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 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.
Subject(s)
Integrin alphaVbeta3/physiology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Thiazoles/pharmacology , Animals , Cell Growth Processes/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Copper Radioisotopes , Dasatinib , Focal Adhesions/drug effects , Glioblastoma/blood supply , Glioblastoma/diagnostic imaging , Glioblastoma/metabolism , Glioblastoma/pathology , Heterocyclic Compounds, 1-Ring/pharmacokinetics , Humans , Integrin alphaVbeta3/analysis , Male , Mice , Mice, SCID , Oligopeptides/pharmacokinetics , Organometallic Compounds/pharmacokinetics , Positron-Emission Tomography/methods , src-Family Kinases/antagonists & inhibitorsABSTRACT
UNLABELLED: Successful treatment of pheochromocytoma requires accurate diagnosis and localization of tumors. Herein, we investigated the accuracy of PET using 3,4-dihydroxy-6-(18)F-fluoro-phenylalanine ((18)F-FDOPA), an amino acid transporter substrate, as an independent marker for detection of benign and malignant pheochromocytomas. METHODS: The study comprised 25 consecutive patients (9 men, 16 women) whose median age was 51 y (range, 25-68 y), with known or suspected pheochromocytoma. Eleven patients underwent standardized (18)F-FDOPA PET and 14 patients underwent (18)F-FDOPA PET/CT studies, with a median of 511 MBq of (18)F-FDOPA (range, 206-625 MBq). Two readers, unaware of the reports of other imaging studies and clinical data, analyzed all scans visually and quantitatively (maximum standardized uptake value [SUVmax] and maximum transverse diameter). Histology and long-term clinical follow-up served as the gold standard. Correlation between SUVmax of tumors and biochemical markers was evaluated. SUVmax of the benign and malignant tumors was compared. RESULTS: Seventeen patients underwent surgery. Histology confirmed pheochromocytoma or paraganglioma in 11 cases (8 adrenal, including 2 malignant tumors, and 3 extraadrenal, including 1 malignant tumor). The diagnosis of pheochromocytoma was established by follow-up in 2 additional patients (1 adrenal and 1 unknown location) and ruled out in 6 patients. Visual analysis detected and localized pheochromocytoma in 11 of 13 patients without false-positive results (sensitivity, 84.6%; specificity, 100%; accuracy, 92%). These lesions had an SUVmax of 2.3-34.9 (median, 8.3). Evaluation of the false-negative cases revealed a 13 x 5 mm lesion with an SUVmax of 1.96 in 1 case; no lesion was localized in the second case using multiple additional modalities. Spearman nonparametric analysis did not show statistically significant correlation between SUVmax of the tumors and biochemical markers. The Mann-Whitney nonparametric test did not demonstrate a statistically significant difference between the SUVmax of (18)F-FDOPA in malignant and benign tumors. CONCLUSION: (18)F-FDOPA PET and PET/CT are highly sensitive and specific tools that can provide additional independent information for diagnosis and localization of benign and malignant pheochromocytomas.
