PMID- 18281551
OWN - NLM
STAT- MEDLINE
DCOM- 20080603
LR  - 20211203
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 14
IP  - 4
DP  - 2008 Feb 15
TI  - Suppression of Peutz-Jeghers polyposis by targeting mammalian target of rapamycin 
      signaling.
PG  - 1167-71
LID - 10.1158/1078-0432.CCR-07-4007 [doi]
AB  - PURPOSE: Peutz-Jeghers syndrome (PJS) is a unique disorder characterized by the 
      development of hamartomas in the gastrointestinal tract as well as increased 
      risks for variety of malignancies. Germ-line mutations of LKB1 cause PJS. We have 
      generated Lkb1+/- mice, which model human PJS. Rapamycin and its analogues are 
      promising preventive and therapeutic agents that specifically inhibit signaling 
      from mammalian target of rapamycin (mTOR). Hyperactivation of mTOR signaling has 
      been associated with PJS. The objective of the study is to investigate the 
      efficacy of mTOR inhibition in suppressing Peutz-Jeghers polyposis in Lkb1+/- 
      mice. EXPERIMENTAL DESIGN: We initiated a trial of rapamycin in Lkb1+/- mice at 9 
      months of age (after the onset of polyposis) at the dose of 2 mg/kg/d for a 
      2-month period. We assessed the efficacy of rapamycin by measuring polyp sizes 
      and tumor burden. To examine the effect of rapamycin on mTOR signaling, 
      phosphorylation levels of S6 were evaluated by immunostaining. RESULTS: We 
      observed a significant decrease in mean tumor burden (Student's t test, P = 
      0.023) as well as total tumor burden in rapamycin-treated group compared with 
      control group. Comparison of the polyp size observed in both rapamycin-treated 
      and control groups showed that rapamycin efficiently decreased the tumor burden 
      of large polyps (> 8 mm). This inhibition of rapamycin was associated with a 
      decrease in phosphorylated S6 levels in the polyps. CONCLUSIONS: Rapamycin 
      effectively suppresses Peutz-Jeghers polyposis in a mouse model, suggesting that 
      rapamycin or its analogues may represent a new targeted therapy for the treatment 
      of PJS.
FAU - Wei, Chongjuan
AU  - Wei C
AD  - Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, 
      Houston, Texas 77030, USA.
FAU - Amos, Christopher I
AU  - Amos CI
FAU - Zhang, Nianxiang
AU  - Zhang N
FAU - Wang, Xiaopei
AU  - Wang X
FAU - Rashid, Asif
AU  - Rashid A
FAU - Walker, Cheryl L
AU  - Walker CL
FAU - Behringer, Richard R
AU  - Behringer RR
FAU - Frazier, Marsha L
AU  - Frazier ML
LA  - eng
GR  - CA16672/CA/NCI NIH HHS/United States
GR  - R03 CA123603/CA/NCI NIH HHS/United States
GR  - R03 CA89843/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  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Immunosuppressive Agents)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Stk11 protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - AMP-Activated Protein Kinases
MH  - Animals
MH  - Immunohistochemistry
MH  - Immunosuppressive Agents/*therapeutic use
MH  - Mice
MH  - Mice, Knockout
MH  - Peutz-Jeghers Syndrome/*drug therapy/pathology
MH  - Protein Kinases/*drug effects/metabolism
MH  - Protein Serine-Threonine Kinases/genetics
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*therapeutic use
MH  - TOR Serine-Threonine Kinases
EDAT- 2008/02/19 09:00
MHDA- 2008/06/05 09:00
CRDT- 2008/02/19 09:00
PHST- 2008/02/19 09:00 [pubmed]
PHST- 2008/06/05 09:00 [medline]
PHST- 2008/02/19 09:00 [entrez]
AID - 14/4/1167 [pii]
AID - 10.1158/1078-0432.CCR-07-4007 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2008 Feb 15;14(4):1167-71. doi: 10.1158/1078-0432.CCR-07-4007.