Harnessing DNA Demethylating Agents Could Enhance Cancer Drug Efficacy

Combining PARP inhibitors with DNA Demethylating agents may serve as a treatment for acute myeloid leukemia (AML).

In a current trial, investigators are examining the pairing of the investigational PARP inhibitor talazoparib with DNA methyltransferase (DNMT) inhibitor decitabine—–a drug approved by the FDA to treat myelodysplastic syndrome, a disease that commonly precedes AML.

“Long-term survival with AML is quite poor and, unfortunately, our arsenal for treating it has remained largely unchanged for decades,” said investigator Feyruz Rassool, PhD. “Combination therapies, such as talazoparib and decitabine together, allow us to attach cancer from multiple angles at the most basic level for a greater potential effect.”

Findings from preclinical studies published in Cancer Cell laid the foundation for the trial by demonstrating that the PARP and DMNT inhibitors enhanced each other’s abilities when used in combination, rather than individually.

In the trial, investigators are examining the treatment approach for delivery into clinics and hospitals with AML patients.

“The trick with PARP is that it has to arrive at the site of damage, fix it, and then go away,” said investigator Stephen Baylin, MD. “If it gets trapped there, it kills the cells. The same goes for molecules called DNA methyltransferases, which are important for regulating how genetic instructions are read and acted upon. We found that the DNA methyltransferase actually increases the time that PARP gets trapped at the sites of DNA damage, increasing the effectiveness of the PARP inhibitors.”

AML is an aggressive type of blood cancer that, when advanced, can be difficult to treat. In the United States, nearly 20,000 individuals are diagnosed with AML per year.

“Acute myeloid leukemia is difficult to treat, especially in older patients and in patients who do not respond to initial treatment or who relapse,” said investigator Maria Baer, MD, who is leading the trial. “We hope that this new treatment regimen will help AML patients for whom effective treatments are not currently available.”

Decitabine is an FDA-approved drug for the treatment of MDS and is often used as an off-label chemotherapy for AML. Talazoparib is not yet approved by the FDA.

The trial is underway at the University of Maryland Greenebaum Comprehensive Cancer Center in Baltimore and will soon open at Temple University Fox Chase Cancer Center in Philadelphia, PA, and the University of Southern California in Los Angeles, CA.

The investigators noted that the combination therapy may also have the potential to treat other cancer types, such as those in the breasts and ovaries.

“Our work also shows promise in ovarian cancer and breast cancer—–particularly triple-negative breast cancer, which is notoriously difficult to treat,” Rassool said. “If this first clinical trial is successful, we hope to expand our studies to help more patients.”