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Eur Urol. 2014 Nov;66(5):956-63. doi: 10.1016/j.eururo.2014.04.007. Epub 2014 May 10.

Carbonic anhydrase 9 expression increases with vascular endothelial growth factor-targeted therapy and is predictive of outcome in metastatic clear cell renal cancer.

Author information

1
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.
2
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.
3
Department of Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
4
MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, UK.
5
The Institute of Cancer Research, London, UK.
6
School of Medicine, University of St Andrews, St Andrews, Fife, UK.
7
Scottish Collaboration On Translational Research into Renal Cell Cancer, UK; Royal Free Hospital, London, UK.
8
Netherlands Cancer Institute, Amsterdam, The Netherlands.
9
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.
10
Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, London, UK. Electronic address: thomas.powles@bartshealth.nhs.uk.

Abstract

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-naïve (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-naïve 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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01024205.

KEYWORDS:

Biomarker; CA9; Renal cancer; VEGF TKI

PMID:
24821582
PMCID:
PMC4410300
DOI:
10.1016/j.eururo.2014.04.007
[Indexed for MEDLINE]
Free PMC Article

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