Advances in creating treatment for common childhood blood cancer

Advances in creating treatment for common childhood blood cancer
Advances in creating treatment for common childhood blood cancer

A new drug in development may offer the first alternative to standard chemotherapy for T-cell acute lymphoblastic leukemia, according to results of new research done with mice and human laboratory cells.

Researchers 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 (ALL).

An estimated one-quarter of the 500 US adolescents and young adults with a diagnosis of this aggressive disease fail to respond to standard chemotherapy drugs that target cancer cells, each year.

The enzyme JMJD3 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, according to this research. This enzyme, known as polycomb repressive complex 2 (PRC2), acts, in turn, as an "off" switch for cancer cell proliferation. The study was published in Nature (2014; doi:10.1038/nature13605).

These researchers previously demonstrated that this destabilizing and cutting loose of PRC2 leads to the activation of the NOTCH1 biological pathway. This is a process common to many cancers but especially active in at least half of all people with T-cell acute lymphoblastic leukemia.

"Our investigations are showing incredible promise in fighting this disease at the transcriptional level," said senior study investigator Iannis Aifantis, PhD, a cancer biologist at New York University Langone Medical Center in New York City. "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 GSKJ4 works in further tests to prevent JMJD3 from destabilizing and evicting PRC2, Aifantis said, it could become a first-of-its-kind alternative to standard chemotherapy. This would be the first 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," added Aifantis.

What the study found is that JMJD3 was highly active in both mice and human leukemia cells at all stages of tumor growth and development. By contrast, the enzyme UTX, whose name stands for ubiquitously transcribed tetratricopeptide repeat X-linked protein, was not overly produced in leukemia, but highly active in noncancerous mouse and human cells. When mice and human leukemia cells were treated with the experimental drug GSKJ4, JMJD3 activity stopped and all cancer cells eventually died, the researchers reported.

The findings suggested that UTX production controls several tumor-suppressing genes.

To further confirm their findings, researchers screened more than 200 blood samples from children and adults with T-cell acute lymphoblastic leukemia, revealing several common mutations in UTX.

"Our report serves as a valuable reminder of just how complex cancers [such as] T-cell acute lymphoblastic leukemia can be, and that enzymes can play many, even opposing, roles in both tumor growth and suppression," says Aifantis.
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