Molecular Characterization Trial of Irradiated Rectal Cancer

摘要 分子表征试验 分子表征试验（MCT）是一个临床平台，可采集组织进行切割 边缘实验室和成像研究，以推进辐射生物学领域。MCT总体假设 放疗（RT）对癌症结果的贡献取决于串扰的平衡， 在辐射的肿瘤和正常组织，宿主微生物组和宿主的免疫系统之间。直肠 癌症是一个理想的模型来测试这一假设，因为成像和标本，从病人经历了一个 标准短程放射治疗（SCRT）在RT前后是可获得的 治疗时以及手术时。因此，RT效应可以在每个单一的 组织，然后将其整体整合到模型中，以将生物和成像数据与临床结果相关联。 直肠癌也是一个研究重点，因为它在种族发病率和结果的差异。 罗宾的私家侦探们已经组建了一个由知名调查人员组成的国际团队，来进行同样的试验。 同时，在七个中心，以加快应计和发现。因此，MCT代表罗宾 项目1和项目2都依赖于回答关于RT生物学的基本问题。 新的生物信息学方法将用于整合临床和生物学数据与成像数据， 提高发现的潜力。最初的MCT将为未来的试验创建一个支持结构， 根据相关科学项目的结果测试新的干预措施。项目1将侧重于 肿瘤和患者匹配的非肿瘤组织的分子分析，目的是确定局部免疫 反应RT和RT诱导的基因组变化，并阐明治疗如何影响途径 参与细胞命运的决定，及其对局部结肠粘膜微生物组的影响。第二个项目将使用血液 标本和淋巴结，收集内部或外部的辐射领域，以量化RT诱导的氧化 应激及其对每个免疫细胞亚群的生物学结果。与细胞凋亡相关的通路 还将评估应激反应、细胞死亡和免疫适应性。另外，粪便样本 将对RT之前和之后收集的样品进行分析，以定性和定量地绘制微生物组的变化。 这两个项目都将使用最先进的基因组和蛋白质组方法来解决这些关键问题 结合患者的临床数据和来自正交放射组学研究的多模式成像。 标准化和上传后，所有实验室、临床和成像数据将通过以下方式进行协调和处理： 数据共享和综合分析核心（DSIA）。然后将使用新的综合分析方法分析数据。 生物信息学方法来识别以前无法检测到的与放射反应性相关的模式， 评估其与临床结局的关系。最终输出将汇集到NIH/NCI数据库中， ROBIN网络和整个科学界都可以使用。

ABSTRACT Molecular Characterization Trial The Molecular Characterization Trial (MCT) is a clinical platform to enable tissue acquisition to perform cutting edge laboratory and imaging research to advance the field of radiation biology. The MCT overarching hypothesis is that the contribution of radiotherapy (RT) to the outcome of cancer depends on the balance of the crosstalk among the irradiated tumor and normal tissue, the host microbiome, and the host’s immune system. Rectal cancer is an ideal model to test this hypothesis since imaging and specimens, from patients undergoing a standard short course radiotherapy (SCRT) treatment, are accessible and available at pre- and post RT treatment as well as at time of surgery. As such the RT effects can be analyzed longitudinally in each single tissue and then be integrated globally into a model to correlate biological and imaging data with clinical outcome. Rectal cancer is also a research priority because of its disparity in racial incidence and outcome. The ROBIN P.I.s have assembled an international team of established investigators, to conduct the same trial concurrently, at seven centers, to accelerate accruals and discovery. As such, the MCT represents the ROBIN foundation on which both Project 1 and Project 2 rely to answer fundamental questions regarding RT biology. Novel bioinformatic approaches will be applied to integrate clinical and biological data with imaging data, to enhance the potential for discovery. The initial MCT will create a supporting structure for future trials, iteratively testing new interventions informed by the results of the associated scientific projects. Project 1 will focus on the molecular analyses of tumor and patient’s matched non-tumor tissue with the goals of defining the local immune response to RT and the genomic changes induced by RT and elucidate how the treatment affects the pathways involved in cell fate decisions, and its effects on the local colonic mucosal microbiome. Project 2 will use blood specimens and lymph nodes, collected inside or outside the radiation field, to quantify RT-induced oxidative stress and the biological outcome of it on each immune cell subpopulation. Pathways associated with cellular stress responses, cell death, and immunological fitness will also be evaluated. Additionally, stool samples collected before and after RT will be analyzed to qualitatively and quantitatively map changes in the microbiome. Both projects will address these pivotal questions using state-of-the-art, genomic and proteomic approaches integrated with the patients’ clinical data and multi-modal imaging from an orthogonal radiomic study. After standardization and upload, all laboratory, clinical and imaging data will be harmonized and cured by the Data Sharing and Integrative Analysis Core (DSIA). Data will then be analyzed using novel integrative bioinformatics approaches to identify previously undetectable patterns related to radio-responsiveness and assess their association with clinical outcomes. The final output will converge into NIH/NCI databases and becomes available to the ROBIN network and to the scientific community at large.