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

项目总结 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形式的治疗中受益的患者。神经母细胞瘤是一种恶性肿瘤。 这主要发生在年幼的儿童中。高危疾病的患者最大限度地使用 强化治疗，然而，新诊断患者的存活率仍然很低。神经母细胞瘤是 对辐射敏感，靶向放射性药物131I-间碘苯基胍(131I-MIBG)是活性的 在这种疾病中。131I-MIBG正在进行随机第三阶段试验，作为前线的一个组成部分进行评估 儿童高危神经母细胞瘤的治疗(儿童肿瘤学小组ANBL1531)。初步 研究表明，肿瘤和宿主标志物可以预测131I-MIBG术后的临床结果。作为以下内容的一部分 ANBL1531，我们将评估可能识别最有可能经历生存的患者的生物标记物 治疗后的优势，并可能有助于确定哪些患者最有可能经历与 131I-MIBG治疗。 为了评估可能有助于选择131I-MIBG治疗患者的潜在生物标志物，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的特征，这些特征可能预测131I- MIBG。我们将评估接受和不接受131I-治疗的患者肿瘤中转运蛋白的表达。 MIBG，使用在诊断时和最终手术时获得的标本。此外，我们还将评估 神经母细胞瘤生物学和辐射敏感性相关基因的突变状态和表达。在……里面 目的2，评估影响131I-MIBG治疗相关生存和毒性的宿主因素。我们 将使用接受和不接受131I-MIBG治疗的患者的正常组织(血细胞)来寻找突变 可能是辐射敏感度差异的基础。此外，我们还将研究相关基因表达的变化 131I-MIBG暴露前后采血基因阐明差异的基础 辐射对患者的影响。 在这个项目结束时，我们将识别出可用于选择患者的生物标志物 最有可能从131I-MIBG治疗中受益的神经母细胞瘤。我们的工作可能会改进治疗方法 其他癌症患者的选择和对不同临床反应的更好理解 治疗性放射治疗。

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.