Abstract
1488
Objectives: Inhibitors of the protein kinase mTOR are currently being evaluated in multiple studies for treatment of a variety of malignancies. However, the effects of mTOR inhibitors are cytostatic and standard size criteria do not reliably identify responding tumors. Thus the aim of this study was to evaluate whether response to therapy could be assessed by PET imaging of tumor metabolism. Methods: Glucose metabolism, thymidine utilization and amino acid transport of the human glioma cell lines U87, LN18 and LN229 were assessed in-vitro by measuring uptake of [18F]FDG, [18F]FLT, and [3H]L-tyrosine before and after treatment with the mTOR inhibitor Rapamycin (0.1-10 ng/ml). To dissect the mechanisms for changes in tracer uptake, expression of glucose transporters, hexokinase and thymidine kinase (TK1) were assayed and glucose transport rates and hexokinase activity were measured. In-vivo tumor metabolic activity was monitored by small animal PET imaging of tumor bearing SCID mice. Results: Rapamycin at a concentration of 1 ng/ml significantly inhibited tumor growth in-vitro (p<0.01) and dramatically decreased FDG and FLT uptake within 24 hours. This was associated with inhibition of hexokinase activity (54 ± 4.5 mU to 29 ± 2.7 mU/mg protein p<0.05) and attenuated TK1 expression. In contrast, tyrosine uptake was not affected. Treatment of subcutaneous U-87 tumors with 3 mg/kg Rapamycin/day resulted in significant growth inhibition (p<0.01). PET studies showed a 24% ± 3 % decrease of tumor FDG-uptake and a 43 ± 4 % decrease in FLT uptake within 48 h after start of therapy. However, the reduction of tumor FDG-uptake is difficult to interpret, as Rapamycin caused hyperglycemia (fasting glucose 127± 7 mg/dl vs. 80± 7 mg/dl in controls, p< 0.01). Conclusions: Rapamycin induces a rapid reduction of hexokinase and thymidine kinase expression/activity indicating that FDG -and FLT-PET may be useful for monitoring mTOR inhibition in gliomas. However, in mice the utility of FDG-PET is limited by rapamycin induced hyperglycemia. Tyrosine uptake was not significantly affected by Rapamycin suggesting that PET with tyrosine or tyrosine analogs may be less suited for monitoring treatment with mTOR inhibitors.
- Society of Nuclear Medicine, Inc.