Cargando…

Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies

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-rel...

Descripción completa

Detalles Bibliográficos
Autores principales: Tibes, Raoul, Mesa, Ruben A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975838/
https://www.ncbi.nlm.nih.gov/pubmed/24598114
http://dx.doi.org/10.1186/1756-8722-7-18
_version_ 1782310194134384640
author Tibes, Raoul
Mesa, Ruben A
author_facet Tibes, Raoul
Mesa, Ruben A
author_sort Tibes, Raoul
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3975838
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-39758382014-04-05 Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies Tibes, Raoul Mesa, Ruben A J Hematol Oncol Review 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. BioMed Central 2014-03-05 /pmc/articles/PMC3975838/ /pubmed/24598114 http://dx.doi.org/10.1186/1756-8722-7-18 Text en Copyright © 2014 Tibes and Mesa; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Review
Tibes, Raoul
Mesa, Ruben A
Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies
title Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies
title_full Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies
title_fullStr Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies
title_full_unstemmed Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies
title_short Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies
title_sort targeting hedgehog signaling in myelofibrosis and other hematologic malignancies
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975838/
https://www.ncbi.nlm.nih.gov/pubmed/24598114
http://dx.doi.org/10.1186/1756-8722-7-18
work_keys_str_mv AT tibesraoul targetinghedgehogsignalinginmyelofibrosisandotherhematologicmalignancies
AT mesarubena targetinghedgehogsignalinginmyelofibrosisandotherhematologicmalignancies