PMID- 25688743
OWN - NLM
STAT- MEDLINE
DCOM- 20150430
LR  - 20211203
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 112
IP  - 5
DP  - 2015 Mar 3
TI  - mTOR inhibition improves fibroblast growth factor receptor targeting in 
      hepatocellular carcinoma.
PG  - 841-50
LID - 10.1038/bjc.2014.638 [doi]
AB  - BACKGROUND: Systemic therapy has proven only marginal effects in hepatocellular 
      carcinoma (HCC) so far. The aim of this study was to evaluate the effect of 
      targeting fibroblast growth factor receptor (FGFR) on tumour and stromal cells in 
      HCC models. METHODS: Human and murine HCC cells, endothelial cells (ECs), 
      vascular smooth muscle cells (VSMCs), hepatic stellate cells (HSCs), human HCC 
      samples, FGFR inhibitor BGJ398 and mammalian target of rapamycin (mTOR) inhibitor 
      rapamycin were used. Effects on growth, motility, signalling and angiogenic 
      markers were determined. In vivo subcutaneous and syngeneic orthotopic tumour 
      models were used. RESULTS: In tumour cells and ECs, targeting FGFR showed 
      significant inhibitory effects on signalling and motility. Minor effects of FGFR 
      inhibition were observed on VSMCs and HSCs, which were significantly enhanced by 
      combining FGFR and mTOR blockade. In vivo daily (5 mg kg(-1)) treatment with 
      BGJ398 led to a significant growth inhibition in subcutaneous tumour models, but 
      only a combination of FGFR and mTOR blockade impaired tumour growth in the 
      orthotopic model. This was paralleled by reduced tumour cell proliferation, 
      vascularisation, pericytes and increased apoptosis. CONCLUSIONS: Targeting FGFR 
      with BGJ398 affects tumour cells and ECs, whereas only a combination with mTOR 
      inhibition impairs recruitment of VSMCs and HSCs. Therefore, this study provides 
      evidence for combined FGFR/mTOR inhibition in HCC.
FAU - Scheller, T
AU  - Scheller T
AD  - Department of Surgery, University Hospital Regensburg, University of Regensburg 
      Medical Center, Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany.
FAU - Hellerbrand, C
AU  - Hellerbrand C
AD  - Department of Internal Medicine I, University Hospital Regensburg, University of 
      Regensburg Medical Center, Franz-Josef-Strauss Allee 11, 93053 Regensburg, 
      Germany.
FAU - Moser, C
AU  - Moser C
AD  - Department of Surgery, University Hospital Regensburg, University of Regensburg 
      Medical Center, Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany.
FAU - Schmidt, K
AU  - Schmidt K
AD  - Department of Surgery, University Hospital Regensburg, University of Regensburg 
      Medical Center, Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany.
FAU - Kroemer, A
AU  - Kroemer A
AD  - Department of Surgery, University Hospital Regensburg, University of Regensburg 
      Medical Center, Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany.
FAU - Brunner, S M
AU  - Brunner SM
AD  - Department of Surgery, University Hospital Regensburg, University of Regensburg 
      Medical Center, Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany.
FAU - Schlitt, H J
AU  - Schlitt HJ
AD  - Department of Surgery, University Hospital Regensburg, University of Regensburg 
      Medical Center, Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany.
FAU - Geissler, E K
AU  - Geissler EK
AD  - Department of Surgery, University Hospital Regensburg, University of Regensburg 
      Medical Center, Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany.
FAU - Lang, S A
AU  - Lang SA
AD  - Department of Surgery, University Hospital Regensburg, University of Regensburg 
      Medical Center, Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150217
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Pyrimidines)
RN  - A4055ME1VK (infigratinib)
RN  - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Carcinoma, Hepatocellular/*drug therapy/pathology
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Drug Synergism
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Hep G2 Cells
MH  - Humans
MH  - Liver Neoplasms/*drug therapy/pathology
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasm Transplantation
MH  - Phenylurea Compounds/administration & dosage/*pharmacology
MH  - Pyrimidines/administration & dosage/*pharmacology
MH  - Receptor, Fibroblast Growth Factor, Type 1/*antagonists & inhibitors
MH  - Signal Transduction/drug effects
MH  - Sirolimus/administration & dosage/*pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Xenograft Model Antitumor Assays
PMC - PMC4453944
EDAT- 2015/02/18 06:00
MHDA- 2015/05/01 06:00
PMCR- 2016/03/03
CRDT- 2015/02/18 06:00
PHST- 2014/11/21 00:00 [revised]
PHST- 2014/11/28 00:00 [accepted]
PHST- 2015/02/18 06:00 [entrez]
PHST- 2015/02/18 06:00 [pubmed]
PHST- 2015/05/01 06:00 [medline]
PHST- 2016/03/03 00:00 [pmc-release]
AID - bjc2014638 [pii]
AID - 10.1038/bjc.2014.638 [doi]
PST - ppublish
SO  - Br J Cancer. 2015 Mar 3;112(5):841-50. doi: 10.1038/bjc.2014.638. Epub 2015 Feb 
      17.