Research Project 1: Diffuse Midline Glioma

研究项目1：弥漫性中线胶质瘤

• 批准号: 10712293
• 负责人: DAPHNE A. HAAS-KOGAN
• 金额: $ 37.23万
• 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/10712293
• 关键词: Adult; Artificial Intelligence; Attention; Autopsy; Biological Markers; Biology; Biopsy; Cancer Biology; Cells; Cessation of life; Child; Childhood; Chromatin; Clinical; Clinical Trials; Collection; Complement; Complex; Computer Models; DNA; DNA Repair Pathway; Daphne plant; Data; Data Analyses; Data Science; Data Science Core; Data Set; Development; Diagnosis; Doctor of Medicine; Doctor of Philosophy; Elements; Enzymatic Biochemistry; Epigenetic Process; Equilibrium; Evaluation; Evolution; Fostering; Funding; Genetic; Genomics; Gifts; Goals; Heterogeneity; Histopathology; Image; Laboratory Research; Leadership; Link; Malignant Childhood Neoplasm; Malignant Neoplasms; Matched-Pair Analysis; Methodology; Methods; MicroRNAs; Modality; Molecular; Mutation; Neurocognitive; Normal Cell; Normal tissue morphology; Oncologist; Operative Surgical Procedures; Outcome Assessment; Parents; Pathway interactions; Patient Outcomes Assessments; Patients; Pediatric Neoplasm; Population; Positioning Attribute; Proteomics; Quality of life; Radiation; Radiation Oncologist; Radiation Oncology; Radiation therapy; Radiogenomics; Regimen; Relapse; Research Project Grants; Resistance; Sampling; Specific qualifier value; Testing; Time; Tissues; Toxic effect; Transcend; Tumor Tissue; Variant; anti-cancer; cancer cell; cancer genomics; cell type; cohort; demographics; differential expression; diffuse midline glioma; dosimetry; epigenomics; health related quality of life; insight; longitudinal dataset; macroglia; neoplastic cell; neural; oligodendrocyte progenitor; patient population; precision medicine; programs; prospective; radiation during childhood; radiation resistance; radiation response; radioresistant; response; stem; treatment response; tumor; tumor heterogeneity; tumor microenvironment

Project Summary Conventional wisdom holds that radiation therapy is a physically targeted anti-cancer modality and that its cancer targets are genetically and biologically uniform. However, the stromal composition of tumors is complex and variable giving rise to extrinsic variability of the cancer target. Moreover, recent studies using single cell genomics show intrinsic heterogeneity even within the tumor cells per se. The broad goal of our Harvard/UCSF ROBIN initiative is to test the hypothesis that intra-tumoral variability underlies resistance to - and relapse from – radiotherapy. Towards this goal, our Center has chosen to focus on pediatric cancers of neuro-ectodermal origin. Pediatric tumors have a low mutational burden relative to common adult cancers and thus a cleaner genetic surround for the “low N/high content” Molecular Characterization Trials specified by the ROBIN RFA. Against this backdrop, this project focuses upon diffuse midline glioma (DMG) of children. The majority of DMGs initially respond to radiation, but all progress, and none are cured. In preliminary studies, we have used single cell genomics to show that the malignant cells within DMG are developmentally heterogeneous. Our testable hypothesis is that DMG intratumoral heterogeneity transcends developmental markers to include differential expression/utilization of common DNA repair pathways. This hypothesis makes predictions that will be assessed by drawing upon paired samples of pre-and post-radiotherapy tumor tissue from children treated prospectively with a uniform radiotherapy regimen and profiled in our Molecular Characterization Trial (MCT). We have three specific aims: Aim 1 is to test the prediction that intratumoral heterogeneity is reflected at levels above and beyond tumor cell-specific developmental markers noted our preliminary studies; Aim 2 is to test the prediction that radiotherapy reduces DMG intratumoral heterogeneity via selection of replication-competent, radio-resistant stem-like cancer cells; Aim 3 is to test the prediction that heterogeneous radiation responses within tumor cells underlie patient heterogeneity in radiation-associated toxicities, neurocognitive effects and quality of life. The study plan incorporates contemporary methods in cancer genomics, epigenomics, chromatin biology and DNA enzymology. We will draw upon our Clinical Artificial Intelligence and Imaging Core to develop non-invasive methods to track intra-tumoral heterogeneity in these (surgically challenging) pediatric tumors. With our Molecular Data Science and Advanced Dosimetry Core, we will develop computational modeling of tumor cell evolution and treatment response that will be critical to understanding selection for radioresistant subclones. The co-leaders of this Project have complementary expertise to enable the study plan. Daphne Haas-Kogan, M.D. is a pediatric radiation oncologist who treats patients with DMG and holds leadership positions in two key consortia (COG and PNOC) for pediatric clinical trials. Mariella Filbin, M.D./Ph.D. is a pediatric neuro-oncologist with expertise in single cell genomics and DMG biology.

项目摘要 传统观念认为，放射治疗是一种物理靶向的抗癌方式，它 癌症靶标在生物学上均匀。但是，肿瘤的基质组成很复杂 可变导致癌症靶标的外部变异性。而且，最近使用单细胞的研究 基因组学也显示出固有的异质性，即使在肿瘤细胞中也是如此。我们的广泛目标 哈佛/UCSF Robin倡议是测试以下假设：肿瘤内变异性是对 - 并从放射疗法中继电器。为了实现这一目标，我们的中心选择专注于儿科取消者 神经外皮的起源。小儿肿瘤相对于常见的成人癌症的突变伯嫩较低，并且 因此，针对“低N/高含量”分子表征试验的清洁遗传试验 罗宾RFA。在此背景下，该项目着重于儿童的弥漫性中线神经胶质瘤（DMG）。 大多数DMG最初都对辐射做出反应，但所有进展又无法治愈。在初步 研究，我们已经使用了单细胞基因组学表明DMG中的恶性细胞是开发的 异质。我们可检验的假设是DMG肿瘤内异质性超越了发展 标记包括公共DNA修复途径的差异表达/利用。这个假设提出了 将通过利用后放射治疗后肿瘤组织的配对样品来评估的预测 来自前瞻性治疗的儿童，并在我们的分子中进行了分析 表征试验（MCT）。我们有三个特定的目标：目标1是测试肿瘤内的预测 异质性反映在高于肿瘤细胞特异性发育标记的水平上 初步研究； AIM 2是测试放疗降低DMG肿瘤内异质性的预测 通过选择具有复制能力的，抗射线样的茎样癌细胞；目标3是测试以下预测 肿瘤细胞内的异质辐射反应是患者的异质性，辐射相关的异质性 毒性，神经认知效应和生活质量。 研究计划纳入了癌症基因组学，表观基因组学，染色质的当代方法 生物学和DNA酶学。我们将利用我们的临床人工智能和成像核心 开发非侵入性方法以跟踪这些（手术充满挑战）小儿的肿瘤内异质性 肿瘤。借助我们的分子数据科学和高级剂量核心，我们将开发计算 肿瘤细胞演化和治疗反应的建模，这对于理解选择的选择至关重要 放射性亚克隆。该项目的共同领导者具有全面的专业知识来实现​​这项研究 计划。 Daphne Haas-Kogan，医学博士是一名儿科辐射肿瘤学家，患有DMG患者并保持 小儿临床试验的两个关键联盟（COG和PNOC）的领导职务。 Mariella Filbin， M.D./PH.D。是一名儿科神经综合学家，具有单细胞基因组学和DMG生物学方面的专业知识。