PMID- 32341756
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200501
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 11
IP  - 15
DP  - 2020 Apr 14
TI  - Superior cancer preventive efficacy of low versus high dose of mTOR inhibitor in 
      a mouse model of prostate cancer.
PG  - 1373-1387
LID - 10.18632/oncotarget.27550 [doi]
AB  - The mechanistic target of rapamycin (mTOR) is a PI3K-related kinase that 
      regulates cell growth, proliferation and survival in response to the availability 
      of energy sources and growth factors. Cancer development and progression is often 
      associated with constitutive activation of the mTOR pathway, thus justifying mTOR 
      inhibition as a promising approach to cancer treatment and prevention. However, 
      development of previous rapamycin analogues has been complicated by their 
      induction of adverse side effects and variable efficacy. Since mTOR pathway 
      regulation involves multiple feedback mechanisms that may be differentially 
      activated depending on the degree of mTOR inhibition, we investigated whether 
      rapamycin dosing could be adjusted to achieve chemopreventive efficacy without 
      side effects. Thus, we tested the efficacy of two doses of a novel, highly 
      bioavailable nanoformulation of rapamycin, Rapatar, in a mouse prostate cancer 
      model (male mice with prostate epithelium-specific Pten-knockout). We found that 
      the highest efficacy was achieved by the lowest dose of Rapatar used in the 
      study. While both doses tested were equally effective in suppressing 
      proliferation of prostate epithelial cells, higher dose resulted in activation of 
      feedback circuits that reduced the drug's tumor preventive efficacy. These 
      results demonstrate that low doses of highly bioavailable mTOR inhibitor, 
      Rapatar, may provide safe and effective cancer prevention.
FAU - Antoch, Marina P
AU  - Antoch MP
AD  - Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer 
      Center, Buffalo, NY, USA.
FAU - Wrobel, Michelle
AU  - Wrobel M
AD  - Everon Biosciences, Inc., Buffalo, NY, USA.
FAU - Gillard, Bryan
AU  - Gillard B
AD  - Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer 
      Center, Buffalo, NY, USA.
FAU - Kuropatwinski, Karen K
AU  - Kuropatwinski KK
AD  - Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer 
      Center, Buffalo, NY, USA.
FAU - Toshkov, Ilia
AU  - Toshkov I
AD  - Everon Biosciences, Inc., Buffalo, NY, USA.
FAU - Gleiberman, Anatoli S
AU  - Gleiberman AS
AD  - Everon Biosciences, Inc., Buffalo, NY, USA.
FAU - Karasik, Ellen
AU  - Karasik E
AD  - Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer 
      Center, Buffalo, NY, USA.
FAU - Moser, Michael T
AU  - Moser MT
AD  - Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer 
      Center, Buffalo, NY, USA.
FAU - Foster, Barbara A
AU  - Foster BA
AD  - Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer 
      Center, Buffalo, NY, USA.
FAU - Andrianova, Ekaterina L
AU  - Andrianova EL
AD  - Everon Biosciences, Inc., Buffalo, NY, USA.
FAU - Chernova, Olga V
AU  - Chernova OV
AD  - Everon Biosciences, Inc., Buffalo, NY, USA.
FAU - Gudkov, Andrei V
AU  - Gudkov AV
AD  - Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
LA  - eng
GR  - P30 CA016056/CA/NCI NIH HHS/United States
GR  - R01 GM095874/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20200414
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
PMC - PMC7170500
OTO - NOTNLM
OT  - PTEN
OT  - mTOR
OT  - prevention
OT  - prostate cancer
OT  - rapamycin
COIS- CONFLICTS OF INTEREST M.P.A. and A.V.G. served as consultants for Everon 
      Biosciences, Inc.; O.V.C. and A.V.G. are co-founders and shareholders of Everon 
      Biosciences, Inc.
EDAT- 2020/04/29 06:00
MHDA- 2020/04/29 06:01
PMCR- 2020/04/14
CRDT- 2020/04/29 06:00
PHST- 2020/02/21 00:00 [received]
PHST- 2020/03/14 00:00 [accepted]
PHST- 2020/04/29 06:00 [entrez]
PHST- 2020/04/29 06:00 [pubmed]
PHST- 2020/04/29 06:01 [medline]
PHST- 2020/04/14 00:00 [pmc-release]
AID - 27550 [pii]
AID - 10.18632/oncotarget.27550 [doi]
PST - epublish
SO  - Oncotarget. 2020 Apr 14;11(15):1373-1387. doi: 10.18632/oncotarget.27550. 
      eCollection 2020 Apr 14.