A pair of drugs that may be a one-two punch needed to help combat acute myeloid leukemia (AML), an aggressive blood cancer that kills nearly three-fourths of patients within five years of diagnosis, is the focus of a new multi-center clinical trial that will enroll patients at three sites across the U.S.
The trial pairs an investigational PARP inhibitor, talazoparib, with the DNA methyltransferase (DNMT) inhibitor decitabine, which is already approved for the treatment of myelodysplastic syndrome (MDS), a disease that often precedes AML. Preclinical studies show that combining the drugs may maximize their ability to kill cancer cells.
"Long-term survival with AML is quite poor and, unfortunately, our arsenal for treating it has remained largely unchanged for decades," said Feyruz Rassool, Ph.D., an associate professor of radiation oncology at the University of Maryland School of Medicine, a researcher at the Marlene and Stewart Greenebaum Comprehensive Cancer Center, and a member of the Van Andel Research Institute-Stand Up To Cancer (VARI-SU2C) Epigenetics Dream Team. "Combination therapies, such as talazoparib and decitabine together, allow us to attack cancer from multiple angles at the most basic level for a greater potential effect."
A paper published last fall in Cancer Cell, which describes the laboratory studies that laid the foundation for the trial, discusses how PARP and DMNT inhibitors enhanced each other when used in combination, rather than individually. Now, the new trial seeks to investigate this promising treatment approach for potential delivery into clinics and hospitals for patients who are suffering from AML.
"The trick with PARP is that it has to arrive at the site of the damage, fix it, and then go away. If it gets trapped there, it kills the cell," said Stephen Baylin, M.D., co-leader of the VARI-SU2C Epigenetics Dream Team, along with VARI's Peter Jones, Ph.D., D.Sc., co-head of Cancer Biology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and a Director's Scholar at VARI. "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 inhibitor."
AML begins as abnormal blood cells in the bone marrow and spreads throughout the circulatory system and beyond, if not diagnosed and treated quickly. Almost 20,000 people in the U.S. are diagnosed with AML every 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 Maria Baer, M.D., professor of medicine at the University of Maryland School of Medicine, director of Hematologic Malignancies and co-leader of the Experimental Therapeutics Program at the University of Maryland Greenebaum Comprehensive Cancer Center, who is leading the trial. "We hope that this new treatment regimen will help AML patients for whom effective treatments are not currently available."
The trial is now 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 and University of Southern California in Los Angeles, all affiliated with the VARI-SU2C Epigenetics Dream Team.
The DMNT inhibitor, decitabine, is already FDA-approved to treat MDS and is often used as an off-label chemotherapy for AML. The investigational PARP inhibitor, talazoparib, is being supplied by Medivation, a wholly owned subsidiary of Pfizer, Inc., and is not yet approved by the FDA.
In addition to AML, the combination therapy also has potential to treat other cancers, including 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."
To date, the VARI-SU2C Epigenetics Dream Team has launched four clinical trials in different cancers, including AML, MDS and metastatic colorectal cancer. Following SU2C's revolutionary paradigm, the team unites leading investigators and industry partners from around the world to compete against cancer rather than against each other.