Drug Development Drug Development Offers Potential in Treating Childhood Blood Cancer
Researchers at NYU Langone Medical Center and elsewhere say that blocking the action of an enzyme “switch” needed to activate tumor growth is emerging as a practical strategy for treating T-cell acute lymphoblastic leukemia.
New York/USA – An estimated quarter of the 500 U.S. adolescents and young adults diagnosed each year with this aggressive disease fail to respond to standard chemotherapy drugs that target cancer cells.
In a report on the work conducted with mice and human laboratory cells, and published in the Oct. 23 edition of the journal Nature, the NYU Langone team concludes that the enzyme JMJD3 -- (pronounced ju-mon-ji D3) -- acts as a cancer “on” switch by splitting off a chemical methyl group of another protein that is usually methylated by a tumor-suppressing enzyme. This enzyme, known as polycomb repressive complex 2 (PRC2), acts, in turn, as an “off” switch for cancer cell proliferation.
It is this destabilizing and cutting loose of PRC2, the same researchers previously showed, that leads to the activation of the NOTCH1 biological pathway – a process common to many cancers but especially active in at least half of all people with T-cell acute lymphoblastic leukemia.
Investigations Show Potential
“Our investigations are showing incredible promise in fighting this disease at the transcriptional level,” says senior study investigator and NYU Langone cancer biologist Iannis Aifantis, PhD. “We are blocking the action of enzymes controlling the transcription of proteins involved in leukemia rather than attempting to directly suppress cancer genes.”
The researchers say that the drug manufacturer, GlaxoSmithKline, is already developing an investigational compound called GSKJ4, whose treatment path follows the biological road map revealed in the new research. If GSKJ4works in further tests to prevent JMJD3 from destabilizing and evicting PRC2, Aifantis says, it could become the first of its kind alternative to standard chemotherapy in decades for treating this form of leukemia.
“Revealing the actions of JMJD3, and successfully blocking the enzyme to stall tumor progression, shows that new treatments for T-cell acute lymphoblastic leukemia are not simply theoretical, but practical,” adds Aifantis, chair of the Department of Pathology at NYU Langone, and an early career scientist at the Howard Hughes Medical Institute.
Several Years of Research in Childhood Blood Cancer
Aifantis says the latest findings are the culmination of several years of research by his team to unravel precisely how PRC2 suppresses tumor growth since they first reported the phenomenon in leukemia (Nature Medicine in 2012.) For the current study, they investigated precisely how demethylation ---removal of a methyl chemical bond -- triggers the chain of events that evicts PRC2 from cells, thereby removing PRC2 suppression of NOTCH1, which directly binds to and activates cancer-causing genes.