PMID- 19965685
OWN - NLM
STAT- MEDLINE
DCOM- 20100223
LR  - 20231105
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 115
IP  - 3
DP  - 2010 Jan 21
TI  - Dual targeting of the PI3K/Akt/mTOR pathway as an antitumor strategy in 
      Waldenstrom macroglobulinemia.
PG  - 559-69
LID - 10.1182/blood-2009-07-235747 [doi]
AB  - We have previously shown clinical activity of a mammalian target of rapamycin 
      (mTOR) complex 1 inhibitor in Waldenstrom macroglobulinemia (WM). However, 50% of 
      patients did not respond to therapy. We therefore examined mechanisms of 
      activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR in WM, and mechanisms 
      of overcoming resistance to therapy. We first demonstrated that primary WM cells 
      show constitutive activation of the PI3K/Akt pathway, supported by decreased 
      expression of phosphate and tensin homolog tumor suppressor gene (PTEN) at the 
      gene and protein levels, together with constitutive activation of Akt and mTOR. 
      We illustrated that dual targeting of the PI3K/mTOR pathway by the novel 
      inhibitor NVP-BEZ235 showed higher cytotoxicity on WM cells compared with 
      inhibition of the PI3K or mTOR pathways alone. In addition, NVP-BEZ235 inhibited 
      both rictor and raptor, thus abrogating the rictor-induced Akt phosphorylation. 
      NVP-BEZ235 also induced significant cytotoxicity in WM cells in a 
      caspase-dependent and -independent manner, through targeting the Forkhead box 
      transcription factors. In addition, NVP-BEZ235 targeted WM cells in the context 
      of bone marrow microenvironment, leading to significant inhibition of migration, 
      adhesion in vitro, and homing in vivo. These studies therefore show that dual 
      targeting of the PI3K/mTOR pathway is a better modality of targeted therapy for 
      tumors that harbor activation of the PI3K/mTOR signaling cascade, such as WM.
FAU - Roccaro, Aldo M
AU  - Roccaro AM
AD  - Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, 
      Boston, MA, USA.
FAU - Sacco, Antonio
AU  - Sacco A
FAU - Husu, Emanuel N
AU  - Husu EN
FAU - Pitsillides, Costas
AU  - Pitsillides C
FAU - Vesole, Steven
AU  - Vesole S
FAU - Azab, Abdel Kareem
AU  - Azab AK
FAU - Azab, Feda
AU  - Azab F
FAU - Melhem, Molly
AU  - Melhem M
FAU - Ngo, Hai T
AU  - Ngo HT
FAU - Quang, Phong
AU  - Quang P
FAU - Maiso, Patricia
AU  - Maiso P
FAU - Runnels, Judith
AU  - Runnels J
FAU - Liang, Mei-Chih
AU  - Liang MC
FAU - Wong, Kwok-Kin
AU  - Wong KK
FAU - Lin, Charles
AU  - Lin C
FAU - Ghobrial, Irene M
AU  - Ghobrial IM
LA  - eng
GR  - R21 CA126119/CA/NCI NIH HHS/United States
GR  - R21 1R21CA126119-01/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20091119
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Imidazoles)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Oncogene Protein v-akt)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - RUJ6Z9Y0DT (dactolisib)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacology/therapeutic use
MH  - Cells, Cultured
MH  - Drug Delivery Systems/methods
MH  - Drug Evaluation, Preclinical
MH  - Enzyme Activation/drug effects
MH  - Enzyme Inhibitors/therapeutic use
MH  - Humans
MH  - Imidazoles/pharmacology/*therapeutic use
MH  - Intracellular Signaling Peptides and Proteins/*antagonists & 
      inhibitors/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Oncogene Protein v-akt/*antagonists & inhibitors/metabolism
MH  - PTEN Phosphohydrolase/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Quinolines/pharmacology/*therapeutic use
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases
MH  - Waldenstrom Macroglobulinemia/*drug therapy
PMC - PMC2810978
EDAT- 2009/12/08 06:00
MHDA- 2010/02/24 06:00
PMCR- 2011/01/21
CRDT- 2009/12/08 06:00
PHST- 2009/12/08 06:00 [entrez]
PHST- 2009/12/08 06:00 [pubmed]
PHST- 2010/02/24 06:00 [medline]
PHST- 2011/01/21 00:00 [pmc-release]
AID - S0006-4971(20)49315-2 [pii]
AID - 2009/235747 [pii]
AID - 10.1182/blood-2009-07-235747 [doi]
PST - ppublish
SO  - Blood. 2010 Jan 21;115(3):559-69. doi: 10.1182/blood-2009-07-235747. Epub 2009 
      Nov 19.