PMID- 17942891
OWN - NLM
STAT- MEDLINE
DCOM- 20071212
LR  - 20221109
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 20
DP  - 2007 Oct 15
TI  - A novel small molecule inhibitor of signal transducers and activators of 
      transcription 3 reverses immune tolerance in malignant glioma patients.
PG  - 9630-6
AB  - Overcoming the profound immunosuppression in patients with solid cancers has 
      impeded efficacious immunotherapy. Signal transducers and activators of 
      transcription 3 (STAT3) has recently emerged as a potential target for effective 
      immunotherapy, and in this study, we describe a novel small molecule inhibitor of 
      STAT3 that can penetrate the central nervous system (CNS) in mice and in 
      physiologically relevant doses in vitro and reverse tolerance in immune cells 
      isolated from glioblastoma multiforme (GBM) patients. Specifically, it induces 
      the expression of costimulatory molecules on peripheral macrophages and 
      tumor-infiltrating microglia, stimulates the production of the immune-stimulatory 
      cytokines interleukin 2 (IL-2), IL-4, IL-12, and IL-15, and induces proliferation 
      of effector T cells from GBM patients that are refractory to CD3 stimulation. We 
      show that the functional enhancement of immune responses after STAT3 inhibition 
      is accompanied by up-regulation of several key intracellular signaling molecules 
      that critically regulate T-cell and monocyte activation. Specifically, the 
      phosphorylation of Syk (Tyr352) in monocytes and ZAP-70 (Tyr319) in T cells are 
      enhanced by the STAT-3 inhibitor in marked contrast to toll-like receptor and 
      T-cell receptor agonists, respectively. This novel small molecule STAT3 inhibitor 
      has tremendous potential for clinical applications with its penetration into the 
      CNS, easy parental administration, direct tumor cytotoxicity, and potent immune 
      adjuvant responses in immunosuppressed cancer patients.
FAU - Hussain, S Farzana
AU  - Hussain SF
AD  - Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, 
      Houston, Texas 77030, USA.
FAU - Kong, Ling-Yuan
AU  - Kong LY
FAU - Jordan, Justin
AU  - Jordan J
FAU - Conrad, Charles
AU  - Conrad C
FAU - Madden, Timothy
AU  - Madden T
FAU - Fokt, Isabella
AU  - Fokt I
FAU - Priebe, Waldemar
AU  - Priebe W
FAU - Heimberger, Amy B
AU  - Heimberger AB
LA  - eng
GR  - P20 CA101936/CA/NCI NIH HHS/United States
GR  - R01 CA120813/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (B7-1 Antigen)
RN  - 0 (B7-2 Antigen)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Pyridines)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 0 (Tyrphostins)
RN  - 0 (WP1066)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (SYK protein, human)
RN  - EC 2.7.10.2 (Syk Kinase)
RN  - EC 2.7.10.2 (Syk protein, mouse)
RN  - EC 2.7.10.2 (ZAP-70 Protein-Tyrosine Kinase)
SB  - IM
MH  - Adjuvants, Immunologic/pharmacology
MH  - Animals
MH  - B7-1 Antigen/biosynthesis/immunology
MH  - B7-2 Antigen/biosynthesis/immunology
MH  - Brain Neoplasms/*drug therapy/*immunology
MH  - Glioblastoma/*drug therapy/*immunology
MH  - Humans
MH  - Immune Tolerance/drug effects
MH  - Intracellular Signaling Peptides and Proteins/immunology/metabolism
MH  - Leukocytes, Mononuclear/drug effects/immunology
MH  - Lymphocyte Activation
MH  - Mice
MH  - Mice, Nude
MH  - Phosphorylation/drug effects
MH  - Protein-Tyrosine Kinases/immunology/metabolism
MH  - Pyridines/immunology/*pharmacology
MH  - STAT3 Transcription Factor/*antagonists & inhibitors/immunology
MH  - Syk Kinase
MH  - T-Lymphocytes/drug effects/immunology
MH  - Tyrphostins/immunology/*pharmacology
MH  - ZAP-70 Protein-Tyrosine Kinase/immunology/metabolism
EDAT- 2007/10/19 09:00
MHDA- 2007/12/13 09:00
CRDT- 2007/10/19 09:00
PHST- 2007/10/19 09:00 [pubmed]
PHST- 2007/12/13 09:00 [medline]
PHST- 2007/10/19 09:00 [entrez]
AID - 67/20/9630 [pii]
AID - 10.1158/0008-5472.CAN-07-1243 [doi]
PST - ppublish
SO  - Cancer Res. 2007 Oct 15;67(20):9630-6. doi: 10.1158/0008-5472.CAN-07-1243.