New drug classes may be able to treat a variety of cancers with defective BRCA genes

Scientists have identified a new class of targeted cancer treatments that offer the potential to treat patients whose tumors have an incomplete copy of the BRCA oncogene.

Drugs known as POLQ inhibitors especially kill cancer cell There is a mutation in the BRCA gene while leaving Healthy cells Intact.

And decisively, they can kill cancer cells that have become resistant to PARP inhibitors — existing treatments for patients with BRCA mutations.

Researchers are already planning to test new drug classes in future clinical trials. If successful, POLQ inhibitors may enter the clinic as a new approach to treating a variety of cancers with BRCA mutations, including breast, ovarian, pancreatic, and breast cancer. Prostate cancer..

Scientists and pharmaceutical company Artios at the Cancer Institute in London have investigated the possibility of using POLQ inhibitors to treat cancer cells that are defective in the BRCA gene.

Their research is today Nature CommunicationsWas funded by Artios, Cancer Research UK, and Breast Cancer Now.

Scientists knew that genetic removal of a protein known as POLQ would kill cells with a BRCA gene deficiency, but no drug had been identified to prevent the action of POLQ.

In this new study, researchers identified a prototype drug that not only stopped the function of POLQ, but also killed cancer cells with BRCA mutations.

Both the BRCA gene and POLQ are involved in DNA repair. Cancer cells can survive without one or the other, but if both are blocked or the gene is turned off, the cancer cells will not be able to repair their DNA and will die.

Researchers found that when cells were treated with POLQ inhibitors, cancer cells with BRCA mutations were deprived of their ability to repair DNA and died, but normal cells did not. By killing cancer cells with BRCA mutations while leaving normal cells intact, POLQ inhibitors can provide 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 PARP inhibitors were effective when used at low doses.And in Laboratory test In rats and organoids (laboratory-grown three-dimensional minitumors), POLQ inhibitors shrink BRCA mutant cancers that have stopped responding to PARP inhibitors due to a series of genetic defects known as “Shieldins.” I was able to.

This suggests that POLQ inhibitors can provide alternative treatments when PARP inhibitors fail. Researchers believe that the use of POLQ inhibitors in combination with PARP inhibitors in cancer patients with defective BRCA genes can prevent the development 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 a way to genetically target PARP inhibitors for BRCA mutant cancers, along with colleagues at the Royal Marsden NHS Foundation Trust. We supported the implementation of the test. To be the first PARP inhibitor approved for use.

The next step is to test POLQ inhibitors in Artios-led clinical trials.

Research co-leader Professor Chris Lord, Professor Cancer Genomics at the Cancer Institute in London, and ICR’s current Deputy Director of the Toby Robins Research Center for Breast Cancer said:

“All cells need to be able to repair DNA damage to stay healthy, otherwise mutations will build up and eventually kill the cells. Remove the ability to repair DNA from cancer. We have identified a new class of precision medicine. This new type of treatment may be effective against cancers that already have a weakness in their ability to repair DNA through defects in the BRCA gene, and what is exciting. In addition, the new drug seems to work against cancer as well. cell It may stop responding to existing treatments called PARP inhibitors and open up new ways to overcome drug resistance. I would like to see how they work in clinical trials. “

Professor Paul Workman, Chief Executive Officer of the Cancer Institute in London, said: Most exciting is the possibility of combining POLQ and PARP inhibitors to prevent BRCA-mutated cancers from evolving into more aggressive and drug-resistant forms. This is a major challenge seen in clinics. .. “

Dr. Graeme Smith of Study Co-Leader, Chief Scientific Officer of Artios Pharma in Cambridge, said: A end-of-year clinical program to investigate POLQ inhibition in sensitive cancer types revealed in this study. Planned POLQ inhibitor clinical studies will leverage these results to explore combination treatments with PARP inhibitors and various types of DNA damage agents. Michelle Mitchell, Chief Executive Officer of Cancer Research UK, said: To find newer and better ways to overtake cancer, especially if it becomes unresponsive to current treatments. By reviewing the weaknesses of the BRCA repair pathway, researchers have not only found ways to make PARP inhibitors more effective, but may have identified them completely. A new class of targeted drugs for BRCA cancer, including pancreatic cancer with limited treatment options. We look forward to seeing if these promising results will benefit patients when tested in the trial. “

Dr. Simon Vincent, Director of Breast Cancer Research, Support and Impact, said: “Men and women with a change in one of the BRCA genes are at increased risk of being diagnosed with breast cancer, about 5% of 55,000 people. Breast cancer cases diagnosed annually in the UK are inherited with the BRCA1 and BRCA2 genes. It is caused by a sexually altered gene.

“Therefore, it is very exciting that POLQ inhibitors can provide targeted treatment options for people whose cancer is caused by changes in BRCA. gene.. As a targeted treatment, we hope that POLQ inhibitors will be a kinder alternative with fewer side effects than current treatment options.

“Drug resistance is a major hurdle we must address to prevent women from dying in the breast. cancerTherefore, it is also exciting to offer the hope that POLQ inhibitors will overcome resistance in some cases.

“In future research, POLQ inhibitors breast cancer In these ways. ”

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