Current evaluation of GBM response to therapy involves assessment of contrast enhanced MRI. However, this imaging modality does not adequately address the extent of infiltration of glioma cells into surrounding normal brain. In addition, low grade gliomas generally do not demonstrate contrast enhancement. [18F]-FACBC is a non-metabolized amino acid that depends on the L-type amino acid transporter (LAT1) for entry across the blood-brain and blood-tumor barriers. The PI3K/AKT/mTOR cascade, activated in the majority of GBMs and a major focus of translational glioma research, regulates LAT1 activity. We hypothesize that [18F]-FACBC-PET imaging will identify areas of high and low PI3K/AKT/mTOR signaling, and that this will be a non-invasive assay for inhibition of PI3K during therapy for high grade gliomas.
We first aim to identify molecular determinants of [18F]FACBC uptake in patients with gliomas. Such molecular profiling of tumor tissue may allow identification of a subset of tumors sensitive to a particular therapy. The availability of a non-invasive imaging technique that could guide therapy would represent a major advance in glioma translational research. To correlate imaging with molecular abnormalities, we will analyze tissue from tumor biopsies targeting regions of high and low tracer uptake.
We next aim to determine the effects of PI3K/AKT/mTOR pathway inhibition on [18F]FACBC PET imaging. A subset of patients will receive a PI3K/AKT/mTOR inhibitor before a planned tumor resection and undergo FACBC-PET imaging at baseline (pre-treatment) and again immediately before surgery (i.e., during therapy). We will assess changes in FACBC uptake during treatment in comparison with the molecular analyses of corresponding tissue samples. If FACBC-PET imaging changes correspond with inhibition of PI3K/AKT/mTOR, this will demonstrate that FACBC-PET can serve as a surrogate marker of pathway inhibition. If effective, FACBC-PET can serve as important clinical tool in both the assessment and treatment of brain tumors. Our proposal aims to generate a bridge between tissue analysis and PET imaging.
Finally, we will determine the utility of early FACBC-PET as a predictor of clinical outcome. Patients will undergo FACBC-PET imaging of the brain both at baseline and after 2 weeks of treatment with a PI3K/AKT/mTOR inhibitor. We hypothesize that a reduction in FACBC uptake at this “early” time point will predict radiographic response as measured by MRI at a later time, and that increased or unchanged uptake will predict tumor progression. Such a finding would be highly significant because it would allow discontinuation of an experimental drug after only a few weeks of therapy, sparing patients prolonged therapy with an ineffective and potentially toxic regimen.