A blood cancer gene defect could be treated with drugs already available for cancers with similar defective genes, scientists at Queen’s University Belfast and the University of Birmingham have revealed.
Blood cancer is a type of cancer that affects your blood cells. There are over 250,000 people currently living with this disease and over 40,000 people are being diagnosed every year in the UK alone. Blood cancers are caused by mutations in DNA within the blood cells, causing the cells to behave abnormally.
The research team, funded mainly by Cancer Research UK and the Medical Research Council, found that tumours with mutations in the SF3B1 gene respond to PARP inhibitors, a type of drug used to treat cancers that have similar mutations in the BRCA1 and BRCA2 genes.
The research, published in Cancer Research, a journal of the American Association for Cancer Research, found that the SF3B1 mutation produces similar effects to the faulty BRCA1 gene by damaging DNA, preventing it from being repaired properly, and stopping it from making normal copies of itself. PARP inhibitors target the cell’s DNA repair tools by locking them in place on the DNA. This stops DNA repair, causing the cancer cells to die.
Defective blood cancer genes
The researchers believe that PARP inhibitors could be used to treat patients with tumours carrying the defective SF3B1 gene. This mutation is most often found in certain types of blood cancer, including chronic lymphocytic leukaemia, as well as some rare cancers like uveal melanoma.
Dr Kienan Savage, the lead author and Reader at the Patrick G Johnson Centre for Cancer Research at Queen’s, said: “Our findings have clinical implications for the treatment of many cancers. We specifically focused on this genetic mutation as it is found in several difficult to treat leukaemias and other cancers, and it affects so many cancer patients. By deepening our understanding of this gene mutation, we have identified new ways of treating these cancers that could improve survival rates.”
Currently, PARP inhibitors including olaparib and rucaparib are used to treat some patients with ovarian, breast, prostate, and pancreatic cancers. Typically, patients have inherited a faulty BRCA1 or BRCA2 gene. Around 1 in 400 people have a faulty BRCA1 or BRCA2 gene.
The scientists uncovered that cancer cells with the SF3B1 mutation were sensitive to olaparib, the most common PARP inhibitor, some specific chemotherapies and radiotherapy. Scientists are led to believe that the SF3B1 mutation disrupts the cell’s ability to make DNA repair proteins, leaving it vulnerable to drugs that target these proteins.
The SF3B1 mutation occurs in up to 30% of blood cancers called myelodysplastic syndromes, where blood cells don’t form properly. They are difficult to treat as they occur predominantly in older patients who may not be considered fit for treatment. The mutation is also common among uveal melanoma or cancers of the eye, which currently has limited treatment options.
PARP inhibitor therapy
Dr Katrina Lappin, from Queen’s and first author of the study, added: “Our research shows that cancers with these specific mutations, may be treated effectively with PARP inhibitor therapy drugs, which are less toxic, better at killing cancer cells with these mutations and can be taken at home in tablet form. This could have huge implications for improving outcomes and quality of life of people with these cancers.”
“This work will pave the way for clinical trials using PARP inhibitors for the treatment of patients with this commonly associated cancer mutation, allowing a more personalised approach to the treatment of these cancers.”
The researchers now want to test PARP inhibitors in clinical trials who have the SF3B1 mutation to see if they can stop their cancer from spreading.
Co-author Professor Grant Stewart, of the University of Birmingham, said: “Our work demonstrates that a molecular understanding of how a specific gene mutation affects a cancer cell’s ability to repair damaged DNA can be exploited clinically to specifically tailor the anti-cancer therapy used to treat an individual’s tumour. This will increase the effectiveness of the therapy and hopefully, reduce the chances of re-occurrence.”
Michelle Mitchell, Chief Executive of Cancer Research UK, said: “Our scientists helped to discover the BRCA gene over 25 years ago and since then we’ve led the way in developing PARP inhibitors to treat cancers with BRCA gene faults.
“It’s really exciting to hear about a new mutation, which behaves like the BRCA1 mutation and could in the future be treated in the same way. With PARP inhibitors already widely available, there is huge potential to help people with some of the rarest and most difficult-to-treat cancers known to us.
“Over the past two decades, PARP inhibitors have saved thousands of lives worldwide, and it will be interesting to see if this research in the future could lead to a similar impact for people with rarer cancers.”
