Tumor and host markers of clinical outcomes after MIBG therapy in neuroblastoma

MIBG 治疗神经母细胞瘤后临床结果的肿瘤和宿主标志物

• 批准号: 10153717
• 负责人: ROCHELLE BAGATELL
• 金额: $ 59.45万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153717
• 关键词: Acute; Adult; Aftercare; Avidity; Biological; Biological Markers; Biology; Blood Cells; Blood specimen; Carrier Proteins; Child; Childhood; Clinical; Combined Modality Therapy; DNA; DNA Double Strand Break; DNA Repair; Diagnosis; Disease; Excision; Exposure to; External Beam Radiation Therapy; Future; Gene Expression; Gene Proteins; Genes; Genome; Integration Host Factors; MYCN gene; Malignant Neoplasms; Measures; Mediator of activation protein; Messenger RNA; MicroRNAs; Modality; Modernization; Modification; Molecular; Mutation; Nervous System Neoplasms; Neuroblastoma; Newly Diagnosed; Normal tissue morphology; Operative Surgical Procedures; Outcome; Patient Selection; Patients; Pediatric Oncology Group; Peripheral Blood Mononuclear Cell; Phase III Clinical Trials; Play; Probability; Proteins; RNA; Radiation; Radiation Injuries; Radiation Tolerance; Radiation Toxicity; Radiation therapy; Radiogenomics; Radiopharmaceuticals; Randomized; Refractory; Relapse; Research; Role; Sampling; Selection for Treatments; Specimen; Subgroup; Survival Rate; Sympathetic Nervous System; Targeted Radiotherapy; Techniques; Testing; Therapeutic; Time; Toxic effect; Transcript; Treatment Protocols; Treatment-related toxicity; Variant; Work; cancer therapy; childhood cancer mortality; clinical predictors; design; disorder risk; experience; genotoxicity; high risk; improved; insight; mRNA Expression; metaiodobenzylguanidine; mutational status; noradrenaline transporter; outcome prediction; patient subsets; peripheral blood; phase III trial; potential biomarker; predict clinical outcome; predictive marker; radiation effect; radiation response; response; survival outcome; tool; transcriptome; tumor; vesicular monoamine transporter 2

PROJECT SUMMARY Radiation therapy plays a key role in the treatment of many cancers. Despite its widespread use, we cannot currently identify the patients most likely to benefit from this form of treatment. Neuroblastoma is a malignancy that occurs predominantly in young children. Patients with high-risk disease are treated with maximally intensive therapy, however survival rates for newly diagnosed patients remain poor. Neuroblastoma is sensitive to radiation, and the targeted radiopharmaceutical 131I-metaiodobenzylguanidine (131I-MIBG) is active in this disease. 131I-MIBG is being evaluated in a randomized Phase III trial as a component of frontline treatment for children with high-risk neuroblastoma (Children's Oncology Group ANBL1531). Preliminary studies suggest that tumor and host markers may predict clinical outcomes after 131I-MIBG. As part of ANBL1531, we will evaluate biomarkers that may identify patients most likely to experience a survival advantage after treatment, and could help to identify those patients most likely to experience toxicity related to 131I-MIBG therapy. To evaluate potential biomarkers that could aid in selection of patients for 131I-MIBG therapy, we propose two specific aims. In Aim 1, we will study features of neuroblastoma tumors that may predict outcome after 131I- MIBG. We will assess expression of transporter proteins in tumors from patients treated with and without 131I- MIBG, using specimens obtained at diagnosis and at the time of definitive surgery. In addition, we will evaluate the mutation status and the expression of genes related to neuroblastoma biology and radiation sensitivity. In Aim 2, we will evaluate host factors that may influence survival and toxicity related to 131I-MIBG therapy. We will use normal tissue (blood cells) from patients treated with and without 131I-MIBG to look for mutations that may underlie differences in sensitivity to radiation. In addition, we will study changes in expression of relevant genes in blood samples taken before and after 131I-MIBG exposure to elucidate the basis for differential radiation effects among patients. At the end of this project, we will have identified biomarkers that can be used to select patients with neuroblastoma who are most likely to benefit from 131I-MIBG therapy. Our work may result in improved therapy selection for patients with other cancers and improved understanding of differential clinical responses to therapeutic radiation.

项目摘要 放射治疗在许多癌症的治疗中起着关键作用。尽管它被广泛使用，但我们不能 目前确定最有可能从这种治疗形式中受益的患者。神经母细胞瘤是恶性肿瘤 主要发生在幼儿身上高风险疾病患者应最大限度地 然而，新诊断患者的生存率仍然很低。神经母细胞瘤是 对辐射敏感，靶向放射性药物131 I-间碘苄胍（131 I-MIBG）具有活性 在这种疾病中。131 I-MIBG作为一线治疗的一个组成部分正在一项随机III期试验中进行评估 治疗高危神经母细胞瘤儿童（儿童肿瘤组ANBL 1531）。初步 研究表明，肿瘤和宿主标记物可以预测131 I-MIBG治疗后的临床结果。的一部分 ANBL 1531，我们将评估可能识别最有可能经历生存期的患者的生物标志物。 治疗后的优势，并可能有助于确定那些最有可能发生毒性相关的患者， 131 I-MIBG治疗。 为了评估可能有助于选择患者进行131 I-MIBG治疗的潜在生物标志物，我们提出了两个 明确的目标。在目标1中，我们将研究神经母细胞瘤肿瘤的特征，这些特征可能预测131 I治疗后的结果。 MIBG。我们将评估来自用和不用131 I治疗的患者的肿瘤中转运蛋白的表达。 MIBG，使用诊断时和最终手术时获得的标本。此外，我们将评估 与神经母细胞瘤生物学和辐射敏感性相关的基因的突变状态和表达。在 目的2，我们将评估宿主因素，可能影响生存和毒性相关的131 I-MIBG治疗。我们 将使用来自接受和不接受131 I-MIBG治疗的患者的正常组织（血细胞）来寻找突变， 可能是对辐射敏感性差异的基础。此外，我们还将研究相关表达的变化， 在131 I-MIBG暴露前后采集的血液样品中的基因，以阐明差异表达的基础。 辐射对患者的影响。 在本项目结束时，我们将确定可用于选择患有以下疾病的患者的生物标志物： 神经母细胞瘤患者最有可能受益于131 I-MIBG治疗。我们的工作可能会改善治疗方法 选择患有其他癌症的患者，并提高对 放射治疗