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

项目摘要/摘要 埃弗雷特·莫丁，医学博士，斯坦福大学医学院放射肿瘤学助理教授 医学。他的长期目标是利用他在临床和研究医学方面的综合专业知识，使重要的 辐射和癌症生物学方面的发现为肉瘤患者带来了更好的治疗方法。他希望 利用对人类肿瘤和血液样本的分析，开发一项转化研究计划，以确定关键 辐射抵抗的介体，可以在临床前模型中得到验证，并被利用来增强 放射治疗的疗效。 这个职业发展奖的目标是提供支持和指导，使莫丁博士能够 制定一项成功的独立研究计划。这项提议将在以下指导下实施 医学博士，基因组学生物标志物专家，医学博士，医学博士 博士，肿瘤免疫学和转录分析工具方面的专家，以及大卫·基尔希，医学博士，博士， 辐射生物学和小鼠模型。培训计划包括正式课程、研讨会、会议、 和计划以及非正式的实践和实践活动，以扩大莫丁博士的知识和 擅长1)计算和系统生物学，2)肿瘤免疫学和肉瘤生物学，以及3)实验室 管理、指导和恩赐精神。 软组织肉瘤(STS)是一组不同类型的间叶性肿瘤，主要通过手术和 局部疾病的放射治疗。尽管有一半的高危STS患者会发展为转移性疾病 在最初的治疗后，没有生物标志物来识别有复发风险的患者。此外，多达三分之二的 STS患者在单纯放射治疗后出现局部复发，但潜在的基因改变 调节辐射抵抗力的物质是未知的。通过分析肿瘤和外周血样本从 102名患者参加SU2C-SARC032 II期临床试验，本研究方案旨在1)建立 个体化循环肿瘤DNA分析作为STS患者的生物标志物，2)建立预后模型 结合肿瘤微环境分析、循环肿瘤DNA分析和传统危险因素 提高对患者预后的预测，以及3)使用循环肿瘤DNA分析和肿瘤测序 确定介导肉瘤对放射治疗的反应的基因改变 在新的临床前平台上的验证。这一建议将为今后的前瞻性随机研究奠定基础。 使用循环肿瘤DNA分析和肿瘤基因组学实现个性化治疗方法的试验 STSS患者可提高肿瘤根除的可能性，同时最大限度地减少与治疗相关的毒性。

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.