Cooperative Agreement U01CA294552

PEDIATRIC SOLID TUMOR MICROENVIRONMENT ATLAS - OVERALL SUMMARY/ABSTRACT THE MAJORITY OF SOLID TUMORS IN CHILDREN HAVE A UNIQUE ORIGIN COMPARED TO THOSE IN ADULTS, STEMMING FROM THEIR RISE FROM EMBRYONIC CELLS. DESPITE THIS DISTINCTION, THERE IS STILL LIMITED UNDERSTANDING OF THE DIFFERENCES IN THE MICROENVIRONMENTS OF THESE PEDIATRIC TUMORS COMPARED TO ADULT CANCERS, AND HOW THESE DIFFERENCES MIGHT CONTRIBUTE TO LINEAGE PLASTICITY AND TREATMENT RESISTANCE. TO ADDRESS THIS KNOWLEDGE GAP, WE PROPOSE A COMPREHENSIVE INVESTIGATION INTO THE SPATIAL BIOLOGY OF THESE TUMORS. OUR GOAL IS TO SHED LIGHT ON THE SPECIFIC CELLS AND MECHANISMS WITHIN THE TUMOR MICROENVIRONMENT THAT PLAY A ROLE IN INDUCING THERAPY RESISTANCE IN PEDIATRIC SOLID TUMORS. THIS RESEARCH WILL FOCUS ON PROMINENT PEDIATRIC CANCERS SUCH AS RHABDOMYOSARCOMA, NEUROBLASTOMA, AND WILMS TUMORS. THE PRIMARY GOAL OF THIS MULTI-DISCIPLINARY PROGRAM IS TO ESTABLISH A COMPREHENSIVE PEDIATRIC SOLID TUMOR MICROENVIRONMENT (PSTME) ATLAS THAT WOULD LEAD TO DISCOVERING BASIC MECHANISMS OF DE NOVO AND ACQUIRED RESISTANCE TO MODERN THERAPIES, AND UNCOVERING TUMOR MICROENVIRONMENT (TME) TARGETABLE VULNERABILITIES DRIVEN BY RESISTANCE. THE MOTIVATION FOR CREATING THE PSTME ATLAS IS THE URGENT NEED TO IMPROVE SURVIVAL OF PATIENTS WITH HIGH-RISK SUBTYPES OF THE PROPOSED CANCERS, AND TO DECREASE TREATMENT- RELATED MORBIDITIES. BY DELVING INTO THE INTRICACIES OF THE TUMOR MICROENVIRONMENT AND ITS IMPACT ON TREATMENT RESPONSE, WE AIM TO ADVANCE OUR UNDERSTANDING OF PEDIATRIC SOLID TUMORS AND PAVE THE WAY FOR MORE EFFECTIVE THERAPEUTIC STRATEGIES. THE PROJECT WILL BE SUPPORTED BY COLLABORATION AMONG TWO INSTITUTIONS WITH DISTINCT AND UNIQUE RESOURCES AND TECHNOLOGIES, AND COMPLEMENTARY EXPERTISE: A) CHILDREN'S HOSPITAL LOS ANGELES (CHLA) GROUP WILL PROVIDE WELL ANNOTATED TUMOR SPECIMENS WITH CLINICAL INFORMATION IN AN ETHNICALLY DIVERSE PATIENT POPULATION, AND LEAD IN GENERATING SPATIAL PROTEOMICS DATA USING PEDIATRIC AND TME SPECIFIC ANTIBODY PANELS. B) CALIFORNIA INSTITUTE OF TECHNOLOGY (CALTECH) GROUP WILL PROVIDE INNOVATIVE SPATIAL OMICS TECHNOLOGIES INCLUDING SPATIAL TRANSCRIPTOMICS AND COPY NUMBER, AND NOVEL DATA SCIENCE APPROACHES FOR INTEGRATIVE ANALYSIS OF THE GENERATED DATA. THE SAMPLES WILL BE SELECTED TO REPRESENT SOLID TUMOR DIVERSITY BASED ON ESTABLISHED CLINICAL RISK STRATIFICATIONS, AND CRITICAL POINTS OF TRANSITION (POST CHEMOTHERAPY RESPONSE, RELAPSE) TO ENSURE CAPTURE OF THE DIVERSITY OF PSTME. THE PSTME ATLAS WILL IMPACT THE COMMUNITY THROUGH GENERATION OF EASILY ACCESSIBLE TME ATLAS PROVIDING A USER FRIENDLY, SEARCHABLE DATABASE OF MULTIOMICS SPATIAL ANALYSES OF COMMON EXTRACRANIAL SOLID TUMORS WITH CLINICAL AND OUTCOME DATA. IT WILL ALSO PROVIDE NOVEL COMPUTATIONAL PIPELINES FOR INTEGRATION AND ANALYSIS OF SPATIAL DATA. THESE OPENSOURCE TOOLS WILL BE MADE AVAILABLE TO THE COMMUNITY. IN SUMMARY, THE SIGNIFICANCE OF THE PROPOSED PROJECT IS THE ESTABLISHMENT OF AN ATLAS THAT WILL ALLOW DISCOVERY OF FUNDAMENTAL MECHANISMS OF EXTRINSIC CANCER THERAPY RESISTANCE WITH THE GOAL OF LEADING TO SUBSTANTIVELY IMPROVED PROBABILITY OF CURE COUPLED WITH REDUCED THERAPY-RELATED MORBIDITY FOR CHILDREN AFFLICTED WITH SOLID TUMORS.