Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies

Journal of Hematology & Oncology

Ruben A Mesa¹  Raoul Tibes¹ 

[1] Mayo Clinic Cancer Center, NCI Designated Comprehensive Cancer Center, 13400 E. Shea Blvd, Scottsdale, AZ 85259, USA

关键词: Janus kinase inhibitors;    Hedgehog pathway inhibitors;    Targeted therapy;    Myelofibrosis;   

Others  :  801810
DOI  :  10.1186/1756-8722-7-18

 received in 2014-01-11, accepted in 2014-02-20,  发布年份 2014

【 摘 要 】

Treatment of myelofibrosis (MF), a BCR-ABL–negative myeloproliferative neoplasm, is challenging. The only current potentially curative option, allogeneic hematopoietic stem cell transplant, is recommended for few patients. The remaining patients are treated with palliative therapies to manage MF-related anemia and splenomegaly. Identification of a mutation in the Janus kinase 2 (JAK2) gene (JAK2 V617F) in more than half of all patients with MF has prompted the discovery and clinical development of inhibitors that target JAK2. Although treatment with JAK2 inhibitors has been shown to improve symptom response and quality of life in patients with MF, these drugs do not alter the underlying disease; therefore, novel therapies are needed. The hedgehog (Hh) signaling pathway has been shown to play a role in normal hematopoiesis and in the tumorigenesis of hematologic malignancies. Moreover, inhibitors of the Hh pathway have been shown to inhibit growth and self-renewal capacity in preclinical models of MF. In a mouse model of MF, combined inhibition of the Hh and JAK pathways reduced JAK2 mutant allele burden, reduced bone marrow fibrosis, and reduced white blood cell and platelet counts. Preliminary clinical data also suggest that inhibition of the Hh pathway, alone or in combination with JAK2 inhibition, may enable disease modification in patients with MF. Future studies, including one combining the Hh pathway inhibitor sonidegib and the JAK2 inhibitor ruxolitinib, are underway in patients with MF and will inform whether this combination approach can lead to true disease modification.

【 授权许可】

   
2014 Tibes and Mesa; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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