Abstract
Cox-2 inhibition delays resistance to sunitinib in RCC xenograft models Background: Renal cell carcinoma (RCC) has been found to be responsive to agents that inhibit the vascular endothelial growth factor receptor (VEGFR). Sunitinib, a tyrosine kinase inhibitor of VEGFR, is effective at producing tumor responses; however, resistance to therapy develops at a median of 11 months. Murine xenograft models of acquired sunitinib resistance were generated and transcriptional analyses of resistant tumors showed arginase, a known cox-2-induced protein, to be increased at the time of resistance. Thus, we assessed the effect of the cox-2 inhibitor celecoxib on acquired resistance to sunitinib in these models. Methods: Mice bearing xenografts derived from two RCC cell lines that showed resistance after stabilization on sunitinib, 786-O and A498, were treated when tumors reached 12mm with celecoxib, sunitinib (25mg/kg and 53.6 mg/kg, respectively daily by gavage), the combination or PBS control and growth curves were generated. Tumors were also followed by arterial spin labeled (ASL) MRI to measure changes in tumor perfusion. Results: Mice treated with the combination of sunitinib and celecoxib had significantly longer periods of tumor stabilization compared to those treated with either agent alone or PBS controls (Table). There was a 38% and 50% increase in the time of tumor stabilization with the addition of celecoxib to sunitinib in 786-O and A498 cells, respectively. Additionally, perfusion imaging showed that the combination of sunitinib and celecoxib suppressed tumor perfusion longer than either agent alone or PBS controls. Conclusions: Cox-2 inhibition is a potential means to delay resistance to VEGFR inhibition in RCC. Further exploration, including potential clinical studies of this combination in patients with metastatic RCC is warranted.$$table_{A96D4818-3AE1-4105-8B0C-8E296506CFC6}$$ Table: Length of tumor stabilization with therapy as defined as days for the tumor to grow by 2mm from pretreatment size. *=p<0.01
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 153.
Footnotes
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO
- American Association for Cancer Research