Abstract 1372: Acquired resistance to sunitinib is not associated with functional re-vascularization in 786-O renal cell carcinoma xenografts

Abstract

Abstract Anti-angiogenic therapy has shown considerable efficacy in metastatic renal cell carcinoma (mRCC). However, the ability of drugs such as sunitinib to delay tumour progression and extend survival is limited, due to both innate and evasive drug resistance, thought to arise through alternative, VEGF-independent mechanisms of tumour re-vascularization. Furthermore, there are no validated biomarkers that predict which mRCC patients will benefit from anti-angiogenic therapy. In investigating the response of 786-O RCC xenografts to sunitinib, a model of acquired resistance has been established with chronic treatment. The aims were to evaluate fractional blood volume (fBV) derived from susceptibility contrast MRI with ultrasmall superparamagnetic iron oxide (USPIO) particles as a non-invasive imaging biomarker of response, and interrogate the vascular phenotype of 786-O xenografts exhibiting acquired resistance to sunitinib. Mice bearing established xenografts underwent MRI prior to and two weeks after daily treatment with 40mg/kg sunitinib. USPIO particle uptake was reduced in all treated tumours, resulting in a highly significant reduction in fBV in the absence of any change in tumour volume (Table 1). This response was associated with a significant reduction in the uptake of the perfusion marker Hoechst 33342. The average pre-treatment tumour fBV was significantly positively correlated (R2 = 0.92, p<0.0001) with sunitinib-induced changes in tumour fBV across the cohort. Additional tumour-bearing mice exhibiting acquired resistance to sunitinib (designated 786-O-R) were imaged when their tumours reached at least 4x their volume at commencement of treatment. Resistant 786-O- R xenografts revealed a suppressed fBV whilst still being treated with sunitinib. Pre-treatment tumour fBV is a predictive biomarker of subsequent response to sunitinib in RCC. Acquired resistance to sunitinib is not associated with functional re-vascularization in 786-O RCC xenografts. Table 1 786-O (n = 9)786-O-R (n = 4)PrePostPostTumour volume (mm3)153 ± 17148 ± 24471 ± 63fBV (%)8.3 ± 22.4 ± 0.5**2.1 ± 0.5fBV / Tumour volume6.8 ± 22.5 ± 1*0.5 ± 0.1Hoechst 33342 uptake (%)13.5 ± 56.4 ± 1*n.a. Citation Format: Simon P. Robinson. Acquired resistance to sunitinib is not associated with functional re-vascularization in 786-O renal cell carcinoma xenografts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1372. doi:10.1158/1538-7445.AM2015-1372