PMID- 24290217
OWN - NLM
STAT- MEDLINE
DCOM- 20141002
LR  - 20211203
IS  - 2152-2669 (Electronic)
IS  - 2152-2669 (Linking)
VI  - 13 Suppl 2
DP  - 2013 Sep
TI  - Rationale for targeting the PI3K/Akt/mTOR pathway in myeloproliferative 
      neoplasms.
PG  - S307-9
LID - S2152-2650(13)00253-X [pii]
LID - 10.1016/j.clml.2013.07.011 [doi]
AB  - The chronic myeloproliferative neoplasms (MPNs), are characterized by a Janus 
      Kinase (JAK)-2 V617F point mutation but this molecular abnormality does not 
      explain by itself the pathogenesis of these disorders, or the phenotypic 
      diversity associated with essential thrombocythemia, polycythemia vera (PV), and 
      myelofibrosis. Beyond the JAK/signal transducer and activator of transcription 
      network, a wide number of molecular alterations were described in MPN including 
      the fosfatidilinositolo-3-chinasi (PI3K)/protein kinase B (Akt)/mammalian target 
      of rapamycin (mTOR) pathway constitutive activation. Several pathway inhibitors 
      were developed, including everolimus, up to the latest class of catalytic 
      inhibitors such as BKM120 and BEZ235. In this review, we present some clinical 
      and experimental evidence showing that the PI3K/Akt/mTOR pathway could represent 
      a therapeutic target in MPNs. In in vitro studies, everolimus has been shown to 
      inhibit cell proliferation and clonogenic potential in human and murine JAK2 
      V617F mutated cell lines. Patients with PV and primary myelofibrosis 
      hematopoietic progenitors were significantly more sensitive to everolimus 
      compared with healthy control subjects. Of much interest, a combination of 
      everolimus and the JAK1/2 inhibitor, ruxolitinib, showed strong synergism in 
      inducing cell cycle arrest and blockade of cell proliferation. Similar data were 
      obtained using a dual PI3K/mTOR inhibitor, BEZ235, with activity that was also 
      shown in preclinical murine models. A multicenter phase I/II trial with 
      everolimus in myelofibrosis documented a well tolerated clinical efficiency in 
      terms of spleen size reduction and resolution of systemic symptoms and pruritus. 
      These observations indicate that the PI3K/Akt/mTOR pathway might represent a 
      novel target for treatment in MPN. The synergism demonstrated in vitro with JAK2 
      inhibitors could open additional therapeutic possibilities based on concurrent 
      targeting of different pathways that might optimize efficacy and reduce toxicity 
      in patients.
CI  - Copyright (c) 2013 Elsevier Inc. All rights reserved.
FAU - Bartalucci, Niccolo
AU  - Bartalucci N
AD  - Department of Medical and Surgical Care, Section of Hematology, University of 
      Florence, Florence, Italy.
FAU - Guglielmelli, Paola
AU  - Guglielmelli P
FAU - Vannucchi, Alessandro M
AU  - Vannucchi AM
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - Clin Lymphoma Myeloma Leuk
JT  - Clinical lymphoma, myeloma & leukemia
JID - 101525386
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.2 (Janus Kinase 2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Janus Kinase 2/antagonists & inhibitors/genetics/metabolism
MH  - Molecular Targeted Therapy
MH  - Myeloproliferative Disorders/drug therapy/*metabolism
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
OTO - NOTNLM
OT  - Inhibitor
OT  - JAK2
OT  - Myeloproliferative Neoplasms
OT  - PI3K
OT  - mTOR
EDAT- 2013/12/07 06:00
MHDA- 2014/10/03 06:00
CRDT- 2013/12/03 06:00
PHST- 2013/05/06 00:00 [received]
PHST- 2013/07/29 00:00 [revised]
PHST- 2013/07/29 00:00 [accepted]
PHST- 2013/12/03 06:00 [entrez]
PHST- 2013/12/07 06:00 [pubmed]
PHST- 2014/10/03 06:00 [medline]
AID - S2152-2650(13)00253-X [pii]
AID - 10.1016/j.clml.2013.07.011 [doi]
PST - ppublish
SO  - Clin Lymphoma Myeloma Leuk. 2013 Sep;13 Suppl 2:S307-9. doi: 
      10.1016/j.clml.2013.07.011.