PMID- 23262510
OWN - NLM
STAT- MEDLINE
DCOM- 20130702
LR  - 20220408
IS  - 1523-5866 (Electronic)
IS  - 1522-8517 (Print)
IS  - 1522-8517 (Linking)
VI  - 15
IP  - 2
DP  - 2013 Feb
TI  - On-target JAK2/STAT3 inhibition slows disease progression in orthotopic 
      xenografts of human glioblastoma brain tumor stem cells.
PG  - 198-207
LID - 10.1093/neuonc/nos302 [doi]
AB  - BACKGROUND: Glioblastoma multiforme (GBM) is characterized by an aggressive 
      clinical course, therapeutic resistance, and striking molecular heterogeneity. 
      GBM-derived brain tumor stem cells (BTSCs) closely model this molecular 
      heterogeneity and likely have a key role in tumor recurrence and therapeutic 
      resistance. Emerging evidence indicates that Janus kinase (JAK)2/signal 
      transducer and activator of transcription (STAT)3 is an important mediator of 
      tumor cell survival, growth, and invasion in a large group of GBM. Here, we used 
      a large set of molecularly heterogeneous BTSCs to evaluate the translational 
      potential of JAK2/STAT3 therapeutics. METHODS: BTSCs were cultured from GBM 
      patients and MGMT promoter methylation, and the mutation statuses of EGFR, PTEN, 
      and TP53 were determined. Endogenous JAK2/STAT3 activity was assessed in human 
      GBM tissue, BTSCs, and orthotopic xenografts by immunohistochemistry and Western 
      blotting. STAT3 short hairpin (sh)RNA, cucurbitacin-I, and WP1066 were used to 
      inhibit JAK2/STAT3 activity in vitro and in vivo. RESULTS: The JAK2/STAT3 pathway 
      was demonstrated to be highly activated in human GBM, molecularly heterogeneous 
      BTSCs derived from these tumors, and BTSC xenografts. STAT3 shRNA knockdown or 
      cucurbitacin-I and WP1066 administration resulted in on-target JAK2/STAT3 
      inhibition and dramatically reduced BTSC survival regardless of endogenous MGMT 
      promoter methylation or EGFR, PTEN, and TP53 mutational status. BTSC orthotopic 
      xenografts maintained the high levels of activated JAK2/STAT3 seen in their 
      parent human tumors. Intraperitoneal WP1066 reduced intratumoral JAK2/STAT3 
      activity and prolonged animal survival. CONCLUSION: Our study demonstrates the in 
      vitro and in vivo efficacy of on-target JAK2/STAT3 inhibition in heterogeneous 
      BTSC lines that closely emulate the genomic and tumorigenic characteristics of 
      human GBM.
FAU - Stechishin, Owen D
AU  - Stechishin OD
AD  - Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, 
      Alberta, Canada.
FAU - Luchman, H Artee
AU  - Luchman HA
FAU - Ruan, Yibing
AU  - Ruan Y
FAU - Blough, Michael D
AU  - Blough MD
FAU - Nguyen, Stephanie A
AU  - Nguyen SA
FAU - Kelly, John J
AU  - Kelly JJ
FAU - Cairncross, J Gregory
AU  - Cairncross JG
FAU - Weiss, Samuel
AU  - Weiss S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121221
PL  - England
TA  - Neuro Oncol
JT  - Neuro-oncology
JID - 100887420
RN  - 0 (Pyridines)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 0 (TP53 protein, human)
RN  - 0 (Triterpenes)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (Tyrphostins)
RN  - 0 (WP1066)
RN  - EC 2.1.1.- (DNA Modification Methylases)
RN  - EC 2.1.1.63 (MGMT protein, human)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.2 (JAK2 protein, human)
RN  - EC 2.7.10.2 (Janus Kinase 2)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - EC 6.5.1.- (DNA Repair Enzymes)
RN  - SHQ47990PH (cucurbitacin I)
SB  - IM
MH  - Aged
MH  - Animals
MH  - Apoptosis
MH  - Blotting, Western
MH  - Brain Neoplasms/metabolism/pathology/*prevention & control
MH  - Cell Proliferation
MH  - DNA Methylation
MH  - DNA Modification Methylases/genetics
MH  - DNA Repair Enzymes/genetics
MH  - Disease Progression
MH  - ErbB Receptors/metabolism
MH  - Female
MH  - Flow Cytometry
MH  - Glioblastoma/metabolism/pathology/*prevention & control
MH  - Humans
MH  - Immunoenzyme Techniques
MH  - Janus Kinase 2/antagonists & inhibitors/genetics/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Middle Aged
MH  - Neoplastic Stem Cells/metabolism/*pathology
MH  - PTEN Phosphohydrolase/metabolism
MH  - Promoter Regions, Genetic/genetics
MH  - Pyridines/pharmacology
MH  - RNA, Small Interfering/genetics
MH  - STAT3 Transcription Factor/antagonists & inhibitors/genetics/*metabolism
MH  - Signal Transduction
MH  - Triterpenes/pharmacology
MH  - Tumor Cells, Cultured
MH  - Tumor Suppressor Protein p53/metabolism
MH  - Tumor Suppressor Proteins/genetics
MH  - Tyrphostins/pharmacology
MH  - Xenograft Model Antitumor Assays
PMC - PMC3548588
EDAT- 2012/12/25 06:00
MHDA- 2013/07/03 06:00
PMCR- 2014/02/01
CRDT- 2012/12/25 06:00
PHST- 2012/12/25 06:00 [entrez]
PHST- 2012/12/25 06:00 [pubmed]
PHST- 2013/07/03 06:00 [medline]
PHST- 2014/02/01 00:00 [pmc-release]
AID - nos302 [pii]
AID - 10.1093/neuonc/nos302 [doi]
PST - ppublish
SO  - Neuro Oncol. 2013 Feb;15(2):198-207. doi: 10.1093/neuonc/nos302. Epub 2012 Dec 
      21.