The objectives of this project for positron emission tomograpy (PET) imaging of gliomas are twofold. The first is to investigate biosynthesis of lipids for membrane production and DNA synthesis for cellular proliferation. The PET tracers for this will be [1-11C]acetate (specific aim [SA] 1) and 3'deoxy-3'-fluorothymidine (FLT) (SA2), respectively. The second goal is to study hypoxia as a mechanism of treatment resistance and the extent to which it determines the unfavorable outcome of radio- and chemotherapy in these tumors. The PET tracer for this is [18F]-fluoromisonidazole (FMISO) (SA3). These objectives are a significant redirection of the emphasis of the project which heretofore explored metabolic imaging with [1- 11C]glucose and [18F]-fluorodeoxyglucose. These tracers are clinically useful for assessing tumor grade but are of limited value for estimating extent of disease and assessing response to therapy. PET scans will be performed at several pivotal time points in the patients' clinical courses: before surgery for diagnosis, before and after radiotherapy, and at the point when MRI imaging indicates recurrence of disease or radionecrosis. The PET results will be correlated chiefly with survival and pathological diagnosis and grade as well as proliferation indices and time to progression. Patients with MRI non-enhancing apparent low grade gliomas will also be imaged with PET with all three tracers since 30-40% of these prove to be malignant pathologically and development of an imaging approach to detect these anaplastic tumors early is clinically very important. PET images will be co-registered with MRI images to compare extent of disease estimated by each approach. For SA1 tissue specimens and rat and human glioma cell lines will be studied to measure: (a) uptake of [1-11C]acetate relative to [3H]thymidine, (b) the fraction of acetate incorporated into lipids, (c) monocarboxylic acid transporters. For SA2 correlative studies will include thymidine kinase activity, Ki-67 levels, and flow cytometry for S phase, while for SA3 will include immunocytochemistry for expression of vascular endothelial growth factor, hypoxia inducible factor 1alpha, Ki-67 and p53 espression.
The specific aims are directed at a better understanding of important pathophysiological processes that contribute to poor therapy results that have not improved over the past 20 years. In the future the results of these studies will be incorporated into the design of treatment protocols. This work will expand our knowledge of imaging biology and clarify better the clinical value of PET in neuro-oncology.
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