CCSG Pilot: Point-of-care phase-gradient microscope for non-destructive metabolic imaging on live tumor slices

Abstract: Patient-derived organotypic tumor slices have been explored as the state-of-art clinically relevant cancer models to study tumor biology and cancer therapeutics. Although conducting longitudinal metabolic measurements on the same tumor sample during a course of therapy is critical for understanding the role of metabolism in cancer therapeutics, there are surprisingly few techniques that provide a non-destructive measurement of the key metabolic parameters together on live tumor slices. Several metabolic tools, such as Seahorse Assay and metabolomics, provide standardized metabolic measurements but often require destructive sample preparation. Relying on the non-invasive nature of optical techniques, we aim to develop a novel phase-gradient fluorescence microscope to enable non-destructive metabolic imaging with wide field of view and high resolution on organotypic tumor samples for translational cancer research, thereby filling the critical gap. To maximize the ease and accessibility of our technique, we will develop the phase-gradient microscope with point-of-care and low-cost footprints. Specifically, we will establish a novel phase-gradient microscope to image several key metabolic parameters together on tumor slices in a non-destructive manner and develop a machine-learning algorithm to predict tumor radiotherapy (RT) sensitivity and guide RT selection/design using the key metabolic biomarkers that are relevant to RT. As there is a significant unmet clinical need for breast cancer (BC) radiosensitivity pre- evaluation, we will demonstrate our microscope to pre-evaluate BC RT responses within the decision-making window via longitudinal metabolic characterization of patient tumor slices under radiation stresses. Though we will demonstrate our microscope for BC tumor slices imaging for RT prediction in this proposal, our platform can be used on other tumor models such as in vitro cells and organoids for various types of therapeutic response study (such as chemo- or targeted-therapies) through the lens of tumor metabolism. Our innovative radiosensitivity prediction model will directly impact BC patients by providing a novel paradigm for patients’ radiosensitivity prediction and RT selection/design during the decision-making window. Our studies have significant translation potential because they will set the foundation for utilizing patient tumor samples for effective RT sensitivity pre-evaluation and selection/design. The Redox Metabolism Core will be used to conduct Seahorse Assay experiments in Specific Aim 1. The CCM Metabolism Core will be used in our SIRM studies in Specific Aims 1-2. The BPTP-SRF will be used to harvest BC tumor samples in Specific Aim 2. The Biostatistics & Bioinformatics SRF will be used for data analysis.