Abstract 3238: Imaging sunitinib-induced vascular changes by DCE-MRI to schedule chemotherapy in renal cell carcinoma

The treatment of metastatic renal cell carcinoma (RCC) remains a challenge. Due to the high vascularity of kidney tumors, RCC are ideal candidates for anti-angiogenic therapy. The drug sunitinib (SU11248), a receptor tyrosine kinase (RTK) inhibitor, has demonstrated anti-tumor and anti-angiogenic activities in pre-clinical models. Sunitinib targets both tumor cells and tumor vasculature by inhibiting VEGF and PDGF receptor signaling. Sunitinib was approved by the FDA for RCC treatment in 2006 and clinical trials have reported dramatic responses observed in metastatic sites of disease but its efficacy was limited by adverse events due to toxicity to normal tissues, including cardiotoxicity. The vasculature of RCC tumors consists of abnormal enlarged and leaky vessels causing impaired blood supply that compromises the delivery of chemotherapy drugs to tumor cells. Using an orthotopic KCI-18 model of human RCC xenografts in nude mice, we have recently demonstrated that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was reliable to monitor vascular changes induced by various doses of sunitinib in kidney tumors and in normal kidney tissues. DCE-MRI showed that a daily sunitinib dose of 20mg/kg/day (SU20) mildly affected normal vessels but caused better tumor perfusion of the contrast agent and decreased vascular permeability, in agreement with histological observations of thinning and regularization of tumor vessels. This dose was selected for combination therapy with gemcitabine. Dose titration studies of gemcitabine in KCI-18 kidney tumor-bearing mice showed that doses of 10, 20 and 40 mg/kg given twice a week for two weeks were tolerated by the mice, whereas higher doses were toxic. Based on DCE-MRI findings, mice bearing established KCI-18 kidney tumors were pre-treated on day 10, for 3 days with SU20, and then gemcitabine was given twice a week for 2 weeks with continued daily administration of SU20 up to day 28. We found that gemcitabine at a dose of 20 mg/kg given in combination with SU20 was not toxic and resulted in almost complete tumor growth inhibition, which was much greater than that observed with SU20 or gemcitabine alone. These data were histologically confirmed in tumor sections, by observation of small residual tumor nodules consisting mostly of dying tumor cells and surrounded by normal kidney tissue. In survival studies, the dose and schedule of SU20 and 20 mg/kg gemcitabine, described above, caused a significant increase in