Research Project 2: Neuroblastoma

研究项目2：神经母细胞瘤

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要放射药物表现出巨大的临床承诺，从而获得了监管的批准几个代理商。这种靶向放射疗法使肿瘤细胞暴露于连续的，指数衰减的辐射，从而产生与外束放射疗法不同的生物学作用。尽管如此基本差异，对放射性药物对肿瘤细胞的影响的理解有限肿瘤微环境的种群和其他成分，例如基质细胞，免疫隔室和内皮细胞。拟议的工作将为肿瘤细胞中的新见解和 - 辐射反应的肢体机制，可以为整个放射性药物的研究提供信息肿瘤学。在此背景下，项目2将深入描述样本，成像和数据。用靶向放射性药物131i-MIBG治疗的高危神经母细胞瘤的儿童。在AIM 1中，我们将评估治疗前的肿瘤细胞中性和肿瘤细胞 - 肢体因素，包括躯体和宿主基因组变体，单细胞和大量转录组学以及DNA损伤修复分析。在AIM 2中，我们将评估这些因素的动态变化，以应对131i-MIBG治疗，包括评估肿瘤 131i-MIBG以及串行循环肿瘤DNA样品后切除的材料。在AIM 3中，我们将利用两项大型国家研究，以评估131i-MIBG在这一脆弱的小儿人群中的晚期影响。由结论项目2，我们将了解131i-MIBG治疗后的反应和毒性预测指标，以及从根本上讲，将了解一组全面的分子标记物的变化这种放射性药物治疗后的辐射生物学。我们已经将工作嵌入到有史以来进行的131i-mibg的唯一随机3阶段试验中， COG ANBL1531（NCT03126916）。但是，除了我们利用目标临床试验以实现A之外面向问题的，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。一个主要障碍，限制了我们对放射性药物的生物学作用是在暴露前后获得的配对肿瘤样品缺乏辐射。我们的工作通过利用我们对详细的横断面数据的独特访问来克服这一障碍关于长期的医学，心理和教育成果，再加上配对的纵向生物学标本，剂量学，序列图像，数据科学，机械计算建模和放射线学确定与131i-MIBG反应相关的肿瘤异质性标记的关键变化和后期效果。重要的是，有或没有131i-MIBG治疗的患者提供生物测量在该试验中的治疗，使我们能够验证特定标记为真正的预测性，而不是简单的预后。最后，我们的建议利用了一系列其他由联邦资助的努力来建立一个持久的，在辐射肿瘤学和癌症生物学的交集中，协作计划具有广泛的影响。