DOSIMETRY IN CHILDREN AND YOUNG ADULTS WITH NEUROBLASTOMA OR NEUROENDOCRINE TUMOR

患有神经母细胞瘤或神经内分泌肿瘤的儿童和年轻人的剂量测定

• 批准号: 7658199
• 负责人: DAVID L BUSHNELL
• 金额: $ 30.68万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7658199
• 关键词: 90Y; Amines; Biopsy; Bone Marrow; Carcinoid Tumor; Carrier Proteins; Child; Childhood; Dose; Dose-Limiting; Drug Combinations; Future; Goals; Image; Immunohistochemistry; Isotopes; Kidney; Neural Crest; Neuroblastoma; Neuroendocrine Tumors; Normal tissue morphology; Octreotide; Organ; Patients; Pediatric Neoplasm; Phase I Clinical Trials; Positron-Emission Tomography; Primitive foregut structure; Quality of life; Radiation; Radiation therapy; Radioactivity; Somatostatin Receptor; Targeted Radiotherapy; Test Result; Therapeutic; Toxic effect; Treatment Protocols; base; dosimetry; improved; public health relevance; research clinical testing; single photon emission computed tomography; somatostatin receptor 2; tumor; young adult

DESCRIPTION (provided by applicant): Molecularly targeted radiotherapy using 131I-MIBG has been demonstrated to improve survival in neuroblastoma, but the dose is limited by bone marrow toxicity. Similarly, molecularly targeted therapy with 90Y-DOTA-tyr3-Octreotide has improved quality of life in patients with neuroendocrine tumors, but the dose is limited by toxicity to kidneys. We have demonstrated the theoretical advantage of combined radiotherapy targeting the amine transporter (VMAT1) using 131I-MIBG and a somatostatin receptor (sst2) using 90Y-DOTA-tyr3-Octreotide in order to maximize the radiation dose to tumor while minimizing the dose to bone marrow and kidney. We hypothesize that image-guided dosimetry will enable safe and effective delivery of dual-target, dual-isotope radiotherapy that increases therapeutic dose to tumor without dose limiting toxicity to normal tissues. Our long-term goal is to develop individualized, dosimetry- based, combination radiotherapy for pediatric tumors as a major step forward from the current approach of delivering an empiric radiation dose using a single agent. We will focus our efforts on neural crest and neuroendocrine tumors of childhood, such as neuroblastoma and foregut carcinoid, that express both the amine transporter protein, VMAT1, and the type 2 somatostatin receptor (sst2). Individualized normal organ and tumor dosimetry will be performed in children with neuroblastoma or a neuroendocrine tumor using 124I-MIBG PET and 111In- DOTA-tyr3-Octreotide SPECT in order to determine the feasibility of a future Phase I trial of dosimetry based dual-target, dual-isotope radiotherapy with 131I-MIBG and 90Y-DOTA-tyr3-Octreotide. Accordingly, our Specific Aims are: Aim I. Conduct dosimetry studies in children and young adults with neuroblastoma or neuroendocrine tumors. We will determine the patient specific administered amount of radioactivity of 131I-MIBG and 90Y-DOTA-tyr3-Octreotide that would achieve maximum tumor radiation dose without exceeding established dose limits for critical normal organs. Aim II. Determine if immunohistochemistry and/or qPCR analysis of VMAT1 and sst2 on tumor biopsies will predict which children are best candidates for dual-target, dual-isotope radiotherapy. We will characterize VMAT1 and sst2 expression in the initial tumor biopsy prior to any therapy. Based upon the results from testing of our hypothesis through the completion of the above aims, we will determine whether to proceed to a phase I clinical trial using a therapeutic combination of 131I-MIBG plus 90Y-DOTA-tyr3-Octreotide to treat children and young adults with neuroblastoma and neuroendocrine tumors. We will proceed to clinical testing of this therapeutic regimen if our hypothesis is determined to be true for this drug combination. PUBLIC HEALTH RELEVANCE: Molecularly targeted radiotherapy using 131I-MIBG has been demonstrated to improve survival in neuroblastoma, but the dose is limited by bone marrow toxicity. Similarly, molecularly targeted radiotherapy with 90Y-DOTA-tyr3-Octreotide has improved quality of life in patients with neuroendocrine tumors, but the dose is limited by toxicity to kidneys. We have demonstrated the theoretical advantage of combined radiotherapy targeting these two types of tumors using a combination of 131I-MIBG and 90Y-DOTA-tyr3-Octreotide in order to maximize the radiation dose to tumor while minimizing the dose to bone marrow and kidney. Our long-term goal is to develop patient specific, combination radiotherapy for pediatric tumors as a major step forward from the current approach of delivering an "average patient" radiation dose using a single agent.

描述（由申请人提供）：已证明使用131 I-MIBG的分子靶向放射治疗可提高神经母细胞瘤的生存率，但剂量受到骨髓毒性的限制。类似地，90 Y-DOTA-tyr 3-奥曲肽的分子靶向治疗改善了神经内分泌肿瘤患者的生活质量，但剂量受到肾脏毒性的限制。我们已经证明了联合放射治疗的理论优势，靶向胺转运蛋白（VMAT 1）使用131 I-MIBG和生长抑素受体（SST 2）使用90 Y-DOTA-tyr 3-奥曲肽，以最大限度地提高辐射剂量的肿瘤，同时最小化剂量的骨髓和肾脏。我们假设，图像引导剂量测定将能够安全有效地提供双靶点，双同位素放射治疗，增加治疗剂量的肿瘤，而没有剂量限制毒性正常组织。 我们的长期目标是开发针对儿科肿瘤的个体化、基于剂量测定的联合放疗，作为从目前使用单一药剂递送经验性辐射剂量的方法向前迈出的重要一步。我们将集中我们的努力在神经嵴和神经内分泌肿瘤的儿童，如神经母细胞瘤和前肠类癌，既表达胺转运蛋白，VMAT 1，和2型生长抑素受体（SST 2）。将使用124 I-MIBG PET和111 In-DOTA-tyr 3-Octreotide SPECT对神经母细胞瘤或神经内分泌肿瘤儿童进行个体化正常器官和肿瘤剂量测定，以确定未来基于剂量测定的131 I-MIBG和90 Y-DOTA-tyr 3-Octreotide双靶点双同位素放疗I期试验的可行性。因此，我们的具体目标是： 艾姆岛在患有神经母细胞瘤或神经内分泌肿瘤的儿童和年轻人中进行剂量学研究。 我们将确定131 I-MIBG和90 Y-DOTA-tyr 3-奥曲肽的患者特异性放射性给药量，该放射性给药量将达到最大肿瘤辐射剂量，而不超过关键正常器官的既定剂量限值。 Aim II.确定肿瘤活检组织中VMAT 1和sst 2的免疫组化和/或qPCR分析是否可以预测哪些儿童是双靶点双同位素放疗的最佳候选人。我们将在任何治疗前的初始肿瘤活检中表征VMAT 1和sst 2表达。 基于通过完成上述目标对我们的假设进行检验的结果，我们将确定是否进行I期临床试验，使用131 I-MIBG +90 Y-DOTA-tyr 3-奥曲肽的治疗组合来治疗患有神经母细胞瘤和神经内分泌肿瘤的儿童和年轻人。如果我们的假设对于该药物组合被确定为正确，我们将继续进行该治疗方案的临床试验。 公共卫生相关性：使用131 I-MIBG的分子靶向放射治疗已被证明可以提高神经母细胞瘤的生存率，但剂量受到骨髓毒性的限制。类似地，使用90 Y-DOTA-tyr 3-奥曲肽的分子靶向放射治疗改善了神经内分泌肿瘤患者的生活质量，但剂量受到肾脏毒性的限制。我们已经证明了使用131 I-MIBG和90 Y-DOTA-tyr 3-奥曲肽的组合靶向这两种类型的肿瘤的组合放射治疗的理论优势，以最大化对肿瘤的辐射剂量，同时最小化对骨髓和肾脏的剂量。我们的长期目标是开发针对儿童肿瘤的患者特异性联合放疗，这是从目前使用单一药物提供“平均患者”辐射剂量的方法向前迈出的重要一步。