FLT PET imaging for evaluating molecular therapeutics

DESCRIPTION (provided by applicant): Novel therapeutics are being developed that selectively inhibit signal transduction pathways responsible for driving tumor proliferation. Because only a subset of tumors are likely to respond to a given molecularly targeted agent, it would be ideal to develop biochemical or genetic assays that can predict for the likelihood of response prior to selecting an appropriate therapy. Unfortunately, most of the targeted signal transduction pathways are complex, and identifying appropriate genetic or biochemical predictors of sensitivity has been difficult. Moreover, because many of these agents are primarily cytostatic and may not cause tumor regression, assessing tumor response by anatomic imaging may not be appropriate. As an alternative, we propose that functional imaging could be used to differentiate between responding and non-responding tumors within days of starting therapy. Many novel therapeutics inhibit tumor proliferation as a common mechanism of action, and we propose that proliferation-specific PET ligands would be superior for evaluating novel cytostatic agents as compared with metabolism-specific ligands such as fluorodeoxyglucose (FDG). In preliminary studies, we show that [3H]-FLT accumulation within cells decreases by 72% 24 hours after treatment of U87 glioma cells with the epidermal growth factor receptor kinase inhibitor OSI-774, while [3H]- FDG uptake was suppressed by only 25%. Cellular accumulation of FLT can be affected by nucleoside transporter and kinase activities, and both of these activities are suppressed in GI. We hypothesize that suppression of FLT accumulation is causally related to the G1 arrest induced by OSI-774 and that FLT PET might be useful for monitoring the efficacy of any cytostatic agent that arrests cell cycle progression. In AIM 1, we will follow-up our initial observations and determine whether FLT or FDG PET can be used to differentiate between tumors that are sensitive or resistant to OSl-774 therapy in both tissue culture and animal models. Then in AIM 2, the relationship between cell cycle arrest and FLT uptake will be explored in tumor cell lines treated with a variety of novel cytostatic therapeutic agents. Moreover, defects in nucleoside transport or nucleoside kinase activities will be modeled to provide an understanding of how accurately changes in FLT uptake can predict for sensitivity to cytostatic agents in tumors that lack pathways involved in FLT processing. Taken together, these studies may provide the proof-of-principle that FLT PET could be used as a robust surrogate assay to predict for efficacy of novel cytostatic agents, and that a functional response defined by FLT PET could be used as a criteria for continuing a specific therapy in individual patients.