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

人类软组织肉瘤对放射治疗反应的非侵入性表征

• 批准号: 10448722
• 负责人: Everett James Moding
• 金额: $ 26.22万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448722
• 关键词: Adjuvant; Adjuvant Therapy; Adult; Aftercare; Architecture; Biological Markers; Biology; Blood specimen; Cancer Biology; Cancer Personalized Profiling by Deep Sequencing; Cell Line; Cells; Clinical Research; Clinical Trials; Combined Modality Therapy; Computational Biology; DNA analysis; Data; Disease; Distant Metastasis; Doctor of Philosophy; Enrollment; External Beam Radiation Therapy; Foundations; Future; Gene Expression; Genetic; Genetic Determinism; Genomics; Goals; Histologic; Human; Hybrids; Immunotherapy; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Localized Disease; Malignant Neoplasms; Mediating; Mediator of activation protein; Medicine; Mentors; Mentorship; Mesenchymal; Mesenchymal Cell Neoplasm; Modeling; Modernization; Molecular; Monitor; Mus; Mutation; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Patients; Pattern; Phase II Clinical Trials; Physicians; Plasma; Pre-Clinical Model; Primary Neoplasm; Probability; Radiation Oncology; Radiation Tolerance; Radiation therapy; Radiobiology; Radiosurgery; Randomized; Recurrence; Relapse; Research; Research Proposals; Residual Tumors; Risk Factors; Role; Sampling; Scientist; Soft tissue sarcoma; Systemic Therapy; Systems Biology; Techniques; Testing; Training; Treatment-related toxicity; Tumor Tissue; Universities; Validation; Work; base; design; experimental study; high risk; improved; improved outcome; individual patient; insight; medical schools; mouse model; new combination therapies; novel; patient response; peripheral blood; personalized medicine; pre-clinical; predicting response; professor; prognostic model; programs; prospective; radiation resistance; radiation response; radioresistant; randomized trial; relapse prediction; relapse risk; response; sarcoma; symposium; therapy development; therapy resistant; tool; transcriptomics; translational research program; tumor; tumor DNA; tumor eradication; tumor immunology; tumor microenvironment

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.

项目总结/摘要 埃弗雷特莫丁，医学博士，博士是斯坦福大学放射肿瘤学院的助理教授。 药他的长期目标是利用他在临床和研究医学方面的综合专长， 辐射和癌症生物学的发现，为肉瘤患者带来更好的治疗方法。他希望 开发一个转化研究计划，使用人类肿瘤和血液样本的分析，以确定关键的 可以在临床前模型中验证并用于增强辐射抗性的介质 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，使博士。 建立一个成功的独立研究项目。这项建议将在下列人士的指导下进行： 医生科学家马克西米利安迪恩，医学博士，博士，基因组学为基础的生物标志物专家，阿什阿里扎德，医学博士， 博士，肿瘤免疫学和转录组学分析工具的专家，和大卫基尔希，医学博士，博士，领导者， 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， 和方案沿着与非正式的动手和实践活动，以扩大博士。 专业知识：1）计算和系统生物学，2）肿瘤免疫学和肉瘤生物学，3）实验室 管理、指导和培训。 软组织肉瘤（STS）是一组不同的间叶肿瘤，主要通过手术治疗， 局部疾病的放射治疗。尽管有一半的高危STS患者发生转移性疾病， 在初步治疗后，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患者在单独的放射治疗后会出现局部复发，但潜在的遗传改变 介导辐射抗性的基因是未知的。通过分析收集的肿瘤和外周血样本， 102例患者入组SU 2C-SARC 032 II期临床试验，本研究提案旨在1）建立 个性化循环肿瘤DNA分析作为STS患者的生物标志物，2）建立预后模型 整合肿瘤微环境分析、循环肿瘤DNA分析和传统风险因素， 改善对患者结果的预测，以及3）使用循环肿瘤DNA分析和肿瘤测序， 鉴定介导肉瘤对放射治疗反应的基因改变， 在新的临床前平台中进行验证。这一提议将为未来的前瞻性随机 使用循环肿瘤DNA分析和肿瘤基因组学的试验， STS患者，提高肿瘤根除的可能性，同时最大限度地减少治疗相关的毒性。