Researchers at Cold Spring Harbor Laboratory (CSHL) and 5 other laboratories may have identified a new drug target for the treatment of acute myeloid leukemia (AML).
They pinpointed a protein called Brd4, which contains a distinct region known as bromodomain and is a member of the BET protein family, known for regulating gene expression.
A new drug candidate that inhibits Brd4 was able to suppress AML in experimental models.
“The drug candidate not only displays remarkable anti-leukemia activity in aggressive disease models and against cells derived from patients with diverse, genetic subtypes of AML, but is also minimally toxic to non-cancerous cells,” said Chris Vakoc, MD, PhD, leader of the study at CSHL.
“The drug is currently being developed for therapeutic use for cancer patients by Tensha Therapeutics and is expected to enter clinical trials within 2 years.”
The team used RNAi screening in an AML murine model. The RNAi screen introduced small hairpin-shaped pieces of RNA (shRNA) that encode epigenetic proteins into mice that harbor leukemia-causing mutations.
The mice in this study carried the oncogene Nras and rearranged forms of the MLL gene, both of which are mutations often found in patients whose leukemia is resistant to standard chemotherapy.
The drinking water for the mice was also supplemented with doxycyline.
“Inducing shRNA that shuts down a gene required for the survival of leukemic cells can lead to complete disease remission,” said Johannes Zuber, MD, former postdoctoral researcher at CSHL. “This ability to use shRNA to simulate the effect of an anti-cancer drug illustrates the power of this approach.”
The team also identified another potential target in AML called Myb. The team found that suppressing the activity of Myb also eliminated AML in mice. The team screened more than 1000 shRNAs targeting 243 known epigenetic regulators of chromatin.
They homed in on Brd4 as a target and found that suppressing the protein led to the most dramatic changes in AML. The cell cycle was arrested, the leukemic cells died, leukemia progression was delayed, and the mice survived longer.
Previously, James Bradner, MD, at Dana-Farber Cancer Institute in Boston, and his research team had developed a small molecule inhibitor of Brd4 called JQ1. The two groups collaborated, reproducing the antileukemic effects in the Brd4 shRNA experiments. They consider JQ1 to be an ideal drug candidate.
Their findings were published online in Nature.