Detecting DICER1: A global partnership to cure pediatric lung cancer

检测 DICER1：治愈小儿肺癌的全球合作伙伴关系

• 批准号: 10555261
• 负责人: Kris Ann Pinekenstein Schultz
• 金额: $ 35.85万
• 依托单位: CHILDREN'S HOSPITALS AND CLINICS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555261
• 关键词: 7 year old; Acceleration; Acute; Adult; Alleles; Biological Assay; Biological Markers; Blood; Brain Neoplasms; Cancer Burden; Caring; Cessation of life; Chemoresistance; Chest; Child; Childhood; China; Clinical; Clinical Trials; Codon Nucleotides; Collaborations; Communities; Cystic Neoplasm; Detection; Development; Diagnosis; Diagnostic; Disease Progression; Dose; Early Diagnosis; Embryonic Development; Enrollment; Excision; Face; Future; Industrialization; Infant; International; Intervention; Kidney Neoplasms; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Metastatic malignant neoplasm to brain; Methods; Minnesota; Missense Mutation; Molecular; Monitor; Morbidity - disease rate; Mutation; Operative Surgical Procedures; Pathogenesis; Pathogenicity; Pathologic; Pediatric Hospitals; Pediatric Oncology; Pleuropulmonary Blastoma; Preclinical Drug Development; Predisposition; Prognosis; Progressive Disease; Radiation; Radiation therapy; Rare Diseases; Recurrence; Recurrent disease; Recurrent tumor; Registries; Research; Residual Neoplasm; Rhabdomyosarcoma; Ribonucleases; Risk; Scanning; Schedule; Sedation procedure; Sensitivity and Specificity; Site; Solid; Solid Neoplasm; Technology; Testing; Toxic effect; Translations; Treatment-related toxicity; Tumor Burden; Validation; Variant; Work; X-Ray Computed Tomography; biomarker validation; blood-based biomarker; cancer cell; cell free DNA; chemotherapy; chest computed tomography; clinical practice; clinically significant; companion diagnostics; data registry; design; digital; early childhood; high risk; improved; improved outcome; liquid biopsy; mortality risk; mutant; new technology; novel; novel marker; novel therapeutics; ovarian neoplasm; radiation risk; rare cancer; risk minimization; risk stratification; sarcoma; side effect; specific biomarkers; therapy resistant; thyroid neoplasm; translational study; treatment response; tumor; tumor DNA; young adult

PROJECT SUMMARY/ABSTRACT Project Summary: Pleuropulmonary blastoma (PPB) is the most common lung cancer of childhood, now known to be related to pathogenic variation in DICER1, a critical regulator of embryogenesis. Nearly all clinically significant PPB is diagnosed in children under 7 years of age. Type I PPB is a purely cystic tumor with a layer of primitive malignant cells. Type I PPB may progress to Type II PPB, a mixed cystic and solid tumor, or Type III PPB, a highly aggressive, purely solid sarcoma. Children with Type I PPB are treated with surgery with or without chemotherapy; however it is not clear which children require chemotherapy and which children can be safely observed. Children with Type II or III PPB face an overall survival of only 74 and 53% respectively. In Types I, II and III PPB, there is a need for risk stratification so that children with residual or progressive disease can receive more intensive tumor-directed treatment and children with a favorable prognosis can be spared unnecessary side effects. Since 1988, the International PPB Registry, based at Children’s Minnesota, has been enrolling children with PPB in an effort to improve outcomes for this rare tumor. Our industrial partner, ResourcePath, has developed DICER-Dx, a blood-based assay to detect DICER1hotspot circulating tumor DNA (ctDNA). We hypothesize that the unique molecular pathogenesis of DICER1-related tumors can be exploited to facilitate tumor monitoring in PPB. This project focuses on 1) the clinical validation of novel "liquid biopsy" assays for sensitive detection and quantification of tumor burden in Types I, II and III PPB and 2) delivery of current and future DICER1-related advances to children globally, leveraging our emerging partnership with Beijing Children’s Hospital to increase accrual and accelerating successful completion of the proposed work. Relevance: These assays will apply to children and adults with DICER1-related cancers and improve upon existing tumor monitoring while minimizing the risks of diagnostic radiation and sedation. DICER-Dx provides a new way to measure DICER1-related cancer burden and response to therapy and therefore represents a pioneering application of liquid biopsy technology in childhood cancer. These assays may be useful not only in clinical practice, but also as companion diagnostics in preclinical drug development and clinical trials and will be an essential component of future translational studies for the International PPB/DICER1 Registry. Additionally, validation of these biomarkers is the next critical step in our efforts to develop ctDNA-based biomarkers for use in healthy children and young adults with DICER1 pathogenic variation at elevated risk of DICER1-related cancers.

项目总结/摘要 项目概述：胸膜肺母细胞瘤（PPB）是儿童最常见的肺癌， 已知与DICER 1的致病性变异有关，DICER 1是胚胎发生的关键调节因子。几乎所有 7岁以下儿童被诊断出具有临床意义的PPB。I型PPB是一种纯囊性肿瘤， 一层原始恶性细胞I型PPB可能进展为II型PPB，即囊性和实体混合瘤，或 III型PPB，一种高度侵袭性的纯实体肉瘤。患有I型PPB的儿童通过手术治疗， 或不化疗;然而，尚不清楚哪些儿童需要化疗，哪些儿童可以 安全观察。患有II型或III型PPB的儿童的总体生存率分别仅为74%和53%。在 I、II和III型PPB，需要进行危险分层，以便残留或进行性疾病的儿童 可以接受更密集的肿瘤定向治疗，预后良好的儿童可以幸免 不必要的副作用。自1988年以来，总部设在明尼苏达州儿童中心的国际PPB登记处， 为了改善这种罕见肿瘤的预后，我们一直在招募患有PPB的儿童。我们的工业合作伙伴， ResourcePath开发了DICER-Dx，这是一种基于血液的检测DICER 1热点循环肿瘤DNA的方法 （ctDNA）。我们假设DICER 1相关肿瘤的独特分子发病机制可以被利用 以促进PPB中的肿瘤监测。本项目的重点是1）新型“液体活检”的临床验证 用于I、II和III型PPB中肿瘤负荷的灵敏检测和定量的测定，以及2） 目前和未来的DICER 1相关的进展，全球儿童，利用我们新兴的伙伴关系， 北京儿童医院加大计提力度，加快工作进度，圆满完成建议工作。 相关性：这些检测将适用于患有DICER 1相关癌症的儿童和成人，并改善 现有的肿瘤监测，同时最大限度地减少诊断辐射和镇静的风险。DICER-Dx提供了 一种新的方法来测量DICER 1相关的癌症负荷和对治疗的反应，因此代表了一种 液体活检技术在儿童癌症中的开创性应用。这些测定不仅可用于 临床实践，而且还作为临床前药物开发和临床试验中的伴随诊断， 成为国际PPB/DICER 1登记研究未来翻译研究的重要组成部分。 此外，验证这些生物标志物是我们努力开发基于ctDNA的 用于具有DICER 1致病变异的健康儿童和年轻成人的生物标志物， DICER 1相关癌症