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

• 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
• 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

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 在所有具有高危神经母细胞瘤的儿童中，只有不到一半成为长期生存。目前，不是 可以预测儿童是否将通过标准疗法治愈或注定要中继。此外，标准 临床评估缺乏检测最终导致复发的最小残留疾病（MRD）的敏感性。 这是一个关键的挑战，并且需要开发新的精密生物标志物来识别患者 谁最终对高强度疗法的反应很差，并可能受益于替代方法。 我们将开发新的生物标志物，以使用无细胞DNA（CFDNA）和新颖的，一种指导治疗决策 基于表观遗传学的方法，将识别驱动侵袭性神经母细胞瘤的潜在生物学。许多人 癌症类型，对外周血分离的CFDNA的分析已显示出希望，揭示了生物标志物 诊断，预后和肿瘤监测。 DNA中的胞嘧啶可以未经修饰，甲基化（5- 甲基胞嘧啶，5MC），或含有5MC，5-羟基甲基胞嘧啶（5HMC）的氧化物形式。与5MC不同， 跨基因体的5HMC沉积升高标记活性转录。在此提案中，我们将使用纳米 HMC-SEAL，一种用于分析的全基因组方法，用于CFDNA中的5HMC修饰。最近，我们进行了评估 CFDNA中的5HMC从神经母细胞瘤儿童串行收集，并证明了5HMC曲线 与伯恩疾病和患者结局相关。重要的是，我们还发现了CFDNA 5HMC得出的 生物标志物可以将对治疗反应卓越的患者与高度缓解风险的患者区分开。 5hmc 与诊断性高风险原发性肿瘤相比 临床上侵略性的恶性细胞，其激活中继肿瘤中常见的网络。前瞻性 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生成 从临床注释的连续血样（液体活检）中收集的400名患者的5HMC谱。 关于正在进行的儿童肿瘤学组高危神经母细胞瘤III期研究（ANBL1531， NCT03126916）。我们假设来自神经母细胞瘤儿童的CFDNA 5HMC轮廓将作为 与当前的临床方法相比，用于反应和生存的优质生物标志物，将揭示转录 网络驾驶继电器。具体目的是：1）在诊断时进化和验证反应不佳的生物标志物； 2）前瞻性鉴定最小残留疾病（MRD），并预测串行CFDNA 5HMC轮廓的继电器； 3）实验证实释放时富含CFDNA的候选网络。该提议的成功将 导致：1）前所未有的诊断生物标志物以改善热决策； 2）早期检测和 对救济患者的干预措施，导致MRD； 3）鉴定驱动的表观遗传机制 复发。这项工作将对从早期介绍中受益的患者产生变革性的影响 替代疗法，改善患有侵略性疾病的疗法。