Abstract
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Objectives Studies have shown that the radionucleoside [18F]fluorothymidine enables non-invasive imaging of tumor proliferation with PET. Our aim is to establish FLT as superior surrogate marker for very early prediction of response to targeted drugs therapy in malignant lymphoma.
Methods Thymidine uptake in SCID mice bearing SUDHL-1 or Karpas299 lymphoma xenotransplants was assessed prior to and early in the course of therapy with Hsp90 inhibitor NVP-AUY922, mTOR inhibitor RAD001 or PI3K inhibitor BGT266 using a modern micro PET-CT scanner. Tumor-to-background ratios (TBR) of the FLT-uptake were compared to those of corresponding FDG-PET scans. PET findings were correlated with histopathology and in-vitro data including cellular tracer uptake, cell cycle related protein expression, cell cycle distribution and viability assessment.
Results SUDHL-1 was sensitive to all 3 inhibitors and showed cell cycle arrest in G1. Karpas299 was partially resistance to AUY922 and BGT266. Tumor volume in animals bearing SUDHL-1 lymphomas showed modest increase by 0.25 treated with AUY922 within the first week as compared to a 4-fold increase in control mice. A significant reduction of FLT-uptake was observed (median TBR 0.42; p=0.008) compared to baseline as early as 5d after therapy. Immunostaining showed a decrease of Ki67 labeled nuclei and an increase in caspase 3 stained cells. In contrast, TBR of FDG-uptake did not show significant reduction at early time points (0.99; p=0.73). In Karpas299 xenotransplants, a reduced therapeutic effect was seen after administration of AUY299 and BGT266 resulting in an increase of median FLT-TBR (1.54; p=0.62 and 1.47; p=0.87) on d+2. In contrast, mice receiving RAD001 indicated a slight decrease of TBR by 0.16 (p=0.003), immunostaining revealed reduction of Ki67 but no change of apoptosis.
Conclusions FLT- but not FDG-PET is able to predict response to treatment with specific inhibitors very early in the course of treatment and enabled prediction of resistance to therapy