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 - 摘要与标准光子治疗相比，质子束治疗 (PBT) 具有优越的物理特性辐射，其生物学特性被认为与光子相似。这反映在使用通用相对生物有效性 (RBE) 为 1.1，可衡量两种癌症的物理剂量和正常组织。然而，来自我们小组和其他人的临床前数据表明， PBT 的 RBE 各不相同，可能取决于肿瘤细胞的内在生物学特性。这种 RBE 变化很可能是基因组定义并存在于给定癌症类型的个体肿瘤中。这是一个尚未得到充分研究的随着我们不断提高基因组分析能力，该领域具有潜在的重大临床影响癌症以确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会导致不同基因组肿瘤的 RBE 值存在差异。通过结合协同 MGH 和 MDACC 专业知识，我们将先进的物理计算技术与新颖的生物工具相结合，例如 DNA 双链断裂的核小体分辨率基因组图谱，以研究假设的独特质子产生的生物损伤。我们将进行以下具体目标：（1）模拟DNA 质子与光子辐照的损伤诱导和修复； (2) 实验阐明可靶向性质子与光子照射后 DNA 断裂诱导和去除的差异； (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) 验证临床相关肿瘤模型和患者中生物标志物相关的质子敏感性。这些研究将利用两个机构广泛的临床前肿瘤模型收藏以及临床试验标本。通过引入以下知识，所获得的知识将迅速影响癌症患者的治疗基于预测 PBT 敏感性的基因组生物标志物进行分层的新型临床试验。