JAK2 Inhibitors: Not the Next Imatinib But Researchers See Other Possibilities

Abstract

The hope that imatinib (Gleevec) would usher in a new age of targeted cancer cures has faded. Eight years after the U.S. Food and Drug Administration approved the drug for treating chronic myeloid leukemia (CML), no other agent targeted against a single cancer-causing defect has approached the success of imatinib, which substantially extended median survival in CML. It is still what all targeted therapies are measured against. Four years ago, myeloproliferative disorders (MPDs), a class of diseases similar to CML, seemed ripe for a similar breakthrough. MPDs involve an excess number of red blood cells or myeloid cells (nonlymphocyte white blood cells) that differentiate and function normally. The three major MPDs — polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF) — lack the abnormally short Philadelphia chromosome that distinguishes CML. Together, they’re more common than CML and affect at least 100,000 people in the U.S. The cause of the MPDs remained a mystery until 2005, when four research groups separately reported a point mutation in the gene for Janus kinase 2 (JAK2) in most MPD patients. The mutation activates the JAK2 protein, which normally transmits proliferation and survival signals to blood cells from cell surface receptors. It leads to sustained signaling, similar to the effect of the bcr – abl fusion protein, a product of the Philadelphia chromosome in CML. Kinases such as JAK2 are straightforward drug targets, and many researchers expected a JAK2 inhibitor to be as effective in MPDs as imatinib is in CML. That expectation has been frustrated. In early trials, JAK2 inhibitors have reduced myelofi brosis symptoms, often substantially, but so far don’t appear to reverse the disease. And the genetics of the MPDs are proving more complex than those of CML. Finding a new imatinib may not have been a realistic goal to begin with. But researchers say that the MPDs are already yielding insights that may prove more fruitful for knowledge of cancer in general, and the ability to treat it, than CML ever could.