Radiation synthetic combinations in high-risk Ewing sarcoma

This proposal addresses the interplay of key facets of pediatric cancer research: DNA damage, chromatin accessibility, and the immune response to tumors. The overarching scientific goal of this R01 proposal is to better understand and treat Ewing tumors with STAG2 (stromal antigen 2) loss, a group of Ewing tumors associated with greatly inferior patient ourcomes, by taking advantage of STAG2 deficient tumor vulnerabilities during radiation therapy noted in our preliminary studies. Patients with aggressive (e.g. upfront metastatic and relapsed) Ewing sarcoma often receive radiation therapy for local control and optimizing the therapeutic effectiveness of this treatment is of great interest. The translational goal of this work is to develop novel multi- modality treatment combinations, including agents to induce epigenetic reprogramming and tumor inflammation, to partner with radiation therapy to better treat aggressive Ewing tumors with STAG2 loss. Little is currently understood about radiation therapy-induced changes in immunobiology in Ewing sarcoma. In part, this gap-in- knowledge is due to the lack of patient samples around the time of radiation therapy and no robust immunocompetent in vivo models of Ewing sarcoma. The applicant’s laboratory has validated a humanized, immunocompetent mouse model of Ewing sarcoma and used this model to ask questions about the immunobiology of Ewing tumors with STAG2 loss. Preliminary data show that Ewing tumors with STAG2 loss demonstrate defective responses to interferon and reduced radiation therapy-induced inflammation. This finding was also noted in analyses of human Ewing tumors from patients. This proposal will now build upon the vulnerabilities of STAG2 deficient tumors identified to enhance the response to radiation therapy. This will be accomplished through the aims proposed, including investigation of epigenetic reprogramming and activation of the immune system. The proposed experiments include cutting-edge in vitro analyses, in vivo tumor animal modeling and human specimen analyses. Single-cell RNAseq, ATAC-seq and spatial transcriptomic data generated through these studies will be fully annotated and made accessable to the scientific community. Multi- modality therapies will be tested in vivo both in humanized mice and NSG mice to better understand immune specific contributions to metastatic tumor behavior and and survival. The applicant has an established network of expert collaboartors, including individuals with expertise in radiation oncology, STAG2 biology, sarcoma epigenetics, spatial transcriptomics, the tumor immune-microenvironment, and bioinformatic and statistical analyses, all of whom will contribute to the ultimate success of this proposal. Mayo Clinic is an outstanding research and clinical institution for the study of sarcomas, radiation biology, and immunology, and is an ideal environment in which to investigate multi-modality therapies to pair with radiation therapy for the treatment of aggressive, STAG2 deficient Ewing sarcoma. The Bailey laboratory is dedicated to sharing these findings as preclinical rationale for future clinical trials for patients. Project Number: 1R37CA302677-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Kelly Bailey | Institution: MAYO CLINIC ROCHESTER, ROCHESTER, MN | Award Amount: $659,028 | Activity Code: R37 | Study Section: Radiation Therapeutics and Biology Study Section[RTB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11366203