PROJECT SUMMARY The convergence of radiation oncology, cancer genomics, data science, computational modeling, and artificial intelligence presents spectacular opportunities and challenges. In the Harvard/UCSF ROBIN, we propose to capitalize on these opportunities to improve our understanding of radiation response and resistance. The clinical vehicles for our ROBIN Center are diffuse midline gliomas (DMGs) and neuroblastoma, the two most clinically significant pediatric tumors of neural ectodermal origin. We hypothesize that intratumoral heterogeneity drives radiation response and resistance, and that the mechanisms thereof can be identified by deciphering tumor cell-intrinsic and -extrinsic components of the tumor microenvironment before, during, and after radiotherapy. The Molecular Data Science and Advanced Dosimetry Core (Data Science Core) is an essential component of the Harvard/UCSF ROBIN Center. It will serve as the hub for data storage and management, analysis, and integration of all molecular datatypes generated by the Center, advanced dosimetry modeling, and predictive computational modeling platforms. Specifically, the Core will work to (i) retrieve, curate, and manage molecular data related to the Harvard/UCSF ROBIN Center and provide the infrastructure necessary to efficiently provide access to all data required for achieving the ROBIN goals; (ii) analyze and integrate all molecular data types generated in Projects 1 and 2; (iii) generate advanced dosimetry data, including accurate distributions of dose for radionuclide therapy and dose received by tumor cells, that are required to investigate the biological hypotheses proposed in Projects 1 and 2; (iv) conduct mechanistic modeling of radiation effects and evolution of resistance to radiotherapy that directly supports the aims of Projects 1 and 2 and can inform data collection and address the hypotheses of the ROBIN Center; and (v) share findings and novel methods with the ROBIN Network and the scientific community at large. Toward these ends, the Core will coordinate its activities closely with Projects 1 and 2 and the other cores, in particular with the AI Core, focusing on imaging, radiomics, and natural language processing, and the Molecular Characterization Trial. The Core will also work closely with the Cross-Training Core and the Administrative Core to reach other members of the ROBIN Network and the larger scientific community. The Core will be directed by two investigators, Drs. Michor and Seo, who have expansive and complementary expertise and have assembled a team of experienced investigators to contribute to the goals of the Core. We anticipate that the results of the Data Science Core will be broadly utilized by all components of the ROBIN Center and the larger ROBIN Network as well as the broader scientific community, and will significantly contribute to understanding data science and dosimetry/cancer evolution aspects across a broad suite of cancers and treatments.