Monitoring the vascular response and resistance to sunitinib in renal cell carcinoma in vivo with susceptibility contrast MRI

Anti-angiogenic therapy is efficacious in metastatic renal cell carcinoma (mRCC). However, the ability of anti-angiogenic drugs to delay tumor progression and extend survival is limited, due to either innate or acquired drug resistance. Furthermore, there are currently no validated biomarkers that predict which mRCC patients will benefit from anti-angiogenic therapy. Here we exploit susceptibility contrast magnetic resonance imaging (SC-MRI) using intravascular ultrasmall superparamagnetic iron oxide particles to quantify and evaluate tumor fractional blood volume (fBV) as a non-invasive imaging biomarker of response to the anti-angiogenic drug sunitinib. We also interrogate the vascular phenotype of RCC xenografts exhibiting acquired resistance to sunitinib. SC-MRI of 786-0 xenografts prior to and two weeks after daily treatment with 40mg/kg sunitinib revealed a 71% (p<0.01) reduction in fBV in the absence of any change in tumor volume. This response was associated with significantly lower microvessel density (p<0.01) and lower uptake of the perfusion marker Hoechst 33342 (p<0.05). The average pre-treatment tumor fBV was negatively correlated (R2=0.92, p<0.0001) with sunitinib-induced changes in tumor fBV across the cohort. SC-MRI also revealed suppressed fBV in tumors that acquired resistance to sunitinib. In conclusion, SC-MRI enabled monitoring of the anti-angiogenic response of 786-0 RCC xenografts to sunitinib, which revealed that pre-treatment tumor fBV was found to be a predictive biomarker of subsequent reduction in tumor blood volume in response to sunitinib, and acquired resistance to sunitinib was not associated with a parallel increase in tumor blood volume.

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