inhibit POLQ and PARP to prevent the progression of BRCA mutant cancers to more aggressive, drug-resistant forms – a major challenge we see in the clinic. “
Study co-lead Dr Graeme Smith, Scientific Director of Artios Pharma, Cambridge, said:
âThese exciting preclinical results provide a clear rationale for future clinical studies with a POLQ inhibitor. At Artios, we’re on track to launch our POLQ clinical program before the end of the year to explore the inhibition of POLQ in the susceptible cancer types that this study uncovered. Our planned clinical studies of POLQ inhibitors will build on these findings, exploring combination therapy with PARP inhibitors and different types of DNA damaging agents. “
Over 25 years ago, we helped discover the BRCA gene, which prompted our scientists to work with others to develop PARP inhibitors, which are now benefiting many patients. But we’re always trying to find new and better ways to get past cancer, especially when it stops responding to current treatments. By revisiting the weaknesses of the BRCA repair pathway, the researchers not only found a way to make PARP inhibitors more effective, but they also may have identified a whole new class of drugs targeted for BRCA cancers, which could include pancreatic cancer which has limited treatment options. . We look forward to seeing if these promising lab results translate into benefits for patients when tested in trials. “
Michelle Mitchell, Managing Director of Cancer Research UK
Dr Simon Vincent, Director of Research, Support and Influence at Breast Cancer Now, said:
âMen and women with a change in one of their BRCA genes are at higher risk of being diagnosed with breast cancer, and around 5% of the 55,000 cases of breast cancer diagnosed in the UK each year are caused by an inherited altered gene, which includes BRCA1 and BRCA2 genes.
âIt is therefore extremely exciting that POLQ inhibitors may provide a targeted treatment option for people whose cancer is caused by altered BRCA genes. As a targeted treatment, we hope that POLQ inhibitors could be a milder alternative, with fewer side effects than current treatment options.
âDrug resistance is a major hurdle we must overcome to prevent women from dying from breast cancer, so it is also exciting that POLQ inhibitors offer hope for overcoming resistance in some cases.
“We hope that future research will confirm that POLQ inhibitors can benefit people with breast cancer in these ways.”