Studying heterogeneity in [18F] FDG accumulation at the individual cell level using Betabox technology to better understand PET scans of patient tumors

University Of California Los Angeles, Los Angeles CA

Investigators

Abstract

PROJECT SUMMARY [18F]FDG PET is a key imaging approach used regularly for the diagnosis, staging, and identification of recurrences of various cancer types including lung, colorectal, and esophageal cancers. Studies have also shown that decreases in tumor [18F]FDG accumulation can function as a biomarker of drug efficacy. [18F]FDG PET is well-studied at the level of bulk cell populations, but studies of [18F]FDG accumulation at the level of individual cells that could yield information on cell subpopulations are lacking. Studies of cancer cell genomes and transcriptomes at the level of individual cells demonstrate important heterogeneity and subpopulations in bulk cell populations. Similarly, the few available studies of [18F]FDG accumulation at the level of individual cells suggest potentially important heterogeneity but this remains largely unexplored. Identifying subpopulations of cells with differing levels of [18F]FDG accumulation could improve how we interpret pre-clinical and clinical [18F]FDG PET scans at baseline and following treatment by, for example, identifying which subpopulation is the main driver of [18F]FDG PET signal measured in bulk. We recently developed the BetaBox, a new technology platform for measuring PET radiotracer accumulation at the individual cell level. Our preliminary data using the BetaBox demonstrates heterogeneity in [18F]FDG accumulation in cancer cells as well as our ability to use the BetaBox to measure [18F]FDG accumulation at the level of individual cells. However, prior research by our group and others on [18F]FDG accumulation at the level of individual cells is limited to four cell lines and mostly involves untreated cells in culture. Additionally, the current BetaBox is limited in the number of cells that can be studied at any one time and has no mechanism for isolating and further studying potentially interesting cells. The goal of this proposal is to use the BetaBox to study [18F]FDG accumulation at the level of individual cells across model systems in culture and in vivo including cell lines, patient-derived sphere cultures, and patient-derived xenografts with and without drug treatment, and to use this information to identify subpopulations of cells that differ in their [18F]FDG accumulation for comparison across samples. An additional goal is to develop next generation BetaBox technology to enable hundreds of cells to be studied simultaneously and for interesting cells to be isolated for further functional characterization. We propose to accomplish this through the following three Specific Aims: (1) To develop the next generation BetaBox to increase throughput and enable isolation of individual cells for further analysis. (2) To characterize cell subpopulations based on [18F]FDG accumulation in individual cells across model systems in culture and in vivo. (3) To study based on [18F]FDG accumulation in individual cells how cell subpopulations change in response to targeted kinase inhibitors.