Project Summary Basic scientists and clinical investigators from Dana-Farber/Harvard Cancer Center (DF/HCC) join forces with their counterparts at University of California, San Francisco’s (UCSF) Helen Diller Family Comprehensive Cancer Center to propose a Harvard/UCSF ROBIN Center. Our Objective is to improve potency and selectivity of two key radiation modalities--external beam radiation and radiopharmaceuticals. A distinctive feature of our ROBIN Center is its selection of two clinically aggressive pediatric tumors--diffuse midline glioma (DMG) and high-risk neuroblastoma (NBL) – as scientific vehicles for the study plan. The genetic drivers of these two pediatric cancers are found also in more common adult solid tumors. Moreover, the low mutational burden of these pediatric cancers provides a clean genetic background for the “low N/high content” Molecular Characterization Trials (MCTs) specified by the ROBIN RFA. The malignant cells within DMG and NBL are heterogenous with respect to developmental stage. The central hypothesis of our study plan is that this developmental heterogeneity is echoed at the level of radiation-response mechanisms and enables radiation resistance. Our study plan features two research projects configured to test predictions of this hypothesis. Project 1 draws upon paired samples of pre-and post-radiotherapy tumor tissue from children treated prospectively with a uniform radiotherapy regimen to test the prediction that radiation selects for radioresistant intra-tumoral variants. Project 2 tests the prediction that 131I-MIBG therapy of aggressive neuroblastoma selects for intra-tumoral subtypes with unfavorable responses to treatment. Our ROBIN MCT provides resources needed to complete the objectives and specific aims of the two Projects. Multimodal analysis and mathematical modeling of data from the Projects and the MCT will be performed in a Clinical Artificial Intelligence and Imaging Core and a Molecular Data Science and Advanced Dosimetry Core. A Cross- Training Core and an Administrative Core will support scientific activities and serve also as the Center’s “outward face” to the broader scientific community and lay public. The Center will serve as a “value-added” component of the NCI’s extramural support mission by leveraging (i) P30 core facilities of DF/HCC and UCSF, (ii) a U54-funded DFCI Physical Sciences Oncology Center, and (iii) the NCI's Experimental Therapeutics Clinical Trials Network and National Clinical Trials Networks. Conversely, an NCI ROBIN award to the Harvard/UCSF Center would be “value-added” to the field of radiation oncology by catalyzing productive interactions between radiation biology, artificial intelligence, and data science – disciplines that are well-established in Boston and San Francisco but have never been applied coordinately to the problem of radioresistance. Center co-leads, Professors Daphne Haas-Kogan M.D. and Franziska Michor, Ph.D. have much experience in management of mult...