Blood Cancer Gene Defect Could Be Treated by Existing PARP Inhibitors

Blood Cancer Gene Defect Could Be Treated by Existing PARP Inhibitors
Credit: Dr_Microbe/Getty Images

Researchers at Queen’s University Belfast and the University of Birmingham, U.K. have published research showing that a defective gene found in about 30% of all blood cancers could be treated by already approved PARP inhibitor drugs.

The research, funded in part by Cancer Research UK and the Medical Research Council, fund that a mutation in the SF3B1 gene in blood cancers produces similar effects of the BRCA1 gene via damage to the DNA that prevents it from repairing itself, and preventing it from making normal copies of itself.

“Our findings have clinical implications for the treatment of many cancers,” noted Dr. Kienan Savage, lead author of the study and eader at the Patrick G Johnson Centre for Cancer Research at Queen’s University. “We specifically focused on this genetic mutation as it is found in several difficult to treat leukemias 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.”

The research, published last week in Cancer Research, a journal of the American Association for Cancer Research suggests that PARP inhibitors such as olaparib and rucaparib, which are already used in some instances to treat ovarian, breast, prostate, and pancreatic cancers—most in patients who have inherited mutations in the BRCA1 or BRCA2 genes—could also be used to target cancers with a mutated SF3B1 gene.

The current research into the role of SF3B1 in these cancers and the possibility of it being a potential target for PARP inhibitors was based on two prior research studies about the role of the gene, Savage told Inside Precision Medicine. “Originally, we had identified SF3B1 as part of a DNA damage induced protein complex with BRCA1. This complex promotes the splicing and mRNA stability of key genes required for an efficient DNA damage response, including DNA repair genes,” he said. This research was published in 2014 in Molecular Cell, with Savage as first author. This research hinted at the possibility that SF3B1 had a role in promoting genome stability.

A second study, published the following year, led by Jacqueline Boultwood of the University of Oxford and published in the journal Leukemia, provided additional data pointing toward SF3B1 having a role within the cellular DNA damage response pathway, which Kienan and teams set out to test in the newest study.

But the research was not without its hurdles. Chief among them, Kienan said, was the scarcity of cell lines harboring SF3B1 mutations, which were necessary to assess the effect of cancer-associated SF3B1 mutations on the DNA repair pathway, and how these might be targeted therapeutically. To solve this the researchers “set out to develop an isogenic model system (a genetically identical cell line pair; one with wild-type SF3B1 and one with mutant SF3B1), which could be used to specifically test the impact of the cancer associated SF3B1 mutation K700E,” Kienan said. The team used CRISPR/Cas9 gene editing to add the knock-in mutation, but found that few of the available cell lines were able to tolerate this, and it became a rather “painstaking” process.

Once the team had successfully developed the isogenic cell line model, it set out to test the role of SF3B1 in DNA repair. Once it found a defect in DNA repair, the team confirmed it was due to defective homologous recombination, the same defect observed in BRCA1/2 mutant cancers.

“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,” said first author Dr. Katrina Lappin of Queen’s University. “This could have huge implications for improving outcomes and quality of life of people with these cancers.”

Kienan said the team is now in the process of seeking funding and research partners in the U.K. for PARP inhibitor trials in SF3B1 mutant myelodysplastic syndrome, acute myeloid leukemia, and uveal melanoma.