Poly(ADP-ribose) polymerase inhibitors (PARPis) are an exciting class of cancer drugs currently used in the clinic. To date, however, patients with acute myeloid leukemia--a cancer with a notoriously poor outcome after diagnosis--have failed to respond to them. Scientists have recently shown that combining PARPis with an epigenetic modifier significantly reduces cancer growth and survival of leukemia cells.
Senior author Feyruz Rassool and her colleagues at the University of Maryland published their results in the journal Cancer Cell.
PARP1 is a protein that repairs single-strand breaks of DNA, and so a therapeutic strategy to target cancer cells is to inhibit this protein, leading to DNA damage and cell death. It fails to show any benefit in AML patients, however, and effective AML drug development therefore remains an unmet need.
Using both a cell line and a mouse model, Rassool and her group combined an investigational PARPis drug (called talazoparib) with a DNA methyltransferase inhibitor (DNMTi) and found a significant reduction in the growth and survival of these cancer cells. The addition of DNMTi is thought to boost the interaction of PARPis to further block DNA repair, leading to greater cell death in the AML cancers.
The research group believes the effect of combining the two drugs isn’t simply additive but rather synergistic, meaning there’s a direct interaction between the drugs, improving the response to both.
"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 Rassool in a statement.
She believes that despite a measly 10% long-term survival rate of patients with AML, this therapeutic approach may be the solution. It’s also thought that this combination may help other patients, such as those with lung, prostate and ovarian cancers.