The overall goals of this research are to improve our understanding of glucose metabolism in malignant gliomas and selected somatic malignancies to address the following areas of uncertainty. [F-18]-FDG, with PET is widely used to visualize tumors but with an incomplete understanding of the underlying biology. The relationship between FDG uptake and actual glucose utilization rate by tumors has not heretofore been clarified. PET imaging with FDG provides insights only into the earliest steps of glucose metabolism, viz., transport and phosphorylation, but not into deeper glucose metabolic routes. Imaging science has not fleshed out thoroughly how metabolic images can be used to gauge in the early post-treatment period whether tumor responses to radiotherapy or chemotherapy have occurred. High dose radiotherapy of brain tumors directed to regions of highest malignancy determined by metabolic imaging is now possible with state-of-the-art PET scans and computerized treatment planning methods so that it is timely for such clinical trials to commence Our hypotheses are: (1) Hexokinase (HK) in tumors differs from that in normal tissue due to a shift in isozymes from type I to type II and/or a shift in the intracellular location of HKII in malignant gliomas may result from deletions of chromosome 10 which carries the gene for HKI. The changes in HK result in an increase in the LC of FDG, the proportionality factor that relates the uptake of FDG in tissues to that of glucose. (2) An elevated lumped constant in somatic tumors correlates with degree of malignancy. (3) Based on preliminary evidence an increase in the measured glucose metabolic rate (MRGlc) determined by PET of 1-[C-11]-glucose correlates with a favorable response to therapy in malignant gliomas. (4) Such an increase is due to a shift of glucose metabolism from glycolysis (lactate production) to oxidative metabolism (via the tricarboxylic acid cycle). (5) Radiotherapy boost to 7940 cGy in gliomas to the region showing increased FDG uptake will increase survival time and prevent local recurrences. These hypotheses combine basic biochemical and molecular biological approaches to validate PET imaging results from 1-[C-11]-glucose and FDG studies. Hypotheses 3 and 5 are clinical. Hypotheses 5 is based on current thinking that FDG images define viable malignant tissue. Completion of this project will expand our knowledge of imaging biology and clarify better the utility of PET with FDG in oncology.
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