Abstract
BackgroundRenal cell carcinoma (RCC) responds to agents that inhibit vascular endothelial growth factor (VEGF) pathway. Sorafenib, a multikinase inhibitor of VEGF receptor, is effective at producing tumor responses and delaying median progression free survival in patients with cytokine refractory RCC. However, resistance to therapy develops at a median of 5 months. In an effort to increase efficacy, we studied the effects of increased sorafenib dose and intermittent scheduling in a murine RCC xenograft model.MethodsMice bearing xenografts derived from the 786-O RCC cell line were treated with sorafenib according to multiple doses and schedules: 1) Conventional dose (CD) continuous therapy; 2) high dose (HD) intermittent therapy, 3) CD intermittent therapy and 4) HD continuous therapy. Tumor diameter was measured daily. Microvessel density was assessed after 3 days to determine the early effects of therapy, and tumor perfusion was assessed serially by arterial spin labeled (ASL) MRI at day 0, 3, 7 and 10.ResultsTumors that were treated with HD sorafenib exhibited slowed tumor growth as compared to CD using either schedule. HD intermittent therapy was superior to CD continous therapy, even though the total dose of sorafenib was essentially equivalent, and not significantly different than HD continuous therapy. The tumors exposed to HD sorafenib had lower microvessel density than the untreated or the CD groups. ASL MRI showed that tumor perfusion was reduced to a greater extent with the HD sorafenib at day 3 and at all time points thereafter relative to CD therapy. Further the intermittent schedule appeared to maintain RCC sensitivity to sorafenib as determined by changes in tumor perfusion.ConclusionsA modification of the sorafenib dosing schedule involving higher dose intermittent treatment appeared to improve its efficacy in this xenograft model relative to conventional dosing. MRI perfusion imaging and histologic analysis suggest that this benefit is related to enhanced and protracted antiangiogenic activity. Thus, better understanding of dosing and schedule issues may lead to improved therapeutic effectiveness of VEGF directed therapy in RCC and possibly other tumors.
Highlights
Renal cell carcinoma (RCC) responds to agents that inhibit vascular endothelial growth factor (VEGF) pathway
Sorafenib is a multityrosine kinase inhibitor whose targets include vascular endothelial growth factor receptor-2 (VEGFR2) and its activity is thought to be based on its inhibition of this target
High dose therapy is more effective in slowing tumor growth than low dose therapy We treated mice bearing 786-O tumor xenografts on the 4 described treatment regimens: 1) Conventional dose continuous, 2) high dose intermittent therapy, 3) conventional dose intermittent therapy, and 4) high dose continuous therapy
Summary
Renal cell carcinoma (RCC) responds to agents that inhibit vascular endothelial growth factor (VEGF) pathway. Placebo-controlled phase III trial sorafenib prolonged progression free survival (PFS) from 2.8 months (placebo group) to 5.5 months [1] Based on these and other data, sorafenib received FDA approval for treatment of patients with RCC in late 2005. This mechanism is relevant in kidney cancer as opposed to other cancer types (e.g., HCC) where the inhibition of the serine-threonine kinase Raf is likely at least as important as the inhibition of VEGFR-2 While these effects are highly significant, strategies to prolong the effects of sorafenib and other VEGFR TKI targeted agents are important as tumors typically develop resistance to therapy within 5-11 months. Tivozonib)[6] combination regimens, sequencing of agents and schedule alterations [7]
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