Metabolic Phenotyping with PET to Monitor /Predict Respo

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Imaging of tumor metabolism by positron emission tomography (PET) represents an attractive approach for assessing the efficacy of kinase inhibitors in cancer patients. (1) Many signaling pathways altered in malignant tumors play a central role in the regulation of cellular metabolism (e.g. MEK/MAPK, PI3K, and mTOR). (2) Increased metabolic activity is a common feature of most malignant tumors in patients. (3) There are a number of clinically established molecular imaging probes targeting various aspects of tumor metabolism. (4) By using these probes changes in tumor metabolism can be measured clinically with high sensitivity. In contrast to gastrointestinal stromal tumor and chronic myeloid leukemia, only a small subset of patients with common solid tumors appears to benefit from targeted kinase inhibitor treatment. The molecular determinants of treatment response are currently poorly understood. Therefore, the early recognition of tumor responses by molecular imaging would offer obvious advantages to the treating clinician and to the patient, as well as to the design of clinical trials studying the effectiveness of kinase inhibitors in cancer patients. We propose a 3-aim project whereby metabolic phenotyping with PET is introduced for monitoring of cancer patients undergoing targeted kinase inhibitor treatment. Tumor metabolism will be assessed by clinically established molecular imaging probes for glucose ([18F]Flurodeoxyglucose), nucleoside ([18F]Fluorothymidine) and amino acid ([18F]Fluorodopa) utilization. Aim 1 includes both a collaborative effort with the UCLA lung cancer SPORE to monitor changes in tumor metabolism in response to Gefitinib and a collaborative effort to assess the effects of experimental mTor and EGFR kinase inhibitors on glioblastomas. In aim 2 we will elucidate, in cell cultures, the mechanisms responsible for kinase inhibitor induced changes in metabolism. In Aim 3 we use xenograft models to determine - in this preclinical setting - how to optimize the ability of PET analysis of metabolic effects in response to targeted kinase inhibitors to distinguish therapy-specific responders and nonresponders. In summary, we will expand the currently used molecular imaging approaches and will introduce "metabolic phenotyping" with PET as a technique to monitor treatment responses to targeted kinase inhibition in cancer patients.