Teaching Old Drugs New Tricks

Understanding why RUNX deficiencies result in leukemia has led to new applications for PARP inhibitors.

AsianScientist (Aug. 25, 2014) – A team of scientists has found that a drug originally designed for killing a limited type of cancer cells with DNA repair defects could potentially be used to treat leukemia and other cancers.

The new study published in Cell Reports suggests that treatment with poly (ADP-ribose) polymerase (PARP) inhibitors, together with standard chemotherapy drugs, could be more effective in combating leukemia. In the same study, researchers found that the inactivation of RUNX genes causes DNA repair defects and promotes the development of leukemia and other cancers.

Unlike other cancers which are more commonly seen in the elderly, leukemia is notorious for its high prevalence among young people. Chemotherapy with or without hematopoietic stem cell transplantation remains the current standard of care, resulting in a cure rate of around 50 percent.

The RUNX family genes are among the most frequently inactivated genes in leukemia and other cancers. According to previous studies, RUNX1 is one of the most frequently mutated genes in leukemia and RUNX3 is associated with the development of the disease.

The researchers found that a double deficiency in both RUNX1 and RUNX3 resulted in an inability to produce blood cells and a massive expansion of abnormal hematopoietic cells. Recognizing that these clinical manifestations are symptoms of a rare human congenital disease known as Fanconi anemia, they started investigating RUNX functions in the DNA repair pathway known to be involved in the disease.

Further research showed that RUNX proteins play a critical and central role in the Fanconi anemia pathway by facilitating the recruitment of a protein involved in the repair of DNA damage called FANCD2 to sites of DNA damage. This previously unknown relationship between RUNX and Fanconi anemia prompted the research team to test the possibility that PARP inhibitors, originally designed for killing a limited type of cancer cells with DNA repair defects, could be applied in the treatment of leukemia and cancers with RUNX alterations which were previously not thought to have DNA repair defects.

The researchers demonstrated that the drug was effective in the treatment of leukemia and other cancers in cell culture experiments.

Senior author of the study, Dr. Motomi Osato from the National University of Singapore said, “Common sense is often a veil that keeps us from understanding the truth.”

“PARP inhibitors have been with us for quite some time, but nobody has realized their application for leukaemia. Our study has shed light on the possibility of a more effective treatment using a combined therapy with PARP inhibitors which can potentially be extended to other types of common cancers.”

The team is currently conducting further drug efficacy testing with xenograft models, as a preclinical study.

The article can be found at: Wang et al. (2014) Disruption of Runx1 and Runx3 Leads to Bone Marrow Failure and Leukemia Predisposition due to Transcriptional and DNA Repair Defects.


Source: National University of Singapore; Photo: Umberto Salvagnin/Flickr/CC.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

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