Non-invasive characterization of human soft tissue sarcoma response to radiation therapy

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PROJECT SUMMARY/ABSTRACT Everett Moding, MD, PhD is an Assistant Professor of Radiation Oncology at Stanford University School of Medicine. His long-term goal is to use his combined expertise in clinical and research medicine to make important discoveries in radiation and cancer biology that lead to better treatments for patients with sarcomas. He hopes to develop a translational research program using analysis of human tumor and blood samples to identify critical mediators of radiation resistance that can be validated in preclinical models and leveraged to enhance the efficacy of radiation therapy. The goal of this career development award is to provide support and mentorship to enable Dr. Moding to develop a successful independent research program. The proposal will be carried out under the mentorship of physician scientists Maximilian Diehn, MD, PhD, an expert in genomicsbased biomarkers, Ash Alizadeh, MD, PhD, an expert in tumor immunology and transcriptomic analysis tools, and David Kirsch, MD, PhD, a leader in radiation biology and mouse models. The training plan incorporates formal coursework, seminars, conferences, and programs along with informal hands-on and practical activities to expand Dr. Moding’s knowledge and expertise in 1) computational and systems biology, 2) tumor immunology and sarcoma biology, and 3) laboratory management, mentoring, and grantsmanship. Soft tissue sarcomas (STS) are a diverse group of mesenchymal tumors primarily managed with surgery and radiation therapy for localized disease. Although half of patients with high risk STS develop metastatic disease after initial therapy, there are no biomarkers to identify patients at risk of relapse. In addition, up to two-thirds of patients with STS develop local recurrences after radiation therapy alone, but the underlying genetic alterations that mediate radiation resistance are unknown. By analyzing tumor and peripheral blood samples collected from 102 patients enrolled on the SU2C-SARC032 phase II clinical trial, this research proposal aims to 1) establish personalized circulating tumor DNA analysis as a biomarker in patients with STS, 2) build a prognostic model integrating tumor microenvironment profiling, circulating tumor DNA analysis, and traditional risk factors to improve prediction of patient outcomes, and 3) use circulating tumor DNA analysis and tumor sequencing to identify genetic alterations that mediate the response of sarcomas to radiation therapy for rapid functional validation in novel preclinical platforms. This proposal will lay the groundwork for future prospective randomized trials using circulating tumor DNA analysis and tumor genomics to enable personalized treatment approaches in patients with STSs that improve the probability of tumor eradication while minimizing treatment-related toxicity.