Pharmacologic and Genomic Imaging Core

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Summary: Glioblastoma represents a complex disease in which heterogeneity in both tumor composition and drug distribution needs to be considered for understanding treatment response. Genetic, epigenetic and developmental programs that differ between malignant cells influence the response to any drug candidates (DC). Additionally, pathophysiological barriers of the microenvironment and vasculature, such as the blood- brain barrier (BBB), produce heterogeneous distribution of DC, de facto exposing heterogeneous malignant cells and their microenvironment to variable drug concentrations. Assessing these variable parameters is paramount to precisely dissect the response of glioblastoma to any DC. Many targeted therapy trials have failed to incorporate such measurements, hampering our ability to interpret results. The Pharmacological and Genomic Imaging Core (PGIC) of the Harvard/Stanford U19 Program will provide state-of-art technical expertise and resources for characterizing drug concentration and glioblastoma response in patient tumor samples and in comprehensively characterized orthotopic mouse patient-derived xenografts (PDX) glioma models. PGIC brings together multiscale technologies from microscale analysis to macroscale organ in vivo imaging with micro- and macro-scale registration. PGIC provides an integrated platform to fuse detailed histopathology, drug distribution, metabolomics, and single-cell transcriptomics with registration to in vivo imaging when available. Specifically, PGIC will: (Aim1) perform spatially-resolved measurements of DC and metabolic pathways in brain tissue specimens sampled from both clinical trials and experimental models; (Aim 2) perform single-nucleus RNA-sequencing analysis of glioma and microenvironmental cells from frozen clinical samples and pre-clinical models of glioblastoma; (Aim 3) perform spatial analysis of dynamic therapeutic effects in glioblastoma patient samples and models using spatial transcriptomics and multiplex digital imaging. We have developed innovative and efficient clinical pipelines and multi-site clinical trials infrastructure to obtain samples for PGIC analysis and put in place systematic workflows in the hospital setting. Our analyses will be performed on frozen samples, facilitating the flow of acquired specimen across multiple sites in the Harvard/Stanford GTN. PGIC will provide consistent workflows, standardize the acquisition of samples and data, provide expert personnel, facilitate the sharing of knowledge within the program, and maintain the sophisticated equipment necessary to generate data for all Projects which is critical for data reproducibility and data sharing across projects. PGIC will be led Dr. Mario Suvà, Dr Nathalie Agar and Dr. Keith Ligon who will contribute their expertise in single-cell technologies, mass spectrometry imaging and neuropathology.