PMID- 27751351
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200930
IS  - 1936-5233 (Print)
IS  - 1936-5233 (Electronic)
IS  - 1936-5233 (Linking)
VI  - 9
IP  - 5
DP  - 2016 Oct
TI  - Activity of Pan-Class I Isoform PI3K/mTOR Inhibitor PF-05212384 in Combination 
      with Crizotinib in Ovarian Cancer Xenografts and PDX.
PG  - 458-465
LID - S1936-5233(16)30120-6 [pii]
LID - 10.1016/j.tranon.2016.08.011 [doi]
AB  - The Phosphatidyl inositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin 
      (mTOR) and c-Met signaling pathways are often deregulated in cancer. The two 
      pathways are interconnected and at least c-Met has been implicated in drug 
      resistance. The aim of the study was to assess in ovarian cancer preclinical 
      models, the efficacy and tolerability of a dual PI3K mTOR inhibitor (PF-05212384 
      or gedatolisib) and a c-Met inhibitor (crizotinib) either as single agents or in 
      combination. In vitro, both PF-05212384 and crizotinib showed a concentration 
      dependent activity in the two ovarian cancer cell lines. The combination of the 
      two did not result in synergistic activity. A subline resistant to gedatolisib 
      was obtained and showed an increased expression of MDR-1 gene. In vivo results 
      show that crizotinib alone did not display any activity in all the tumors 
      investigated, while PF-05212384 alone had some marginal activity. The combination 
      of the two resulted in all the experiments superior to single agents with a good 
      tolerability. Considering that crizotinib did not show activity in the models 
      used, the results indicate that crizotinib is able to potentiate the activity of 
      PF-05212384. Although the activity of the combination was not striking in these 
      three models of ovarian cancer, due to the good tolerability of the combination, 
      the results would suggest the possibility to combine the two drugs in settings in 
      which gedatolisib or crizotinib alone have already some significant activity.
CI  - Copyright (c) 2016 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Iezzi, Alice
AU  - Iezzi A
AD  - Laboratory of Molecular Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche 
      "Mario Negri", Milan, Italy. Electronic address: alice.iezzi@marionegri.it.
FAU - Caiola, Elisa
AU  - Caiola E
AD  - Laboratory of Molecular Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche 
      "Mario Negri", Milan, Italy. Electronic address: elisa.caiola@marionegri.it.
FAU - Broggini, Massimo
AU  - Broggini M
AD  - Laboratory of Molecular Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche 
      "Mario Negri", Milan, Italy. Electronic address: massimo.broggini@marionegri.it.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Transl Oncol
JT  - Translational oncology
JID - 101472619
PMC - PMC5067927
EDAT- 2016/10/19 06:00
MHDA- 2016/10/19 06:01
PMCR- 2016/10/14
CRDT- 2016/10/19 06:00
PHST- 2016/06/17 00:00 [received]
PHST- 2016/08/30 00:00 [accepted]
PHST- 2016/10/19 06:00 [pubmed]
PHST- 2016/10/19 06:01 [medline]
PHST- 2016/10/19 06:00 [entrez]
PHST- 2016/10/14 00:00 [pmc-release]
AID - S1936-5233(16)30120-6 [pii]
AID - 10.1016/j.tranon.2016.08.011 [doi]
PST - ppublish
SO  - Transl Oncol. 2016 Oct;9(5):458-465. doi: 10.1016/j.tranon.2016.08.011.