This Article Full Text Full Text (PDF) All Versions of this Article: 0008-5472.CAN-08-3390v1 69/7/3173    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Dumont, R. A. Articles by Weber, W. A. Search for Related Content PubMed PubMed Citation Articles by Dumont, R. A. Articles by Weber, W. A.

Noninvasive Imaging of _Vβ₃ Function as a Predictor of the Antimigratory and Antiproliferative Effects of Dasatinib

Departments of ¹ Molecular and Medical Pharmacology and ² Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; ³ Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria; ⁴ Division of Radiopharmacy, University Hospital of Tübingen, Tübingen, Germany; and ⁵ Department of Nuclear Medicine, University of Freiburg, Freiburg, Germany

Requests for reprints: Rebecca A. Dumont, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California at Los Angeles, 26-059 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095-6948. Phone: 310-206-7008; Fax: 310-267-2538; E-mail: rdumont{at}ucla.edu.

Key Words: RGD peptide • _Vβ₃ • PET imaging • dasatinib

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 _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 _Vβ₃-expressing cancers early in the course of therapy. [Cancer Res 2009;69(7):3173–9]