DOSIMETRY IN CHILDREN AND YOUNG ADULTS WITH NEUROBLASTOMA OR NEUROENDOCRINE TUMOR

描述（由申请人提供）：使用131I-MIBG进行分子靶向放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。同样，90y - dota -tyr3-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。我们已经证明了使用131I-MIBG靶向胺转运体（VMAT1）和使用90y - dota -tyr3-奥曲肽靶向生长抑素受体（sst2）的联合放疗在理论上的优势，以便最大化肿瘤的辐射剂量，同时最小化骨髓和肾脏的剂量。我们假设，图像引导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，而不会对正常组织产生剂量限制毒性。我们的长期目标是为儿童肿瘤开发个体化、基于剂量学的联合放疗，这是目前使用单一药物提供经验辐射剂量的重要一步。我们将重点研究儿童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）。将对神经母细胞瘤或神经内分泌肿瘤患儿使用124I-MIBG PET和111In- dota -tyr3-奥曲肽SPECT进行个个化正常器官和肿瘤剂量测定，以确定未来基于剂量测定的双靶点、双同位素放射治疗131I-MIBG和90y - dota -tyr3-奥曲肽的I期试验的可行性。因此，我们的具体目标是：

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.