Outwitting Chronic Myeloid Leukemia

Chronic myeloid leukemia may wither when STAT5 inhibited

/ Author:  / Reviewed by: Joseph V. Madia, MD

(RxWiki News) About 20 percent of all leukemias in the Western world are chronic myeloid leukemia (CML). Today's treatments target an abnormal chromosome that causes the disease, but new theories about how to outwit this resilient disease are sprouting.

Austrian researchers are questioning the value of theories about ways to fight CML that has become resistant to the gold standard therapy, Gleevec (imatinib). They have their own theories for new therapeutic solutions.

"Ask your oncologist to explain how you'll know if a drug stops working."

CML is caused by a mutation in what's been dubbed the "Philadelphia chromosome," named after the place in which it was discovered by two scientists in 1960. This chromosome results from the faulty fusion of two genes - Bcr from chromosome 22, and Abl on chromosome 9. The fusion protein - BCR-ABL - is known as a tyrosine kinase.

Today's medications, called tyrosine kinase inhibitors, target this protein. Most patients taking these medications, including Gleevec (imatinib), respond well and disease is halted -  at least initially.

However, the disease isn't cured. About one third of the time, patients can become unresponsive to Gleevec and have to switch to another tyrosine inhibitor, such as Sprycel (dasatinib) or Tasigna (nilotinib).

To overcome these difficulties, scientists are working on an approach that would target another protein - the so-called JAK2 kinase. However researchers, Veronika Sexl at the University of Veterinary Medicine, and Giulio Superti-Furga at the Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), are questioning this strategy.

JAK2 activates STAT5, another molecule that's needed for CML to develop. Several drugs currently in clinical trials are targeting JAK2 as means of keeping STAT5 from ever becoming activated.

Sexl and her colleagues performed animal studies and were surprised to learn the JAK2 is actually not needed to maintain CML, and blocking it, they say, provided no therapeutic value.

When they targeted and blocked STAT5, however, the leukemia cells stopped multiplying

Sexl says that "at the moment there is simply no rationale for giving leukaemic patients JAK2 inhibitors. If we want to help patients who do not respond to imatinib, we should concentrate instead on developing inhibitors to STAT5," she said.

Houston, Texas oncologist, Atisha Manhas, M.D., told dailyRx, "Imatinib and other medications in its class (tyrosine kinase inhibitors) revolutionized the treatment of CML. However, a small number of patients do not seem to benefit from these agents," she explained.

"Although the current study shows that JAK inhibition is unlikely to be of therapeutic benefit, this research paves the way for new medications directed towards alternate therapeutic targets," Dr. Manhas said.

The study was published online January 29, 2011 in the journal Nature Chemical Biology.

This work was supported by grants WWTF-LS037 and SFB-28-10 to Veronika Sexl and GenAU-PLACEBO to Giulio Superti-Furga and Veronika Sexl.

Reviewed by: 
Last Updated:
November 8, 2012