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 alpha(V)
beta(3) integrin activity with positron emission tomography (PET) and [(64)Cu]
DOTA-
cyclo-(Arg-Gly-Asp-dPhe-Lys) {[(64)Cu]
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 [(64)Cu]
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 [(64)Cu]
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 mm(2) in treated animals versus 122.50+/-17.68 mm(2) in controls; P=0.001). [(64)Cu]
DOTA-c(RGDfK) may provide a sensitive means of monitoring
tumor response to SFK inhibition in alpha(V)beta(3)-expressing
cancers early in the course of
therapy.