PMID- 17363557
OWN - NLM
STAT- MEDLINE
DCOM- 20070419
LR  - 20211203
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 6
DP  - 2007 Mar 15
TI  - RAD001 (Everolimus) delays tumor onset and progression in a transgenic mouse 
      model of ovarian cancer.
PG  - 2408-13
AB  - The mammalian target of rapamycin (mTOR) is thought to play a critical role in 
      regulating cell growth, cell cycle progression, and tumorigenesis. Because the 
      AKT-mTOR pathway is frequently hyperactivated in ovarian cancer, we hypothesized 
      that the mTOR inhibitor RAD001 (Everolimus) would inhibit ovarian tumorigenesis 
      in transgenic mice that spontaneously develop ovarian carcinomas. We used 
      TgMISIIR-TAg transgenic mice, which develop bilateral ovarian serous 
      adenocarcinomas accompanied by ascites and peritoneal dissemination. Fifty-eight 
      female TgMISIIR-TAg mice were treated with 5 mg/kg RAD001 or placebo twice weekly 
      from 5 to 20 weeks of age. To monitor tumor development, mice were examined 
      biweekly using magnetic resonance microimaging. In vivo effects of RAD001 on 
      Akt-mTOR signaling, tumor cell proliferation, and blood vessel area were analyzed 
      by immunohistochemistry and Western blot analysis. RAD001 treatment markedly 
      delayed tumor development. Tumor burden was reduced by approximately 84%. In 
      addition, ascites formation, together with peritoneal dissemination, was detected 
      in only 21% of RAD001-treated mice compared with 74% in placebo-treated animals. 
      Approximately 30% of RAD001-treated mice developed early ovarian carcinoma 
      confined within the ovary, whereas all placebo-treated mice developed advanced 
      ovarian carcinoma. Treatment with RAD001 diminished the expression of vascular 
      endothelial growth factor in tumor-derived cell lines and inhibited angiogenesis 
      in vivo. RAD001 also attenuated the expression of matrix metalloproteinase-2 and 
      inhibited the invasiveness of tumor-derived cells. Taken together, these 
      preclinical findings suggest that mTOR inhibition, alone or in combination with 
      other molecularly targeted drugs, could represent a promising chemopreventive 
      strategy in women at high familial risk of ovarian cancer.
FAU - Mabuchi, Seiji
AU  - Mabuchi S
AD  - Human Genetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 
      19111, USA.
FAU - Altomare, Deborah A
AU  - Altomare DA
FAU - Connolly, Denise C
AU  - Connolly DC
FAU - Klein-Szanto, Andres
AU  - Klein-Szanto A
FAU - Litwin, Samuel
AU  - Litwin S
FAU - Hoelzle, Matthew K
AU  - Hoelzle MK
FAU - Hensley, Harvey H
AU  - Hensley HH
FAU - Hamilton, Thomas C
AU  - Hamilton TC
FAU - Testa, Joseph R
AU  - Testa JR
LA  - eng
GR  - P30 CA006927/CA/NCI NIH HHS/United States
GR  - P50 CA083638/CA/NCI NIH HHS/United States
GR  - CA06927/CA/NCI NIH HHS/United States
GR  - CA83638/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 (Protein Kinase Inhibitors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 9HW64Q8G6G (Everolimus)
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 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - Disease Progression
MH  - Everolimus
MH  - Female
MH  - Matrix Metalloproteinase 2/biosynthesis
MH  - Mice
MH  - Mice, Transgenic
MH  - Neovascularization, Pathologic/drug therapy/metabolism
MH  - Ovarian Neoplasms/blood supply/*drug therapy/metabolism/pathology
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Protein Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction
MH  - Sirolimus/*analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Vascular Endothelial Growth Factor A/biosynthesis
EDAT- 2007/03/17 09:00
MHDA- 2007/04/20 09:00
CRDT- 2007/03/17 09:00
PHST- 2007/03/17 09:00 [pubmed]
PHST- 2007/04/20 09:00 [medline]
PHST- 2007/03/17 09:00 [entrez]
AID - 67/6/2408 [pii]
AID - 10.1158/0008-5472.CAN-06-4490 [doi]
PST - ppublish
SO  - Cancer Res. 2007 Mar 15;67(6):2408-13. doi: 10.1158/0008-5472.CAN-06-4490.