PMID- 24821582
OWN - NLM
STAT- MEDLINE
DCOM- 20151102
LR  - 20220129
IS  - 1873-7560 (Electronic)
IS  - 0302-2838 (Print)
IS  - 0302-2838 (Linking)
VI  - 66
IP  - 5
DP  - 2014 Nov
TI  - Carbonic anhydrase 9 expression increases with vascular endothelial growth 
      factor-targeted therapy and is predictive of outcome in metastatic clear cell 
      renal cancer.
PG  - 956-63
LID - S0302-2838(14)00374-1 [pii]
LID - 10.1016/j.eururo.2014.04.007 [doi]
AB  - BACKGROUND: There is a lack of biomarkers to predict outcome with targeted 
      therapy in metastatic clear cell renal cancer (mccRCC). This may be because 
      dynamic molecular changes occur with therapy. OBJECTIVE: To explore if dynamic, 
      targeted-therapy-driven molecular changes correlate with mccRCC outcome. DESIGN, 
      SETTING, AND PARTICIPANTS: Multiple frozen samples from primary tumours were 
      taken from sunitinib-naive (n=22) and sunitinib-treated mccRCC patients (n=23) 
      for protein analysis. A cohort (n=86) of paired, untreated and 
      sunitinib/pazopanib-treated mccRCC samples was used for validation. Array 
      comparative genomic hybridisation (CGH) analysis and RNA interference (RNAi) was 
      used to support the findings. INTERVENTION: Three cycles of sunitinib 50mg (4 wk 
      on, 2 wk off). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Reverse phase 
      protein arrays (training set) and immunofluorescence automated quantitative 
      analysis (validation set) assessed protein expression. RESULTS AND LIMITATIONS: 
      Differential expression between sunitinib-naive and treated samples was seen in 
      30 of 55 proteins (p<0.05 for each). The proteins B-cell CLL/lymphoma 2 (BCL2), 
      mutL homolog 1 (MLH1), carbonic anhydrase 9 (CA9), and mechanistic target of 
      rapamycin (mTOR) (serine/threonine kinase) had both increased intratumoural 
      variance and significant differential expression with therapy. The validation 
      cohort confirmed increased CA9 expression with therapy. Multivariate analysis 
      showed high CA9 expression after treatment was associated with longer survival 
      (hazard ratio: 0.48; 95% confidence interval, 0.26-0.87; p=0.02). Array CGH 
      profiles revealed sunitinib was associated with significant CA9 region loss. RNAi 
      CA9 silencing in two cell lines inhibited the antiproliferative effects of 
      sunitinib. Shortcomings of the study include selection of a specific protein for 
      analysis, and the specific time points at which the treated tissue was analysed. 
      CONCLUSIONS: CA9 levels increase with targeted therapy in mccRCC. Lower CA9 
      levels are associated with a poor prognosis and possible resistance, as indicated 
      by the validation cohort. PATIENT SUMMARY: Drug treatment of advanced kidney 
      cancer alters molecular markers of treatment resistance. Measuring carbonic 
      anhydrase 9 levels may be helpful in determining which patients benefit from 
      therapy.
CI  - Copyright (c) 2014 European Association of Urology. Published by Elsevier B.V. All 
      rights reserved.
FAU - Stewart, Grant D
AU  - Stewart GD
AD  - Edinburgh Urological Cancer Group, Institute of Genetics and Molecular Medicine, 
      University of Edinburgh, Edinburgh, UK; Scottish Collaboration On Translational 
      Research into Renal Cell Cancer, UK.
FAU - O'Mahony, Fiach C
AU  - O'Mahony FC
AD  - Edinburgh Urological Cancer Group, Institute of Genetics and Molecular Medicine, 
      University of Edinburgh, Edinburgh, UK; Scottish Collaboration On Translational 
      Research into Renal Cell Cancer, UK.
FAU - Laird, Alexander
AU  - Laird A
AD  - Edinburgh Urological Cancer Group, Institute of Genetics and Molecular Medicine, 
      University of Edinburgh, Edinburgh, UK; Scottish Collaboration On Translational 
      Research into Renal Cell Cancer, UK; MRC Human Genetics Unit, MRC IGMM, 
      University of Edinburgh, Edinburgh, UK.
FAU - Rashid, Sukaina
AU  - Rashid S
AD  - Department of Molecular Oncology, Barts Cancer Institute, Queen Mary University 
      of London, London, UK.
FAU - Martin, Sarah A
AU  - Martin SA
AD  - Department of Molecular Oncology, Barts Cancer Institute, Queen Mary University 
      of London, London, UK.
FAU - Eory, Lel
AU  - Eory L
AD  - MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, UK.
FAU - Lubbock, Alexander L R
AU  - Lubbock AL
AD  - MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, UK.
FAU - Nanda, Jyoti
AU  - Nanda J
AD  - Edinburgh Urological Cancer Group, Institute of Genetics and Molecular Medicine, 
      University of Edinburgh, Edinburgh, UK; Scottish Collaboration On Translational 
      Research into Renal Cell Cancer, UK.
FAU - O'Donnell, Marie
AU  - O'Donnell M
AD  - Edinburgh Urological Cancer Group, Institute of Genetics and Molecular Medicine, 
      University of Edinburgh, Edinburgh, UK; Scottish Collaboration On Translational 
      Research into Renal Cell Cancer, UK.
FAU - Mackay, Alan
AU  - Mackay A
AD  - The Institute of Cancer Research, London, UK.
FAU - Mullen, Peter
AU  - Mullen P
AD  - School of Medicine, University of St Andrews, St Andrews, Fife, UK.
FAU - McNeill, S Alan
AU  - McNeill SA
AD  - Edinburgh Urological Cancer Group, Institute of Genetics and Molecular Medicine, 
      University of Edinburgh, Edinburgh, UK; Scottish Collaboration On Translational 
      Research into Renal Cell Cancer, UK.
FAU - Riddick, Antony C P
AU  - Riddick AC
AD  - Edinburgh Urological Cancer Group, Institute of Genetics and Molecular Medicine, 
      University of Edinburgh, Edinburgh, UK; Scottish Collaboration On Translational 
      Research into Renal Cell Cancer, UK.
FAU - Aitchison, Michael
AU  - Aitchison M
AD  - Scottish Collaboration On Translational Research into Renal Cell Cancer, UK; 
      Royal Free Hospital, London, UK.
FAU - Berney, Daniel
AU  - Berney D
AD  - Department of Molecular Oncology, Barts Cancer Institute, Queen Mary University 
      of London, London, UK.
FAU - Bex, Axel
AU  - Bex A
AD  - Netherlands Cancer Institute, Amsterdam, The Netherlands.
FAU - Overton, Ian M
AU  - Overton IM
AD  - MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, UK.
FAU - Harrison, David J
AU  - Harrison DJ
AD  - Edinburgh Urological Cancer Group, Institute of Genetics and Molecular Medicine, 
      University of Edinburgh, Edinburgh, UK; Scottish Collaboration On Translational 
      Research into Renal Cell Cancer, UK; School of Medicine, University of St 
      Andrews, St Andrews, Fife, UK.
FAU - Powles, Thomas
AU  - Powles T
AD  - Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary 
      University of London, London, UK. Electronic address: 
      thomas.powles@bartshealth.nhs.uk.
LA  - eng
SI  - ClinicalTrials.gov/NCT01024205
GR  - G1000419/MRC_/Medical Research Council/United Kingdom
GR  - MC_UU_12018/25/MRC_/Medical Research Council/United Kingdom
GR  - CRUK_/Cancer Research UK/United Kingdom
PT  - Clinical Trial, Phase II
PT  - Controlled Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140510
PL  - Switzerland
TA  - Eur Urol
JT  - European urology
JID - 7512719
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Indoles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrroles)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 4.2.1.1 (CA9 protein, human)
RN  - EC 4.2.1.1 (Carbonic Anhydrase IX)
RN  - EC 4.2.1.1 (Carbonic Anhydrases)
RN  - V99T50803M (Sunitinib)
SB  - IM
CIN - Eur Urol. 2014 Oct;66(4):e69-70. PMID: 24973996
MH  - Aged
MH  - Antigens, Neoplasm/genetics/*metabolism
MH  - Antineoplastic Agents/*therapeutic use
MH  - Biomarkers, Tumor/genetics/*metabolism
MH  - Carbonic Anhydrase IX
MH  - Carbonic Anhydrases/genetics/*metabolism
MH  - Carcinoma, Renal Cell/*drug therapy/enzymology/genetics/secondary
MH  - Cell Line, Tumor
MH  - Comparative Genomic Hybridization
MH  - Humans
MH  - Indoles/*therapeutic use
MH  - Kidney Neoplasms/*drug therapy/enzymology/genetics/pathology
MH  - Male
MH  - Middle Aged
MH  - *Molecular Targeted Therapy
MH  - Pilot Projects
MH  - Predictive Value of Tests
MH  - Protein Kinase Inhibitors/*therapeutic use
MH  - Proteomics/methods
MH  - Pyrroles/*therapeutic use
MH  - RNA Interference
MH  - Reproducibility of Results
MH  - Sunitinib
MH  - Time Factors
MH  - Tissue Array Analysis
MH  - Transfection
MH  - Treatment Outcome
MH  - Up-Regulation
MH  - Vascular Endothelial Growth Factor A/*antagonists & inhibitors/metabolism
PMC - PMC4410300
OTO - NOTNLM
OT  - Biomarker
OT  - CA9
OT  - Renal cancer
OT  - VEGF TKI
EDAT- 2014/05/14 06:00
MHDA- 2015/11/03 06:00
PMCR- 2014/11/01
CRDT- 2014/05/14 06:00
PHST- 2014/01/23 00:00 [received]
PHST- 2014/04/16 00:00 [accepted]
PHST- 2014/05/14 06:00 [entrez]
PHST- 2014/05/14 06:00 [pubmed]
PHST- 2015/11/03 06:00 [medline]
PHST- 2014/11/01 00:00 [pmc-release]
AID - S0302-2838(14)00374-1 [pii]
AID - 10.1016/j.eururo.2014.04.007 [doi]
PST - ppublish
SO  - Eur Urol. 2014 Nov;66(5):956-63. doi: 10.1016/j.eururo.2014.04.007. Epub 2014 May 
      10.