A novel combination has shown promise for treating acute myeloid leukemia (AML) and other cancers, according to preclinical research published in Cancer Cell.
Researchers found that combining a DNMT inhibitor and a PARP inhibitor greatly increases the drugs’ anti-tumor activity, and the combination could be effective in malignancies that are not responsive to PARP inhibitors or DNMT inhibitors alone.
Experiments showed that, when combined, the 2 types of inhibitors cause interactions that significantly disrupt cancer cells’ ability to survive DNA damage.
“Our preclinical data suggest that combining low doses of these inhibitors will enhance the clinical effects of both drugs as a potential treatment for patients with AML,” said study author Feyruz V. Rassool, PhD, of the University of Maryland School of Medicine in Baltimore.
“Moreover, our initial data suggest that subtypes of AML with a poor prognosis are likely to be sensitive to this new therapeutic approach.”
Dr Rassool and her colleagues assessed the activity of a DNMT inhibitor—decitabine or 5-azacytidine—in combination with a PARP inhibitor—veliparib or talazoparib—against AML and breast cancer.
In both AML and breast cancer cells, combination treatment increased cytotoxicity and decreased clonogenicity, compared to treatment with either type of inhibitor alone.
The combination of 5-azacytidine and talazoparib produced “very robust responses” in 2 mouse models of AML (MV411 and MOLM14), according to the researchers.
“[It was] somewhat of a surprise that leukemia cells were this sensitive to the combination treatment,” said study author Stephen B. Baylin, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions in Baltimore.
“And if further research confirms our findings, it looks like it also could be useful for breast cancer and ovarian cancers for which PARP inhibitors have not been useful as yet.”
How the inhibitors work together
Dr Baylin noted that PARP helps repair naturally occurring breaks in strands of DNA, and some cancers rely more frequently on PARP than others.
“[PARP inhibitors] work according to how intensely and durably the PARP enzyme is trapped at certain DNA damage sites,” he explained. “If you can ramp up the duration and intensity of this trapping, you could potentially increase the efficacy of the drug[s].”
“We figured that if we pair 5-azacytidine and a PARP inhibitor like talazoparib, we may be able to increase PARP trapping at DNA damage sites.”
That’s because 5-azacytidine blocks proteins that attach gene-regulating methyl groups to DNA and traps those proteins on DNA. The proteins blocked by 5-azacytidine also interact with PARP enzymes at DNA damage sites.
In fact, the researchers did find that combining 5-azacytidine and talazoparib increased the time that PARP was trapped at sites of DNA damage in cancer cells. The time was extended from 30 minutes to 3-6 hours after treatment.
Next steps
Based on the results of this research, a clinical trial is planned to test whether low doses of decitabine and talazoparib can be safely combined and whether this therapy will be effective in AML patients.
The researchers are especially interested in testing the combination in patients who cannot receive intensive chemotherapy, whose leukemia is resistant to treatment, or who have relapsed after treatment.
“This is really a new paradigm mechanism that is being translated into a clinical trial,” Dr Rassool said. “It’s not just putting 2 drugs together.”
“We have shown in the laboratory that the proteins that these inhibitors target actually interact, so the effects of these inhibitors are enhanced through this interaction. Therein lies the novelty of this new approach.”
