myeloid leukemia (AML) is a blood cancer characterized by the rapid growth of abnormal white
blood cells. It is typically treated with chemotherapy, in some cases
followed by a stem cell transplant. DNA methyltransferase (DNMT) inhibitors are frequently used
to treat patients unlikely to respond to chemotherapy or who have not
responded to chemotherapy.
Researchers have discovered a novel mechanism in a combination drug
therapy that shows potential as a new approach for treating acute
myeloid leukemia and many other cancers. When combined, these
agents cause interactions that significantly disrupt cancer cells'
ability to survive DNA damage, according to a preclinical study
published today in the journal Cancer Cell
‘A novel mechanism in a combination drug therapy that shows potential as a new approach for treating acute myeloid leukemia has been discovered by scientists.’
The study looked at a combination of two drugs, both of which
significantly reduce some cancer cells' ability to survive and
propagate. One was a DNMT inhibitor, while the
other was a poly-ADP-ribose polymerase (PARP) inhibitor, talazoparib.
PARP inhibitors target and block proteins which cancer cells depend on
to repair DNA for their survival. DMNT inhibitors, such as 5-azacytidine
and decitabine, boost the interactions of PARP inhibitors to block
these proteins even further, causing cancer cell death, the researchers
"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," says the senior author,
Feyruz V. Rassool, associate professor of radiation oncology at the
University of Maryland School of Medicine (UM SOM) and a researcher at
the University of Maryland Marlene and Stewart Greenebaum Comprehensive
Cancer Center (UMGCCC).
"Moreover, our initial data suggest that subtypes of AML with a poor
prognosis are likely to be sensitive to this new therapeutic approach,"
she says, adding that less than 10% of patients with certain
forms of AML achieve long-term survival.
Dr. Rassool says that a clinical trial is planned to test whether
low doses of a DNMT inhibitor, decitabine, and an investigational PARP
inhibitor, talazoparib, can be safely combined and whether this therapy
shows efficacy for AML patients, especially those who cannot receive
intensive chemotherapy, whose leukemia is resistant to treatment, or who
have experienced a relapse after treatment. The trial, which will be
led by Maria R. Baer, professor of medicine at UM SOM and director
of hematologic malignancies at UMGCCC, will enroll patients at the
Greenebaum Comprehensive Cancer Center and several other sites.
"This is really a new paradigm mechanism that is being translated
into a clinical trial," Dr. Rassool says. "It's not just putting two
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."
The research, conducted in cell lines and mouse models, explored
enhancing the cancer-killing effects of PARP inhibitors not only in
regard to AML but also triple-negative breast cancer. PARP inhibitors
have shown efficacy for a small group of patients with breast cancer
with inherited mutations in BRCA genes, but have failed in the more
aggressive triple-negative disease. "Our findings suggest that this new
drug combination would also help patients with this type of aggressive
breast cancer as well as other cancers, such as lung, prostate and
ovarian cancers," Dr. Rassool says.
Dr. Rassool and colleagues at UMGCCC and UMSOM collaborated with
scientists at the Sidney Kimmel Comprehensive Cancer Center at Johns
Hopkins and the National Institute on Aging. Stephen B. Baylin, MD, the
Virginia and DK Ludwig Professor of Oncology and Medicine and associate
director for research programs at the Johns Hopkins Kimmel Cancer
Center, is the study's co-senior author.
The research, which builds on previous work by Dr. Rassool and Dr.
Baylin, was funded by a number of grants, including Stand Up To Cancer's
inaugural Laura Ziskin Prize in Translational Research - a $250,000
grant awarded to the two researchers in 2012. Ziskin, a Hollywood film
producer who died of metastatic breast cancer, was a co-founder of Stand
Up To Cancer, an initiative founded in 2008 by nine women in the
entertainment industry to accelerate groundbreaking research and bring
new treatments to patients as quickly as possible.
PARP inhibitors are used primarily to treat tumors linked to defects
in BRCA genes, but may show promise in other cancers when combined with
other drugs. Certain kinds of cancer cells depend heavily on PARP to
repair DNA damage. If PARP is blocked, these cells die. PARP inhibitors
also cause PARP to become trapped in the cancer cells' DNA, a process
that is greatly enhanced when a DMNT inhibitor is added, Dr. Rassool
says. This leads to massive DNA damage that cannot be repaired, and the
cancer cells self-destruct.
DNMT inhibitors suppress DNA methylation, resulting in gene
expression that significantly interferes with cancer cell growth. They
are not usually combined with PARP inhibitors.
"Dr. Rassool and her colleagues have identified an exciting new
mechanism for attacking cancer that may ultimately provide a new option
for treating patients with leukemia and other cancers," says E. Albert
Reece, vice president for medical affairs at the
University of Maryland and the John Z. and Akiko K. Bowers Distinguished
Professor and dean of UMSOM. "We are committed to translational
research, and this is excellent example of how we are able to move an
important scientific discovery in the laboratory into the clinic where
it may potentially benefit patients."