Liquid biopsy approaches to inform neuroblastoma prognosis and disease monitoring

液体活检方法可告知神经母细胞瘤预后和疾病监测

基本信息

批准号：
10440004
负责人：
Mark Andrew Applebaum
金额：
$ 70.44万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-11 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10440004
关键词：
Automobile Driving Biological Biological Markers Biology Biopsy Blood specimen Child Clinical Clinical Trials Clinical assessments Clustered Regularly Interspaced Short Palindromic Repeats Complex Copy Number Polymorphism Cytosine DNA Data Deposition Detection of Minimal Residual Disease Diagnosis Diagnostic Disease Disease Resistance Early Diagnosis Early Intervention Early treatment Enrollment Epigenetic Process Genes Genetic Transcription Goals Growth In Vitro Knock-out Long-Term Survivors MAP Kinase Gene Malignant Neoplasms Methodology Methods Modification Monitor Mutation Neoadjuvant Therapy Neuroblastoma Newly Diagnosed North America Oxides Patient-Focused Outcomes Patients Pediatric Oncology Group Primary Neoplasm Prognosis Recurrence Recurrent disease Refractory Disease Relapse Residual Neoplasm Retrospective cohort Sampling Specificity Therapeutic Therapeutic Intervention Training Tumor Suppressor Proteins Validation Work base burden of illness cancer cell cancer type cell free DNA chemotherapy diagnostic biomarker gene network high risk high risk population improved improved outcome liquid biopsy machine learning method nano novel novel therapeutics peripheral blood phase 3 study predictive marker profiles in patients prognostic prognostic assays prognostication prospective relapse prediction relapse risk research clinical testing response response biomarker risk stratification screening seal success therapy resistant treatment response tumor tumor DNA whole genome

项目摘要

Abstract Fewer than half of all children with high-risk neuroblastoma become long-term survivors. Currently, it is not possible to predict if a child will be cured with standard therapy or is destined to relapse. Furthermore, standard clinical evaluations lack sensitivity to detect minimal residual disease (MRD) that ultimately leads to recurrence. Thus, there is a critical challenge and an unmet need to develop new precision biomarkers to identify patients who will ultimately have a poor response to the high-intensity therapy and may benefit from alternate approaches. We will develop new biomarkers to guide treatment decisions using cell-free DNA (cfDNA) and a novel, epigenetic-based methodology that will identify underlying biology driving aggressive neuroblastoma. In many cancer types, analysis of cfDNA isolated from peripheral blood has shown promise, revealing biomarkers for diagnosis, prognostication, and tumor surveillance. Cytosines in DNA can either be unmodified, methylated (5- methylcytosine, 5mC), or contain an oxidized form of 5mC, 5-hydroxymethylcytosine (5hmC). Unlike 5mC, elevated 5hmC deposition across a gene body marks active transcription. In this proposal, we will use nano- hmC-seal, a whole-genome methodology for analyzing 5hmC modifications in cfDNA. Recently, we evaluated 5hmC in cfDNA collected serially from children with neuroblastoma and demonstrated that 5hmC profiles correlated with disease burden and patient outcome. Importantly, we also found a cfDNA 5hmC derived biomarker can distinguish patients with superior response to treatment from those at high risk for relapse. 5hmC profiles from cfDNA compared to diagnostic high-risk primary tumors demonstrated cfDNA is derived from clinically aggressive, malignant cells with activation of networks common in relapsed tumors. To prospectively determine the prognostic strength of 5hmC-based cfDNA biomarkers, we will use nano-hmC-seal to generate 5hmC profiles from clinically annotated serial blood samples (liquid biopsies) collected from 400 patients enrolled on the ongoing Children’s Oncology Group High-Risk Neuroblastoma Phase III study (ANBL1531, NCT03126916). We hypothesize that cfDNA 5hmC profiles from children with neuroblastoma will serve as superior biomarkers for response and survival compared to current clinical methods and will reveal transcriptional networks driving relapse. The specific aims are: 1) Evolve and validate biomarkers of poor response at diagnosis; 2) Prospectively identify minimal residual disease (MRD) and predict relapse from serial cfDNA 5hmC profiles; 3) Experimentally confirm candidate networks enriched in cfDNA at relapse. The success of this proposal will lead to: 1) unprecedented diagnostic biomarkers to improve therapeutic decisions; 2) early detection and interventions for patients with relapse causing MRD; 3) identification of epigenetic mechanisms which drive relapse. This work will have a transformative impact by to identifying patients who benefit from early introduction of alternate therapy, improving outcomes for those with aggressive disease.

抽象的目前，只有不到一半的高危神经母细胞瘤儿童能够成为长期幸存者。可以预测孩子是否会通过标准治疗治愈或注定会复发此外，标准。临床评估缺乏检测微小残留病（MRD）的敏感性，最终导致复发。因此，开发新的精准生物标志物来识别患者面临着严峻的挑战和未满足的需求最终对高强度治疗反应不佳的人可能会从替代方法中受益。我们将使用游离 DNA (cfDNA) 和一种新颖的、基于表观遗传学的方法将识别驱动许多侵袭性神经母细胞瘤的潜在生物学。从外周血中分离出的 cfDNA 分析已显示出希望，揭示癌症类型的生物标志物 DNA 中的胞嘧啶可以是未修饰的、甲基化的（5-）。甲基胞嘧啶，5mC），或含有 5mC 的氧化形式，5-羟甲基胞嘧啶（5hmC），与 5mC 不同，基因体中 5hmC 沉积的增加标志着转录活跃。 hmC-seal，一种用于分析 cfDNA 中 5hmC 修饰的全基因组方法。从神经母细胞瘤儿童中连续收集的 cfDNA 中的 5hmC 并证明 5hmC 谱重要的是，我们还发现了 cfDNA 5hmC 衍生的。生物标志物可以区分对治疗有良好反应的患者和 5hmC 复发风险高的患者。 cfDNA 与诊断性高风险原发性肿瘤的比较表明 cfDNA 源自临床上具有侵袭性的恶性细胞，其网络激活常见于复发性肿瘤。为了确定基于 5hmC 的 cfDNA 生物标志物的预后强度，我们将使用 nano-hmC-seal 来生成来自 400 名入组患者收集的临床注释连续血液样本（液体活检）的 5hmC 概况关于正在进行的儿童肿瘤组高风险神经母细胞瘤 III 期研究（ANBL1531， NCT03126916），我们着迷于神经母细胞瘤儿童的 cfDNA 5hmC 图谱将作为与目前的临床方法相比，具有更好的反应和生存生物标志物，并将揭示转录驱动复发的网络的具体目标是：1）发展和验证诊断时反应不佳的生物标志物； 2) 通过连续 cfDNA 5hmC 图谱前瞻性识别微小残留病 (MRD) 并预测复发； 3）通过实验确认复发时富含 cfDNA 的候选网络。导致：1）前所未有的诊断生物标志物，以改善治疗决策2）早期检测和对导致 MRD 的复发患者进行干预；3）识别驱动的表观遗传机制；这项工作将通过识别从早期引入中受益的患者来产生变革性的影响。替代疗法，改善患有侵袭性疾病的患者的治疗结果。