PROJECT SUMMARY – CORE B The U19 Molecular Profiling and Bioinformatics Core (Core B) will provide state-of-the-art genomics and bioinformatics technology and expertise to advance each of the projects in the City of Hope U19 program. In anticipation of delivering on the larger mission of the Glioblastoma Translational Network (GTN), Core B will provide CAP-certified, CLIA-approved exome and transcriptome sequencing that returns data for patient care decision-making. Core B bridges bench discovery of molecular determinants of glioblastoma vulnerability to the three novel agents in this U19 and the clinical setting, in which precision use of these treatments may have the highest likelihood of benefiting patients. Core B will achieve this by: A) Providing comprehensive CLIA-certified genomic profiling for patients enrolled on our U19 clinical trials, as well as genomic sequencing of preclinical models, and offering single cell/nuclei transcriptomic analyses of harvested cell infiltrates collected from the tumor bed following resection or dispersed tissue. These studies will provide granular insight into tumor heterogeneity, tumor sensitivity or resistance, and tumor evolution. B) Identifying signatures of vulnerability to the agents being evaluated. For Project 1, GBM exome and transcriptomic data will be analyzed to identify features that modify susceptibility to oncolytic herpes virus infection, the impact of alleles of genes that play a role in HSV replication, and deconvolution of patient tumors to depict the host cell infiltrate comprising the pretreatment microenvironment immune status of syngeneic models and glioma patients enrolled in the oncolytic virus/anti CD-47 clinical trial. For Project 2, exome and transcriptome data from tumors of patients enrolled in the clinical trial evaluating tasquinimod will be deconvoluted to discern populations of immune cell infiltrates to compare with post-treatment single cell transcriptomic analysis of resection cavity fluid collected from surgically placed catheters. Tumors from syngeneic glioma models receiving different treatments will analyzed by single nuclei transcriptomics for cell deconvolution. For Project 3, we will further develop a synergy signature indicative of GBM vulnerability to the combination of pevonedistat + etoposide, leading to a patient-enrichment strategy for future clinical trials. Preliminary data indicates that PTEN status (copy number, mutation, expression levels) serves as a determinant for likelihood of response to the neddylation inhibitor, pevonedistat, as well as the synergistic activity of etoposide (TOP2A inhibitor) with pevonedistat. C). Deliver state-of-the-art biomedical informatics and data analytics expertise and services. Core B will provide state-of-the-art bioinformatics methods, including machine learning techniques, to derive highest value from the preclinical and clinical data in each project. Core B will also foster data and information exchange and collaboration with individual Projects/Cores across the GTN. The long term goal of Core B is to participate in the design, development, and adoption of an adaptive, signature-guided umbrella clinical trial supporting all new treatments emerging from the GTN.