COX-2 inhibitor extends sunitinib activity in renal cell carcinoma

By Lucy Piper, Senior medwireNews Reporter

The effectiveness of sunitinib for the treatment of renal cell carcinoma (RCC) could be enhanced with the addition of a cyclooxygenase-2 (COX-2) inhibitor, study findings show.

The study researchers say that this is of great importance because resistance to sunitinib, a tyrosine kinase inhibitor (TKI), is common.

"While the beneficial effects of TKIs are significant… responses are almost exclusively partial and tumors develop tumor progression on therapy at a median of less than 1 year," they comment in the British Journal of Cancer.

The researchers studied the effects of sunitinib, which primarily targets vascular endothelial growth factor, and the COX-2 inhibitor celecoxib in mice carrying various human clear cell (cc)RCC xenografts, including tumor tissue directly obtained from a patient at the time of nephrectomy for ccRCC.

The researchers found initially that sunitinib treatment resulted in tumor hypoxia and COX-2 expression was increased in areas of hypoxic tumor cells, giving weight to their hypothesis that COX-2 inhibition may enhance sunitinib activity.

Indeed, the combination of sunitinib and celecoxib significantly prolonged progression compared with sunitinib treatment alone, whereas celecoxib treatment alone had little impact.

For example, in mice harboring A498 xenografts, the median time to progression was 34.5 days following sunitinib treatment and 20.0 days following sunitinib plus celecoxib treatment, whereas it was just 13 days in celecoxib-treated mice and 5 days in vehicle-treated mice.

Rupal Bhatt (Harvard Medical School, Boston, Massachusetts, USA) and colleagues note that the effect of the combination was dependent on timing. Switching to celecoxib therapy compared with continuous sunitinib therapy significantly shortened the time to progression in mice harboring 786-O xenografts (median 10 vs 12 days), as did delayed addition of celecoxib (median 10 days).

This suggests that "the activity of celecoxib depends on dynamic changes induced by sunitinib treatment," say Bhatt et al.

They note the potential benefits of identifying surrogate markers for COX-2 activity that could be monitored over the course of sunitinib therapy in patients with RCC so that a COX-2 inhibitor such as celecoxib could be administered at the time of COX-2 elevation, thus "sparing the cost and toxicity associated with upfront combination therapy."

The researchers say: "However, in the absence of such biomarkers, our data support the study of the initial combination of celecoxib and sunitinib in patients with advanced ccRCC."

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