Noninvasive Imaging of αVβ3 Function as a Predictor of the Antimigratory and Antiproliferative Effects of Dasatinib

Abstract

Src family kinases (SFKs) are commonly deregulated in cancer cells. Among other functions, SFKs are critical for cellular migration and invasion. SFK inhibitors are being studied as targeted cancer drugs, but there are no biomarkers for noninvasive assessment of SFK inhibition. The aim of this study was to evaluate whether imaging of α_Vβ₃ integrin activity with positron emission tomography (PET) and [⁶⁴Cu]DOTA-cyclo-(Arg-Gly-Asp-dPhe-Lys) {[⁶⁴Cu]DOTA-c(RGDfK)} can be used for monitoring response to the SFK inhibitor dasatinib. Severe combined immunodeficient mice bearing U87MG xenografts were gavaged daily over 72 hours with 72 or 95 mg/kg of dasatinib or vehicle. Tumor uptake of [⁶⁴Cu]DOTA-c(RGDfK) was measured by small-animal PET. In parallel, fluorodeoxyglucose (FDG) scans were performed to assess tumor metabolism in response to dasatinib treatment. Dasatinib significantly (P < 0.0001) reduced [⁶⁴Cu]DOTA-c(RGDfK) uptake by up to 59% in U87MG xenografts [2.10 ± 0.14% injected dose/gram (ID/g) in the 95 mg/kg group and 3.12 ± 0.18% ID/g in the 72 mg/kg group, versus 5.08 ± 0.80% ID/g in controls]. In contrast, tumor FDG uptake showed no significant reduction with dasatinib therapy (8.13 ± 0.45% ID/g in treated versus 10.39 ± 1.04% ID/g in controls; P = 0.170). Histologically, tumors were viable at the time of the follow-up PET scan but showed inhibition of focal adhesion kinase. Continued dasatinib treatment resulted in a significant inhibition of tumor growth (tumor size on day 10 of therapy: 21.13 ± 2.60 mm² in treated animals versus 122.50 ± 17.68 mm² in controls; P = 0.001). [⁶⁴Cu]DOTA-c(RGDfK) may provide a sensitive means of monitoring tumor response to SFK inhibition in α_Vβ₃-expressing cancers early in the course of therapy. [Cancer Res 2009;69(7):3173–9]