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: 7538899
• 负责人: DAVID L BUSHNELL
• 金额: $ 30.85万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7538899
• 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; Public Health; Quality of life; Radiation; Radiation therapy; Radioactivity; Range; Somatostatin Receptor; Targeted Radiotherapy; Test Result; Therapeutic; Toxic effect; Treatment Protocols; base; dosimetry; improved; 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)：使用131I-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存活率，但剂量受到骨髓毒性的限制。同样，90Y-DOTA-Tyr3-Octrebon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。我们已经证明了以~(131)I-MIBG为靶点的胺转运体(VMAT1)和以90Y-DOTA-Tyr3-Octrebon为靶点的生长抑素受体(Sst2)联合放射治疗的理论优势，以最大限度地增加肿瘤的辐射剂量，同时最大限度地减少对骨髓和肾脏的剂量。我们假设，图像引导的剂量学将能够安全有效地提供双靶点、双同位素放射治疗，增加对肿瘤的治疗剂量，而不会限制对正常组织的剂量毒性。我们的长期目标是开发针对儿童肿瘤的个体化、基于剂量学的联合放射治疗，这是从目前使用单一试剂提供经验辐射剂量的方法向前迈出的重要一步。我们将集中精力研究儿童的神经嵴和神经内分泌肿瘤，如神经母细胞瘤和前肠类癌，它们同时表达胺转运蛋白VMAT1和2型生长抑素受体(Sst2)。在神经母细胞瘤或神经内分泌肿瘤的儿童中，将使用124I-MIBG PET和111In-DOTA-tyr3-octrebon SPECT进行个体化的正常器官和肿瘤剂量测定，以确定未来131I-MIBG和90Y-DOTA-tyr3-octrebon基于剂量学的双靶点、双同位素放射治疗I期试验的可行性。因此，我们的具体目标是： 目的一、对患有神经母细胞瘤或神经内分泌肿瘤的儿童和年轻人进行剂量学研究。我们将确定患者特定剂量的131I-MIBG和90Y-DOTA-Tyr3-Octrepay的放射性剂量，以便在不超过关键正常器官的既定剂量限值的情况下实现最大肿瘤辐射剂量。 目的II.确定肿瘤活检组织中VMAT1和Sst2的免疫组织化学和/或定量聚合酶链式反应分析是否可以预测哪些儿童最适合进行双靶点、双同位素放射治疗。我们将在任何治疗前的初始肿瘤活检中确定VMAT1和Sst2的表达。 根据通过完成上述目标对我们的假设进行测试的结果，我们将决定是否继续进行I期临床试验，使用131I-MIBG和90Y-DOTA-Tyr3-Octrebon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。如果我们的假设被确定对这种药物组合是正确的，我们将继续对这种治疗方案进行临床测试。 公共卫生相关性：使用131I-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存活率，但其剂量受到骨髓毒性的限制。同样，90Y-DOTA-Tyr3-Octrebon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。我们用~(131)I-MIBG和~(90)Y-DOTA-Tyr3-奥曲肽联合治疗这两种类型的肿瘤，以最大限度地增加肿瘤的放射剂量，同时最大限度地减少对骨髓和肾脏的剂量，从而证明了联合放射治疗的理论优势。我们的长期目标是开发针对儿童肿瘤的针对患者的联合放射治疗，这是从目前使用单一剂型提供“平均患者”辐射剂量的方法向前迈出的重要一步。