Drug Development

Drug Development Offers Potential in Treating Childhood Blood Cancer

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Specifically, they focused on a protein controlled and methylated by PRC2 called histone 3 lysine 27 (H3K27) as well as two other enzymes closely tied to H3K27 -- JMJD3, and UTX, the latter short for ubiquitously transcribed tetratricopeptide repeat X-linked protein.

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, UTX 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 report.

Subsequent genetic experiments showed that in leukemic mice bred so they are unable to make JMJD3, NOTCH1 activity declined, while UTX activity remained the same. The disease also progressed much faster, they found, in mice bred without UTX, while mice lived longer if they produced UTX. The findings suggest that UTX production controls several tumor-suppressing genes.

Discovery of Mutations Spawned Drug Development

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. Plans are underway, Aifantis says, to test GSKJ4 against human leukemia cells transplanted into mice. Other experiments will use the drug molecule in combination with standard chemotherapy in animals with leukemia.

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