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

项目3-摘要 而与标准光子相比，质子束疗法(PBT)具有更优越的物理特性 辐射，其生物学特性一直被认为类似于光子。这反映在使用 用于衡量两种癌症的物理剂量的通用相对生物有效性(RBE)为1.1 和正常组织。然而，来自我们团队和其他人的临床前数据正在浮现，表明 PBT的RBE多种多样，可能依赖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，并存在于特定癌症类型的单个肿瘤中。这是一个被极少研究的 具有重大临床影响的潜在领域，因为我们正在提高我们的基因组图谱分析能力 癌症以确定候选预测生物标记物。因此，我们的总体目标是建立明确的 PBT相对于光子辐射的生物学特性，并确定这些不同的特性是否会导致 不同基因组肿瘤的RBE值不同。通过将协同MGH和MDAcc相结合 专业知识，我们将把先进的物理计算技术与新型生物工具相结合，例如 DNA双链断裂的核小体分辨基因组图谱，以研究假设的唯一性 质子造成的生物损害。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与修复；(2)实验阐明靶向 质子和光子照射后DNA断裂的诱导和去除的差异；(3)识别 候选基因组生物标记物可预测注释癌细胞中质子RBE的增加；(4)验证 临床相关肿瘤模型和患者中与生物标记物相关的质子敏感性。这些研究将 利用两家机构广泛的临床前肿瘤模型收集和临床试验标本。 所获得的知识将很快影响癌症患者的治疗 根据预测PBT敏感性的基因组生物标记物进行分层的新临床试验。

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.