Research Project 2: Neuroblastoma

研究项目2：神经母细胞瘤

• 批准号: 10712294
• 负责人: Dipanjan Chowdhury
• 金额: $ 37.74万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712294
• 关键词: Acute; Address; Artificial Intelligence; Biological; Biological Markers; Biological Models; Biology; Blood specimen; Cancer Biology; Carrier Proteins; Catalogs; Cells; Child; Childhood; Classification; Clinical; Clinical Trials; Cohort Studies; Collaborations; Combined Modality Therapy; Computer Models; Coupled; DNA; DNA Repair; Data; Data Science; Development; Diagnosis; Disease; Disease-Free Survival; Education; Endothelial Cells; Evaluation; Exposure to; Failure; Functional disorder; Funding; Gene Expression Profile; Genetic Transcription; Genomics; Goals; Growth; Heterogeneity; Image; Immune; Late Effects; Long-Term Survivors; Malignant Childhood Neoplasm; Measures; Mediating; Medical; MicroRNAs; Modality; Molecular; Neuroblastoma; Nodal; Normal tissue morphology; Oncology; Outcome; Patients; Pediatric Oncologist; Pediatric Oncology Group; Play; Point Mutation; Population; Populations at Risk; Radiation; Radiation Dose Unit; Radiation Oncology; Radiation Tolerance; Radiation therapy; Radiobiology; Radiopharmaceuticals; Randomized; Relapse; Research Project Grants; Resected; Resistance; Resources; Role; Sampling; Scientist; Second Primary Neoplasms; Series; Specimen; Stromal Cells; Survivors; Systemic disease; Targeted Radiotherapy; Testing; Thyroid Gland; Time; Toxic effect; Treatment Failure; Tumor Markers; Work; adverse outcome; case control; cohort; design; dosimetry; genetic variant; high risk; improved; improved outcome; innovation; insight; irradiation; large datasets; metaiodobenzylguanidine; molecular marker; neoplastic cell; novel; peripheral blood; phase III trial; predicting response; predictive marker; prognostic; prophylactic; protein expression; psychologic; radiation response; radiomics; randomized trial; response; serial imaging; skills; theranostics; transcriptomics; treatment strategy; tumor; tumor DNA; tumor heterogeneity; tumor microenvironment

Project Summary Radiopharmaceuticals have shown tremendous clinical promise, resulting in regulatory approvals of several agents. Such targeted radiotherapy exposes tumor cells to continuous, exponentially decaying radiation, resulting in biological effects distinct from those of external beam radiotherapy. Despite this fundamental difference, there is limited understanding of the impact of radiopharmaceuticals on tumor cell populations and other components of the tumor microenvironment such as stromal cells, immune compartments, and endothelial cells. The proposed work will provide novel insights into tumor cell-intrinsic and -extrinsic mechanisms of radiation response that can inform the study of radiopharmaceuticals across oncology. Against this backdrop, Project 2 will deeply characterize samples, imaging, and data from a cohort of children with high-risk neuroblastoma treated with the targeted radiopharmaceutical 131I-MIBG. In Aim 1, we will evaluate pre-treatment tumor cell-intrinsic and tumor cell-extrinsic factors, including somatic and host genomic variants, single cell and bulk transcriptomics, and DNA damage repair profiling. In Aim 2, we will assess dynamic changes in these factors in response to 131I-MIBG therapy, including evaluation of tumor materials resected after 131I-MIBG as well as serial circulating tumor DNA samples. In Aim 3, we will leverage two large national studies to assess the late effects of 131I-MIBG in this vulnerable pediatric population. By the conclusion of Project 2, we will understand predictors of response and toxicity following 131I-MIBG therapy and, more fundamentally, will understand the changes in a comprehensive set of molecular markers reflective of radiation biology following treatment with this radiopharmaceutical. We have embedded our work within the only randomized phase 3 trial of 131I-MIBG ever conducted, COG ANBL1531 (NCT03126916). However, beyond our utilization of goal-oriented clinical trials to enable a question-oriented, hypothesis-driven study plan in close collaboration with our Data Science and AI Cores, Project 2 advances several transformative innovations. A major barrier limiting our understanding of the biological effects of radiopharmaceuticals is a lack of paired tumor samples obtained before and after exposure to radiation. Our work overcomes this barrier by exploiting our unique access to detailed, cross-sectional data on long-term medical, psychological, and educational outcomes, coupled with paired, longitudinal biologic specimens, dosimetry, serial images, data science, mechanistic computational modeling, and radiomics to identify the critical changes in our markers of tumor heterogeneity that are associated with 131I-MIBG response and late effects. Importantly, biospecimens are available from patients treated with or without 131I-MIBG therapy on this trial, enabling us to validate specific markers as truly predictive rather than simply prognostic. Finally, our proposal leverages a series of other federally-funded efforts in order to establish an enduring, collaborative initiative with broad impacts at the intersection of radiation oncology and cancer biology.

项目摘要 放射性药物已经显示出巨大的临床前景，导致监管机构批准 几个特工。这种靶向放射治疗使肿瘤细胞暴露于连续的、指数衰减的环境中， 辐射，导致不同于外部束放射治疗的生物效应。尽管如此 根本区别在于，对放射性药物对肿瘤细胞的影响的理解有限 细胞群和肿瘤微环境的其他组分，如基质细胞、免疫细胞、肿瘤微环境中的细胞因子和肿瘤微环境中的细胞因子。 隔室和内皮细胞。这项工作将为研究肿瘤细胞的内在机制提供新的视角， - 辐射反应的外在机制，可以为放射性药物的研究提供信息， 肿瘤学 在此背景下，项目2将深入表征来自一组受试者的样本、成像和数据。 用靶向放射性药物131 I-MIBG治疗高危神经母细胞瘤的儿童。目标1： 将评价治疗前肿瘤细胞内源性和肿瘤细胞外源性因素，包括体细胞和宿主 基因组变异、单细胞和批量转录组学以及DNA损伤修复谱。在目标2中，我们将 评估这些因素对131 I-MIBG治疗的响应的动态变化，包括肿瘤的评估。 131 I-MIBG后切除的材料以及系列循环肿瘤DNA样品。在目标3中， 两项大型国家研究，以评估131 I-MIBG在这一脆弱儿科人群中的晚期效应。由 项目2的结论，我们将了解131 I-MIBG治疗后反应和毒性的预测因素， 更根本的是，将了解一套全面的分子标记物的变化， 放射生物学在用这种放射性药物治疗之后。 我们已经将我们的工作嵌入到有史以来进行的唯一一项131 I-MIBG随机III期试验中， COG ANBL 1531（NCT 03126916）。然而，除了我们利用以目标为导向的临床试验， 以问题为导向，假设驱动的研究计划与我们的数据科学和AI核心密切合作， 项目2推进了几项变革性创新。一个主要的障碍限制了我们对 放射性药物的生物学效应是缺乏暴露前后获得的配对肿瘤样本 辐射。我们的工作克服了这一障碍，利用我们独特的访问详细，横截面数据 长期的医疗，心理和教育结果，加上配对的，纵向的生物学， 标本、剂量测定、序列图像、数据科学、机械计算建模和放射组学， 确定与131 I-MIBG反应相关的肿瘤异质性标志物的关键变化 和迟效。重要的是，生物标本可从接受或未接受131 I-MIBG治疗的患者中获得 这项试验的治疗，使我们能够验证特定的标志物作为真正的预测，而不仅仅是预后。 最后，我们的建议利用了一系列其他联邦资助的努力，以建立一个持久的， 在放射肿瘤学和癌症生物学的交叉点具有广泛影响的合作倡议。