TY - JOUR
T1 - Investigational histone deacetylase inhibitors (HDACi) in myeloproliferative neoplasms
AU - Bose, Prithviraj
AU - Verstovsek, Srdan
N1 - Funding Information:
This paper has been supported in part by the MD Anderson Cancer Center Support Grant from the National Cancer Institute (P30CA016672).
Publisher Copyright:
© 2016 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Introduction: The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) mainly comprise polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF, primary or post-PV/ET). Therapy in PV and ET focuses on minimizing thrombosis and bleeding risk, while in MF, prolongation of survival is an important goal. Different cytoreductive agents are employed in high risk PV and ET, while the JAK inhibtior ruxolitinib is the cornerstone of therapy in MF. Histone deacetylase inhibitors (HDACi) are pleiotropic agents with diverse epigenetic and non-epigenetic actions, selectively in transformed cells. A number of HDACi have been or are being investigated in MPN. Areas covered: The mechanisms of action of HDACI in neoplastic cells are summarized, and the preclinical rationale and data supporting their development in MPN specifically examined, particularly their synergism with JAK inhibitors. Major findings of clinical trials of HDACi, both alone and in combination with ruxolitinib, in MPN are then discussed, with particular attention to their toxicities and disease-modifying effects. Expert opinion: HDACi are clearly active in MPN, and there is good preclinical rationale for this. Their combination with ruxolitinib in MF is promising, but the long-term tolerability of these agents is an important concern. Further development in PV or ET appears unlikely.
AB - Introduction: The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) mainly comprise polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF, primary or post-PV/ET). Therapy in PV and ET focuses on minimizing thrombosis and bleeding risk, while in MF, prolongation of survival is an important goal. Different cytoreductive agents are employed in high risk PV and ET, while the JAK inhibtior ruxolitinib is the cornerstone of therapy in MF. Histone deacetylase inhibitors (HDACi) are pleiotropic agents with diverse epigenetic and non-epigenetic actions, selectively in transformed cells. A number of HDACi have been or are being investigated in MPN. Areas covered: The mechanisms of action of HDACI in neoplastic cells are summarized, and the preclinical rationale and data supporting their development in MPN specifically examined, particularly their synergism with JAK inhibitors. Major findings of clinical trials of HDACi, both alone and in combination with ruxolitinib, in MPN are then discussed, with particular attention to their toxicities and disease-modifying effects. Expert opinion: HDACi are clearly active in MPN, and there is good preclinical rationale for this. Their combination with ruxolitinib in MF is promising, but the long-term tolerability of these agents is an important concern. Further development in PV or ET appears unlikely.
KW - Histone deacetylase inhibitors
KW - JAK inhibitors
KW - epigenetic
KW - essential thrombocythemia
KW - myelofibrosis
KW - myeloproliferative neoplasms
KW - polycythemia vera
KW - rational combinations
KW - ruxolitinib
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U2 - 10.1080/13543784.2016.1250882
DO - 10.1080/13543784.2016.1250882
M3 - Review article
C2 - 27756180
AN - SCOPUS:84996598080
SN - 1354-3784
VL - 25
SP - 1393
EP - 1403
JO - Expert Opinion on Investigational Drugs
JF - Expert Opinion on Investigational Drugs
IS - 12
ER -