New cancer drug breakthrough targets

According to a new study, a new type of drug could treat a range of cancers caused by the Angelina Jolie gene.

British researchers have identified a new class of targeted cancer drugs that have the potential to treat patients whose tumors have faulty copies of the BRCA cancer genes.

The drugs known as POLQ inhibitors specifically kill cancer cells with mutations in the BRCA genes, while healthy cells remain intact.

And 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 active ingredients in upcoming clinical trials.

If the studies are successful, POLQ inhibitors could come to the clinic as a new approach to treating a number of cancers with BRCA mutations, such as breast, ovarian, pancreatic and prostate cancers.

Mutations in the BRCA1 and BRCA2 genes can affect the body’s ability to repair DNA damage in its cells – increasing the risk of cancer by a factor of thirty.

They cause ten to 20 percent of ovarian and six percent of breast cancers.

Hollywood actress Angelina Jolie had her breasts, ovaries and fallopian tubes removed because of her high risk of cancer. Many, like her, have surgery. Others are given preventive medication or are checked more regularly.

Scientists from the Institute of Cancer Research, London, and the pharmaceutical company Artios analyzed the potential of using POLQ inhibitors to treat cancer cells with defects in the BRCA genes.

The study, published in the journal Nature Communications, was funded by Artios, Cancer Research UK, and Breast Cancer Now.

Scientists have known for some time that genetic removal of a protein called POLQ killed cells with BRCA gene defects, although no drugs have been identified that would prevent POLQ from working.

Now researchers have identified prototypes of drugs that not only stop the effects of POLQ, but also kill cancer cells with BRCA gene mutations.

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

Scientists found that when cells were treated with POLQ inhibitors, cancer cells with BRCA gene mutations were deprived 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 intact, POLQ inhibitors could offer treatment for cancer with relatively few side effects.

The researchers also found that POLQ inhibitors work very well when used together with PARP inhibitors.

They believe that using a POLQ inhibitor in combination with a PARP inhibitor in cancer patients with defective BRCA genes could prevent the development of resistance in the first place.

ICR scientists discovered how PARP inhibitors can be genetically targeted against BRCA-mutant cancers and, along with colleagues from the Royal Marsden NHS Foundation Trust, helped conduct clinical trials that led to the approval of the first PARP inhibitor.

The next step will now be to test POLQ inhibitors in clinical trials led by Artios.

Study co-leader, Professor Chris Lord of the ICR, said, “All cells must be able to repair damage to their DNA in order to stay healthy – otherwise mutations will 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 defects in their ability to repair their DNA due to defects in their BRCA genes.

“And excitingly, the new drugs also seem to work against cancer cells that no longer respond to an existing treatment called PARP inhibitors – and may open up a new way of overcoming drug resistance. I am very curious to see how you will perform in clinical studies. “.”

Professor Paul Workman, Chief Executive Officer of the ICR, said: “It is exciting that the new POLQ inhibitors offer a different approach to treating cancers with BRCA gene defects – and in particular that this class of drugs should maintain activity in cancers that are resistant to PARP Inhibitors.

“Most excitingly, the potential of combining POLQ and PARP inhibitor drugs to prevent the development of BRCA-mutant cancers into more aggressive, drug-resistant forms – a major challenge we are seeing in the clinic.”

Study co-director Dr. Graeme Smith, Chief Scientific Officer at Artios Pharma, based in Cambridge, said, “These exciting preclinical results provide a clear rationale for future clinical trials with a POLQ inhibitor.

“At Artios, we are well on the way to launching our POLQ clinical program before the end of the year to investigate POLQ inhibition in the susceptible cancers that this study has uncovered.”

Michelle Mitchell, Chief Executive of Cancer Research UK, said, “We helped discover the BRCA gene more than 25 years ago, which led our scientists to work with others to develop PARP inhibitors, many of which are now patients benefit.

“But we are always trying to find new and better ways to overcome cancer, especially when it no longer responds to current treatments.

“By re-examining weaknesses in the BRCA repair pathway, not only have the researchers found a way to make PARP inhibitors more effective, but they may have identified an entirely new class of targeted drugs for BRCA cancer, which could include pancreatic cancer that was only dealt with limited options.

“We are curious to see whether these promising results in the laboratory will be transferred to studies that will benefit patients.”

Dr. Simon Vincent, Director of Research at Breast Cancer Now, said: “Men and women with a change in one of their BRCA genes are at higher risk of developing breast cancer and about five percent of the 55,000 breast cancer cases” diagnosed each year in the UK , are caused by an inherited altered gene that includes the BRCA1 and BRCA2 genes.

“It is therefore very exciting that POLQ inhibitors could represent a targeted treatment option for people whose cancer is caused by altered BRCA genes.

“We hope that as a targeted treatment, POLQ inhibitors could be a cheaper alternative with fewer side effects than current treatment options.”

He added, “Drug resistance is a major hurdle that we must overcome in order to prevent women from dying from breast cancer. It is therefore also exciting that POLQ inhibitors offer hope of overcoming resistance in some cases.

“We hope that future research will confirm that POLQ inhibitors can benefit people with breast cancer in this way.”

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