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Novel therapeutic agents provide hope for patients with hard-to-treat blood disorders
Date:12/9/2012

hat had previously shown limited utility for patients with myelofibrosis.

Myelofibrosis is a chronic malignant blood disorder commonly caused by mutations in the JAK2 pathway (which normally signals the body to create blood cells), including most commonly the JAK2 V617F mutation. This mutation leads to the overproduction of scar tissue in the bone marrow and shifts red and white blood cells and platelets from the bone marrow into the spleen and liver, enlarging the organs and leading to anemia, infection, inflammation, and easy bleeding and bruising.

The first approved treatment for myelofibrosis is ruxolitinib, a therapy that targets the JAK2 mutation by blocking the action of all JAK-related genes in the body, including those from both healthy and diseased cells. However, clinical results have been modest to date. In particular, resistance to JAK inhibitors has been associated with an increase in JAK2 levels, which leads to continued JAK2 activity despite ruxolitinib treatment. This resistance can be reversed by inhibiting heat shock protein 90 (HSP 90), which destabilizes JAK2 and reduces JAK2 protein levels. Since cancer cells are continually dividing, they constantly burden the cell system and depend on HSP90 function to allow the JAK2 protein to maintain cancer cells' function and growth.

Recognizing HSPs as a potential target for treatment, researchers have recently explored the possibility of blocking HSP90 to treat blood cancers. Unlike ruxolitinib, which blocks the function of the abnormal JAK2 protein that maintains the function of the cancerous cell, HSP90 inhibitors block the function of HSP90 in the cells. This allows for the breakdown of the JAK2 protein and weakens the cell's ability to grow and divide, allowing it to become sensitive to treatment. PU-H71, a HSP90 inhibitor, previously shown to have efficacy in different cancer cells and animal models including myelofibrosis, is currently undergoing Phase I clinical trials
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Contact: Andrea Slesinski
aslesinski@hematology.org
614-352-5096
American Society of Hematology
Source:Eurekalert

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