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.

摘要 只有不到一半的高风险神经母细胞瘤患儿能够长期存活。目前， 可以预测一个孩子是否会被标准治疗治愈或注定复发。此外，标准 临床评估缺乏检测最终导致复发的微小残留病（MRD）的灵敏度。 因此，存在开发新的精确生物标志物以识别患者的关键挑战和未满足的需求。 这些患者最终对高强度治疗反应不佳，并可能从替代方法中获益。 我们将开发新的生物标志物，使用无细胞DNA（cfDNA）和一种新的， 基于表观遗传学的方法，将确定驱动侵袭性神经母细胞瘤的潜在生物学。在许多 对于癌症类型，从外周血中分离的cfDNA的分析显示出希望，揭示了癌症的生物标志物。 诊断、鉴别和肿瘤监测。DNA中的胞嘧啶可以是未修饰的、甲基化的（5-甲基化的）， 甲基胞嘧啶，5 mC），或含有5 mC的氧化形式，5-羟甲基胞嘧啶（5 hmC）。与5 mC不同， 5 hmC在基因体上沉积的升高标志着转录的活跃。在本提案中，我们将使用纳米- hmC-seal，一种用于分析cfDNA中5 hmC修饰的全基因组方法。最近，我们评估了 从神经母细胞瘤儿童中连续收集cfDNA中的5 hmC，并证明5 hmC谱 与疾病负担和患者结局相关。重要的是，我们还发现了一个cfDNA 5 hmC衍生的 生物标志物可以区分对治疗有上级反应的患者与复发的高风险患者。5hmC 与诊断性高风险原发性肿瘤相比，来自cfDNA的谱证明cfDNA来源于 具有复发性肿瘤中常见的网络激活的临床侵袭性恶性细胞。前瞻性 为了确定基于5 hmC的cfDNA生物标志物的预后强度，我们将使用nano-hmC-seal来生成 从入组的400例患者中采集的临床注释系列血液样本（液体活检）的5 hmC谱 正在进行的儿童肿瘤组高危神经母细胞瘤III期研究（ANBL 1531， NCT03126916）。我们假设神经母细胞瘤患儿的cfDNA 5 hmC谱将作为 与目前的临床方法相比，用于缓解和生存的上级生物标志物， 网络驱动复发。具体目标是：1）发展和验证诊断时反应差的生物标志物; 2)从一系列cfDNA 5 hmC谱鉴定微小残留病（MRD）并预测复发; 3)实验确认复发时cfDNA富集的候选网络。这项提案的成功将 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复发的患者进行干预; 3）确定导致MRD复发的表观遗传机制， 复发这项工作将产生变革性的影响，以确定谁受益于早期引进的患者 替代疗法，改善侵袭性疾病患者的预后。