PMID- 20606035
OWN - NLM
STAT- MEDLINE
DCOM- 20101220
LR  - 20211203
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 16
IP  - 14
DP  - 2010 Jul 15
TI  - The efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with 
      rapamycin in renal cell carcinoma.
PG  - 3628-38
LID - 10.1158/1078-0432.CCR-09-3022 [doi]
AB  - PURPOSE: Inhibitors of TORC1 have been shown to be active in patients with 
      metastatic renal cell carcinoma (RCC). As the phosphatidylinositol 3-kinase 
      (PI3K) pathway activates numerous other kinases, transcription factors, and 
      proteins associated with cell growth and survival besides mammalian target of 
      rapamycin (mTOR), disruption of this pathway upstream of mTOR may be more 
      effective than inhibition of TORC1 alone. EXPERIMENTAL DESIGN: To investigate 
      this possibility, the dual PI3K/mTOR inhibitor NVP-BEZ235 was compared with 
      rapamycin in RCC cell lines and xenografts generated from 786-O and A498 cells. 
      RESULTS: Treatment of RCC cell lines with NVP-BEZ235 in vitro resulted in the 
      nuclear translocation of p27, greater reduction in tumor cell proliferation, and 
      more complete suppression of Akt, Mnk-1, eIF4E, and 4EBP-1 phosphorylation and 
      cyclin D1 and hypoxia-inducible factor 2alpha (HIF2alpha) expression than that 
      achieved with rapamycin. The reduction of HIF2alpha levels correlated with 
      reduced HIF activity as determined by luciferase assay. NVP-BEZ235 induced growth 
      arrest in both the 786-O and A498 xenografts that was associated with inhibition 
      of Akt and S6 phosphorylation as well as the induction of apoptosis and reduction 
      in markers of tumor cell proliferation. In contrast, rapamycin induced only 
      minimal growth retardation. CONCLUSION: Dual inhibition of PI3K/mTOR with 
      NVP-BEZ235 induced growth arrest in RCC cell lines both in vitro and in vivo more 
      effectively than inhibition of TORC1 alone. These results provide the rationale 
      for the clinical assessment of agents such as NVP-BEZ235 in patients with 
      advanced RCC.
CI  - Copyright 2010 AACR.
FAU - Cho, Daniel C
AU  - Cho DC
AD  - Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, 
      Boston, Massachusetts 02215, USA. dcho1@bidmc.harvard.edu
FAU - Cohen, Matthew B
AU  - Cohen MB
FAU - Panka, David J
AU  - Panka DJ
FAU - Collins, Michael
AU  - Collins M
FAU - Ghebremichael, Musie
AU  - Ghebremichael M
FAU - Atkins, Michael B
AU  - Atkins MB
FAU - Signoretti, Sabina
AU  - Signoretti S
FAU - Mier, James W
AU  - Mier JW
LA  - eng
GR  - 1K08CA142890/CA/NCI NIH HHS/United States
GR  - P50 CA101942/CA/NCI NIH HHS/United States
GR  - K08 CA142890/CA/NCI NIH HHS/United States
GR  - P50 CA101942-078709/CA/NCI NIH HHS/United States
GR  - 2P50CA101942/CA/NCI NIH HHS/United States
GR  - K08 CA142890-01/CA/NCI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20100706
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 (CRTC2 protein, human)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Imidazoles)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proteins)
RN  - 0 (Quinolines)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - RUJ6Z9Y0DT (dactolisib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
ECI - Clin Cancer Res. 2019 Jul 1;25(13):4194. PMID: 31263033
MH  - Animals
MH  - Carcinoma, Renal Cell/*drug therapy
MH  - Cell Death/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Disease Models, Animal
MH  - Enzyme Inhibitors/*pharmacology
MH  - Female
MH  - Humans
MH  - Imidazoles/*pharmacology
MH  - Kidney Neoplasms/*drug therapy
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Nude
MH  - Multiprotein Complexes
MH  - Neoplasm Transplantation
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Proteins/antagonists & inhibitors
MH  - Quinolines/*pharmacology
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/antagonists & inhibitors
MH  - Xenograft Model Antitumor Assays
PMC - PMC2905505
MID - NIHMS212448
EDAT- 2010/07/08 06:00
MHDA- 2010/12/21 06:00
PMCR- 2011/07/15
CRDT- 2010/07/08 06:00
PHST- 2010/07/08 06:00 [entrez]
PHST- 2010/07/08 06:00 [pubmed]
PHST- 2010/12/21 06:00 [medline]
PHST- 2011/07/15 00:00 [pmc-release]
AID - 1078-0432.CCR-09-3022 [pii]
AID - 10.1158/1078-0432.CCR-09-3022 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2010 Jul 15;16(14):3628-38. doi: 10.1158/1078-0432.CCR-09-3022. 
      Epub 2010 Jul 6.