October 12, 2011 — The experimental drug I-BET151 (GlaxoSmithKline) could potentially treat a highly resistant type of cancer known as mixed-lineage leukemia (MLL), according to a study published online October 2 in Nature.
In contrast to therapies that target cell-surface proteins or directly attack DNA, the small molecule inhibitor serves to accelerate cellular death and prevent the propagation of leukemia genes.
MLL, once thought to be a subset of acute lymphoblastic leukemia, is the most common type of leukemia in children younger than 2 years and accounts for 10% of adult cases. The disease is associated with recurrent chromosomal translocations involving 11q23, which give rise to the formation of genetic MLL fusion proteins.
"MLL leukemia is very hard to treat, and often the only option for patients who have become resistant to standard treatments is a bone marrow transplant," noted Brian Huntly, MD, study coleader, in a news release from Cancer Research UK. "We hope these findings may, in the future, mean that fewer children need this procedure."
Dr. Huntly is a senior clinical fellow at the Cambridge Institute for Medical Research at the University of Cambridge, United Kingdom.
In the study, researchers found that MLL fusions, as part of the super elongation complex (SEC) and the polymerase-associated factor complex (PAFc), are linked to the BET family of acetyl-lysine, recognizing chromatin-adaptor proteins.
"Our work shows that this type of leukemia is reliant on MLL being able to bind to chromatin via BET proteins, Tony Kouzarides, PhD, study coauthor, said in the news release. "This "epigenetic" approach to therapy — which targets chromatin rather than DNA — is an exciting new avenue for drug discovery that we hope will be useful for other types of cancer, in addition to MLL leukemias."
Epigenetic dysregulation of these chromatin "tags" using the BET inhibitor I-BET151 to prevent histone binding was evaluated in human and murine leukemic cell lines. Results showed that the drug significantly improved survival through the potent induction of apoptosis and downregulation of DNA transcription.
After 40 days, more than 60% of mice given I-BED151 were still alive, an effect that was also observed in animals with a more established, aggressive form of the disease.
The study was funded by GlaxoSmithKline, Cancer Research UK, and Cellzome AG.
Nature. Published online October 2, 2011. Abstract
In contrast to therapies that target cell-surface proteins or directly attack DNA, the small molecule inhibitor serves to accelerate cellular death and prevent the propagation of leukemia genes.
MLL, once thought to be a subset of acute lymphoblastic leukemia, is the most common type of leukemia in children younger than 2 years and accounts for 10% of adult cases. The disease is associated with recurrent chromosomal translocations involving 11q23, which give rise to the formation of genetic MLL fusion proteins.
"MLL leukemia is very hard to treat, and often the only option for patients who have become resistant to standard treatments is a bone marrow transplant," noted Brian Huntly, MD, study coleader, in a news release from Cancer Research UK. "We hope these findings may, in the future, mean that fewer children need this procedure."
Dr. Huntly is a senior clinical fellow at the Cambridge Institute for Medical Research at the University of Cambridge, United Kingdom.
In the study, researchers found that MLL fusions, as part of the super elongation complex (SEC) and the polymerase-associated factor complex (PAFc), are linked to the BET family of acetyl-lysine, recognizing chromatin-adaptor proteins.
"Our work shows that this type of leukemia is reliant on MLL being able to bind to chromatin via BET proteins, Tony Kouzarides, PhD, study coauthor, said in the news release. "This "epigenetic" approach to therapy — which targets chromatin rather than DNA — is an exciting new avenue for drug discovery that we hope will be useful for other types of cancer, in addition to MLL leukemias."
Epigenetic dysregulation of these chromatin "tags" using the BET inhibitor I-BET151 to prevent histone binding was evaluated in human and murine leukemic cell lines. Results showed that the drug significantly improved survival through the potent induction of apoptosis and downregulation of DNA transcription.
After 40 days, more than 60% of mice given I-BED151 were still alive, an effect that was also observed in animals with a more established, aggressive form of the disease.
The study was funded by GlaxoSmithKline, Cancer Research UK, and Cellzome AG.
Nature. Published online October 2, 2011. Abstract
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