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.

项目摘要/摘要 埃弗里特·乔布（Everett），医学博士，博士是斯坦福大学学校的辐射肿瘤学助理教授 药品。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来提高重要 放射线和癌症生物学的发现，可为肉瘤患者提供更好的治疗方法。他希望 使用人类肿瘤和血液样本的分析制定转化研究计划以识别关键 可以在临床前模型中验证的辐射抗性介体，并杠杆以增强 放射治疗的功效。 这个职业发展奖的目标是提供支持和心态，以使Moding博士能够 制定成功的独立研究计划。该提议将在 医师科学家Maximilian Diehn，医学博士，博士，基于基因组学的生物标志物专家，医学博士Ash Alizadeh， 博士学位，肿瘤免疫学和转录组分析工具的专家，以及医学博士David Kirsch，博士学位，博士学位 辐射生物学和小鼠模型。培训计划包括正式的课程，半小伙，会议， 和计划以及非正式的实践和实践活动，以扩大米丁博士的知识和 1）计算和系统生物学专业知识，2）肿瘤免疫学和肉瘤生物学，以及3）实验室 管理，心理和授予技巧。 软组织肉瘤（STS）是一组潜水员的间充质肿瘤，主要通过手术和 局部疾病的放射疗法。尽管一半的高风险ST患者患上转移性疾病 初始治疗后，没有生物标志物可以识别有退休风险的患者。此外，最多三分之二 STS患者仅放射治疗后就会产生局部回报，但是基本的遗传改变 介导辐射阻力是未知的。通过分析从中收集的肿瘤和外周血样本 102名参加SU2C-SARC032 II期临床试验的患者，该研究建议旨在建立 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分析以及传统的风险因素 改善患者预后的预测，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遗传改变 在新颖的临床前平台中进行验证。该提议将为未来的潜在随机分组奠定基础 使用循环肿瘤DNA分析和肿瘤基因组学以实现个性化治疗方法的试验 患有STS的患者可以提高肿瘤辐射的可能性，同时最大程度地减少与治疗相关的毒性。