PMID- 19690197
OWN - NLM
STAT- MEDLINE
DCOM- 20091211
LR  - 20211203
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 15
IP  - 17
DP  - 2009 Sep 1
TI  - mTOR is a promising therapeutic target both in cisplatin-sensitive and 
      cisplatin-resistant clear cell carcinoma of the ovary.
PG  - 5404-13
LID - 10.1158/1078-0432.CCR-09-0365 [doi]
AB  - PURPOSE: Mammalian target of rapamycin (mTOR) plays a central role in cell 
      proliferation and is regarded as a promising target in cancer therapy, including 
      for ovarian cancer. This study aimed to examine the role of mTOR as a therapeutic 
      target in clear cell carcinoma of the ovary, which is regarded as an aggressive, 
      chemoresistant histologic subtype. EXPERIMENTAL DESIGN: Using tissue microarrays 
      of 98 primary ovarian cancers (52 clear cell carcinomas and 46 serous 
      adenocarcinomas), the expression of phospho-mTOR was assessed by 
      immunohistochemistry. Then, the growth-inhibitory effect of mTOR inhibition by 
      RAD001 (everolimus) was examined using two pairs of cisplatin-sensitive parental 
      (RMG1 and KOC7C) and cisplatin-resistant human clear cell carcinoma cell lines 
      (RMG1-CR and KOC7C-CR) both in vitro and in vivo. RESULTS: Immunohistochemical 
      analysis showed that mTOR was more frequently activated in clear cell carcinomas 
      than in serous adenocarcinomas (86.6% versus 50%). Treatment with RAD001 markedly 
      inhibited the growth of both RMG1 and KOC7C cells both in vitro and in vivo. 
      Increased expression of phospho-mTOR was observed in cisplatin-resistant RMG1-CR 
      and KOC7C-CR cells, compared with the respective parental cells. This increased 
      expression of phospho-mTOR in cisplatin-resistant cells was associated with 
      increased activation of AKT. RMG1-CR and KOC7C-CR cells showed greater 
      sensitivity to RAD001 than did parental RMG1 and KOC7C cells, respectively, in 
      vitro and in vivo. CONCLUSION: mTOR is frequently activated in clear cell 
      carcinoma and can be a promising therapeutic target in the management of clear 
      cell carcinoma. Moreover, mTOR inhibition by RAD001 may be efficacious as a 
      second-line treatment of recurrent disease in patients previously treated with 
      cisplatin.
FAU - Mabuchi, Seiji
AU  - Mabuchi S
AD  - Department of Obstetrics and Gynecology, Osaka University Graduate School of 
      Medicine, Suita, Osaka, Japan. smabuchi@gyne.med.osaka-u.ac.jp
FAU - Kawase, Chiaki
AU  - Kawase C
FAU - Altomare, Deborah A
AU  - Altomare DA
FAU - Morishige, Kenichirou
AU  - Morishige K
FAU - Sawada, Kenjiro
AU  - Sawada K
FAU - Hayashi, Masami
AU  - Hayashi M
FAU - Tsujimoto, Masahiko
AU  - Tsujimoto M
FAU - Yamoto, Mareo
AU  - Yamoto M
FAU - Klein-Szanto, Andres J
AU  - Klein-Szanto AJ
FAU - Schilder, Russell J
AU  - Schilder RJ
FAU - Ohmichi, Masahide
AU  - Ohmichi M
FAU - Testa, Joseph R
AU  - Testa JR
FAU - Kimura, Tadashi
AU  - Kimura T
LA  - eng
GR  - CA06927/CA/NCI NIH HHS/United States
GR  - P30 CA006927-45/CA/NCI NIH HHS/United States
GR  - R01 CA077429-02/CA/NCI NIH HHS/United States
GR  - P50 CA083638-10/CA/NCI NIH HHS/United States
GR  - P30 CA006927/CA/NCI NIH HHS/United States
GR  - CA83638/CA/NCI NIH HHS/United States
GR  - R01 CA077429/CA/NCI NIH HHS/United States
GR  - P50 CA083638/CA/NCI NIH HHS/United States
GR  - CA77429/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 - 20090818
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 (Antineoplastic Agents)
RN  - 0 (Immunosuppressive Agents)
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  - Q20Q21Q62J (Cisplatin)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adenocarcinoma, Clear Cell/*drug therapy/pathology
MH  - Animals
MH  - Antineoplastic Agents/therapeutic use
MH  - Cell Line, Tumor
MH  - Cisplatin/therapeutic use
MH  - Drug Resistance, Neoplasm/drug effects/physiology
MH  - Everolimus
MH  - Female
MH  - Humans
MH  - Immunosuppressive Agents/pharmacology/therapeutic use
MH  - Mice
MH  - Mice, Nude
MH  - Ovarian Neoplasms/*drug therapy/pathology
MH  - Protein Kinases/drug effects/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Sirolimus/analogs & derivatives/pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases
MH  - Tissue Array Analysis
MH  - Xenograft Model Antitumor Assays
PMC - PMC2743856
MID - NIHMS125079
EDAT- 2009/08/20 09:00
MHDA- 2009/12/16 06:00
PMCR- 2010/09/01
CRDT- 2009/08/20 09:00
PHST- 2009/08/20 09:00 [entrez]
PHST- 2009/08/20 09:00 [pubmed]
PHST- 2009/12/16 06:00 [medline]
PHST- 2010/09/01 00:00 [pmc-release]
AID - 1078-0432.CCR-09-0365 [pii]
AID - 10.1158/1078-0432.CCR-09-0365 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2009 Sep 1;15(17):5404-13. doi: 10.1158/1078-0432.CCR-09-0365. 
      Epub 2009 Aug 18.