piperidines and alovudine

APO866 is a new anti-tumor compound inhibiting nicotinamide phosphoribosyltransferase (NAMPT). APO866 has an anti-tumor effect in several pre-clinical tumor models and is currently in several clinical phase II studies. 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) is a tracer used to assess cell proliferation in vivo. The aim of this study was non-invasively to study effect of APO866 treatment on [18F]FLT and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake.. In vivo uptake of [18F]FLT and [18F]FDG in human ovary cancer xenografts in mice (A2780) was studied at various time points after APO866 treatment. Baseline [18F]FLT or [18F]FDG scans were made before treatment and repeated after 24 hours, 48 hours and 7 days. Tumor volume was followed with computed tomography (CT). Tracer uptake was quantified using small animal PET/CT. One hour after iv injection of tracer, static PET scans were performed. Imaging results were compared with Ki67 immunohistochemistry.. Tumors treated with APO866 had volumes that were 114% (24 h), 128% (48 h) and 130% (Day 7) relative to baseline volumes at Day 0. In the control group tumor volumes were 118% (24 h), 145% (48 h) and 339% (Day 7) relative to baseline volumes Day 0. Tumor volume between the treatment and control group was significantly different at Day 7 (P = 0.001). Compared to baseline, [18F]FLT SUVmax was significantly different at 24 h (P<0.001), 48 h (P<0.001) and Day 7 (P<0.001) in the APO866 group. Compared to baseline, [18F]FDG SUVmax was significantly different at Day 7 (P = 0.005) in the APO866 group.. APO866 treatment caused a significant decrease in [18F]FLT uptake 24 and 48 hours after treatment initiation. The early reductions in tumor cell proliferation preceded decrease in tumor volume. The results show the possibility to use [18F]FLT and [18F]FDG to image treatment effect early following treatment with APO866 in future clinical studies.

Topics: Acrylamides; Animals; Antineoplastic Agents; Biological Transport; Cell Proliferation; Clinical Trials, Phase II as Topic; Dideoxynucleosides; Drug Monitoring; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Gene Expression; Humans; Ki-67 Antigen; Mice; Mice, Nude; Nicotinamide Phosphoribosyltransferase; Ovarian Neoplasms; Piperidines; Positron-Emission Tomography; Radiography; Radiopharmaceuticals; Tumor Burden; Xenograft Model Antitumor Assays

The ability of PET to image functional changes in tumors is increasingly being used to evaluate response and predict clinical benefit to conventional and novel cancer therapies. Although the use of (18)F-FDG PET is well established, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET has potential advantages as a more specific marker of cellular proliferation. c-MET signaling is frequently dysregulated in cancer and is therefore an attractive therapeutic target. Crizotinib (PF-2341066) is a novel adenosine triphosphate-competitive c-MET kinase inhibitor with antitumor activity in a range of tumor models. The aim of this study was to investigate the utility of PET of glucose metabolism and cell proliferation to monitor tumor response to crizotinib in 2 cell lines with aberrant c-MET signaling.. Mice bearing GTL-16 or U87MG xenografts were evaluated for changes in tumor volume and (18)F-FDG and (18)F-FLT uptake after daily oral treatment with up to 50 mg/kg crizotinib. GTL-16 and U87MG cells were treated with crizotinib in vitro and analyzed for (3)H-2-deoxyglucose uptake and expression of activated MET, AKT, and ERK by immunoblotting.. Treatment of c-MET-amplified GTL-16 xenografts with 50 mg/kg crizotinib caused tumor regression that was associated with a slow reduction in (18)F-FDG uptake (P < 0.05, day 13) and reduced expression of the glucose transporter 1, GLUT-1. Although baseline (18)F-FDG uptake into U87MG tumors was substantially higher than in GTL-16 tumors, (18)F-FDG uptake into U87MG tumors remained unchanged on treatment at 50 mg/kg crizotinib, despite tumor growth inhibition of 93% on day 8 of treatment. These findings were confirmed in vitro, where treatment of U87MG cells with 1 μM crizotinib had no demonstrable effect on glucose uptake. Furthermore, these cells demonstrated constitutive, crizotinib-independent phosphoinositide 3-kinase pathway signaling as demonstrated by phosphorylated AKT and ribosomal protein S6. Both U87MG and GTL-16 tumors showed high baseline uptake of (18)F-FLT, which was reduced by 50% and 53% on days 4 and 8 of treatment, respectively.. While the results provide a strong rationale to investigate the use of (18)F-FLT PET as a clinical biomarker for monitoring tumor response to c-MET inhibition, (18)F-FDG PET may be a less robust marker.

Topics: Animals; Biomarkers; Cell Line, Tumor; Cell Proliferation; Crizotinib; Dideoxynucleosides; Disease Models, Animal; Fluorodeoxyglucose F18; Glucose; Glucose Transporter Type 1; Humans; Mice; Mice, Inbred BALB C; Mice, SCID; Neoplasm Transplantation; Piperidines; Positron-Emission Tomography; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Signal Transduction