HSP90 Inhibitor Useful Against Some Types of Blood Cancers

A novel treatment for the myeloproliferative neoplasms (MPN) family of blood cancers is based on inhibition of the heat shock protein, HSP90, which acts as a chaperone for the oncogenic protein JAK2 (Janus kinase 2).

Mutations in the JAK2 gene have been implicated in polycythemia vera, essential thrombocythemia, and other myeloproliferative disorders. This mutation, a change of valine to phenylalanine at the 617 position, appears to render hematopoietic cells more sensitive to growth factors such as erythropoietin and thrombopoietin. On the other hand, loss of Jak2 is lethal by embryonic day 12 in mice.

The role of JAK2 in triggering MPN has elicited drug developers to search for drugs to block its activity. So far, however, clinical trials of candidate drugs have shown limited efficacy and apparent toxicities.

In a new report published in the September 13, 2010, edition of the Journal of Clinical Investigation, investigators at the Memorial Sloane Kettering Cancer Center (New York, NY, USA) described an indirect approach to reducing JAK2 activity by pharmacologically targeting HSP90, a protein that stabilizes JAK2. They used the experimental drug PU-H71 to treat MPN polycythemia vera (PV) cells growing in culture and in a mouse model.

Inhibition of HSP90 by PU-H71 treatment caused potent, dose-dependent inhibition of cell growth and signaling in JAK2 mutant cell lines and in primary MPN patient samples. PU-H71 treatment of mice resulted in JAK2 degradation, inhibition of JAK-STAT signaling, normalization of peripheral blood counts, and improved survival in MPN models at doses that did not degrade JAK2 in normal tissues or cause substantial toxicity.

The investigators concluded that, "Our data demonstrate that HSP90 inhibition represents an alternative approach to JAK2 inhibition of potential benefit for the treatment of patients with JAK2-dependent malignancies. Targeting HSP90, perhaps in combination with JAK2 inhibition, may be the way forward in the treatment of patients with MPN.”

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Memorial Sloane Kettering Cancer Center