Project 3: Enhanced Sensitivity of Tumors to Proton Beam Therapy: Mechanisms and Biomarkers.

项目 3：增强肿瘤对质子束治疗的敏感性：机制和生物标志物。

基本信息

批准号：
10491858
负责人：
DAVID R GROSSHANS
金额：
$ 60.17万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-21 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10491858
关键词：
Area Back Bioinformatics Biological Biological Assay Biological Factors Biological Markers Brain Breast Cancer Patient Cancer cell line Cell Line Cells Characteristics Clinical Clinical Data Clinical Trials Collection Computational Technique DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA lesion DNA mapping Data Defect Deposition Derivation procedure Dose Double Strand Break Repair Esophagus Excision Funding Future Gene Expression Profile Gene Mutation Genomics Goals Individual Institution Interdisciplinary Study Knowledge Lead Linear Energy Transfer Liver Location Malignant Neoplasms Malignant neoplasm of pancreas Mission Modeling Mus National Cancer Institute Normal tissue morphology Nucleosomes Organoids Pancreas Pathway interactions Patients Photons Property Protons Public Health Radiation Radiation therapy Reaction Relative Biological Effectiveness Research Research Support Resolution Site Specimen Stratification Stratification Factors Study models Techniques Testing Therapeutic Toxic effect Tumor Cell Biology Tumor-Derived University of Texas M D Anderson Cancer Center Validation Variant Xenograft Model Xenograft procedure base biophysical model cancer cell cancer rehabilitation cancer therapy cancer type candidate marker clinically relevant genomic biomarker genomic profiles improved in vivo individual patient innovation irradiation molecular marker novel particle pre-clinical predicting response predictive marker proton beam proton therapy repaired response small molecule inhibitor therapeutic DNA tool tumor

项目摘要

Project 3 - SUMMARY While proton beam therapy (PBT) has superior physical characteristics compared to standard photon radiation, its biological properties have been thought to be similar to photons. This is reflected in the use of a generic relative biological effectiveness (RBE) of 1.1 to scale the physical dose delivered for both cancer and normal tissues. However, pre-clinical data from our groups and others are emerging to indicate that the RBE of PBT varies and may be dependent on intrinsic tumor cell biology. Such RBE variations are likely genomically defined and exist across individual tumors of a given cancer type. This is a vastly understudied area with potential for substantial clinical impact as we are advancing our ability to genomically profile cancers to identify candidate predictive biomarkers. Thus, our overall objective is to establish distinct biological properties of PBT relative to photon radiation and determine if these differential properties result in variable RBE values across genomically diverse tumors. By combining synergistic MGH and MDACC expertise, we will integrate advanced physical computation techniques with novel biological tools, such as nucleosome-resolution genomic mapping of DNA double-strand breaks, to study the hypothesized unique biological damage produced by protons. We will conduct the following Specific Aims: (1) Simulate DNA damage induction and repair for proton vs photon irradiation; (2) Experimentally elucidate targetable differences in the induction and removal of DNA breaks following proton vs photon irradiation; (3) Identify candidate genomic biomarkers that predict increased proton RBE in annotated cancer cell lines; (4) Validate biomarker-correlated proton sensitivity in clinically relevant tumor models and in patients. These studies will leverage extensive pre-clinical tumor model collections as well as clinical trial specimens at both institutions. The knowledge gained will quickly influence the treatment of cancer patients through the introduction of novel clinical trials with stratification based on genomic biomarkers that predict sensitivity to PBT.

项目3-摘要与标准光子相比，质子束治疗（PBT）具有优越的物理特征辐射，其生物学特性被认为与光子相似。这反映在使用通用的相对生物学有效性（RBE）为1.1，以扩展为两种癌症提供的物理剂量和正常组织。但是，我们小组和其他人的临床前数据正在出现，以表明 PBT的RBE各不相同，可能取决于固有的肿瘤细胞生物学。这样的RBE变化很可能在基因组上定义并存在于给定癌症类型的个体肿瘤中。这是一个大量研究的随着我们在基因组上提高我们的能力，具有重大临床影响的区域癌症鉴定候选预测生物标志物。因此，我们的总体目标是建立独特的 PBT相对于光子辐射的生物学特性，并确定这些差异特性是否导致基因组多样性肿瘤的RBE值可变。通过结合协同MGH和MDACC 专业知识，我们将将先进的物理计算技术与新颖的生物学工具相结合，例如 DNA双链断裂的核小体分辨率基因组映射，研究假设的独特质子产生的生物损害。我们将执行以下特定目的：（1）模拟DNA 质子与光子照射的损伤诱导和修复；（2）实验阐明可定位的质子与光子照射后，DNA断裂的诱导和去除差异；（3）识别预测注释癌细胞系中质子RBE增加的候选基因组生物标志物；（4）验证在临床相关的肿瘤模型和患者中，生物标志物相关的质子敏感性。这些研究会在这两个机构中利用广泛的临床前肿瘤模型收集以及临床试验标本。获得的知识将通过引入基于基于基因组生物标志物的分层的新型临床试验预测对PBT的敏感性。