There is currently no methodology to measure the highly interdependent levels of available molecular drug targets, amount of drug binding and the resulting cellular response in a single dynamic, living system. Furthermore, monitoring targeted drug interactions and the resultant intracellular signaling cascades is difficult, and to-date no methodology exists for simultaneous measurement in live cells and tissues. To overcome these limitations, we have developed a dynamic, fluorescence-based, three-compartment model termed intracellular paired-agent imaging (iPAI). iPAI can bridge this technological gap, providing the ability to visualize and quantify the interaction between drugs, molecular targets, and downstream signal cascades using fluorescently-labeled small molecule imaging agents in live cells and tissues. In proof of concept studies, we have developed targeted and untargeted, spectrally distinct, fluorescently labeled versions of the kinase inhibitor Erlotinib. Our overarching goal is to develop a rapid assay to predict personalized therapeutic outcomes using iPAI in patient derived tissues where we will quantify an individual’s response to targeted therapy by measuring: 1) available proteins for drug binding (drug-target availability, DTA), 2) proteins bound by therapeutic drug (drug-target occupancy, DTO) and 3) resultant downstream signaling events indicative of therapeutic response and cellular death (drug phosphorylation response, DPR). Development of our novel iPAI platform will establish the critical drug target interactions in patient derived tissues that results in therapeutic efficacy and minimal toxicity providing truly personalized cancer therapy. Overall, we anticipate that iPAI will usher in the next generation of individualized therapy improving both therapy selection and understanding of resistance.

Quantitative imaging of protein phosphorylation and therapeutic efficacy in cancer

2019 Spring National Meeting

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