Levels of carbonic anhydrase 9 (CA9) increase with the use of vascular endothelial growth factor (VEGF)-targeted therapy for metastatic clear-cell renal cancer (mccRCC), and high expression of this protein is associated with increased survival, show study results reported in European Urology.
The researchers found “consistent dynamic changes to CA9 at chromosomal and protein levels” and suggest the results may have relevance for mccRCC patients with tumours refractory to sunitinib.
“CA9 modulation to overcome anti-VEGF therapy resistance may be a potential therapeutic area of investigation in the future”, write Thomas Powles (Queen Mary University of London, UK) and co-workers.
The findings could also help address the current, few validated molecular methods of improving prognosis or predicting the response of mccRCC patients to targeted therapies, they add.
The team evaluated the presence of 55 proteins known to be relevant in RCC pathogenesis or sunitinib response in the tumour tissues of 22 sunitinib-naïve and 23 sunitinib-treated mccRCC patients.
Overall, 30 of the 55 proteins were differentially expressed in treated and untreated patients, with four displaying particularly increased intra-tumour variance after sunitinib: CA9, B-cell CLL/lymphoma 2, mutL homolog 1, and mechanistic target of rapamycin.
After further evaluation of these proteins in paired treated and untreated tumour samples from a separate validation cohort (n=86), only CA9 was significantly increased in the treated tissues. Indeed, a high expression of CA9 was associated with improved overall survival, reducing the risk of death from mccRCC by a significant 74%, reports the research team.
Multivariate analysis adjusted for potentially confounding prognostic factors revealed that a low Fuhrman grade and high CA9 expression in nephrectomy tissue samples were associated with significantly improved overall survival (hazard ratios=0.51 and 0.48, respectively).
Powles and colleagues also conducted a functional analysis of CA9 in theCAKI-2 and RCC11 renal cancer cell lines and found that CA9 silencing through RNA interference blocked the antiproliferative effects of sunitinib.
“These results support the findings from the clinical tissue , where low levels of CA9 were associated with poor outcome from sunitinib therapy”, the researchers write.
Powles et al continue: “The work presented here shows that not only does targeted therapy increase the expression of CA9, but these changing levels are also prognostic.” This raises the possibility of a predictive biomarker in this setting.
“A randomised trial comparing continued therapy with a change in therapy in those patients who failed to gain a rise in CA9 level with therapy would test this biomarker prospectively”, they conclude.
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