Project 4: New Approaches to Improving the Effectiveness of Radionuclide Targeted Treatments in Neuroendocrine Tumors

项目4：提高神经内分泌肿瘤放射性核素靶向治疗有效性的新方法

• 批准号: 9551538
• 负责人: DAVID L BUSHNELL
• 金额: $ 27.21万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9551538
• 关键词: 90Y; Adult; Adverse effects; Affinity; Alternative Therapies; Apoptotic; Basic Science; Binding; Biological Assay; Bone Marrow; Carcinoid Tumor; Cell Surface Receptors; Cell surface; Cells; Characteristics; Child; Clinical; Clinical Trials; Competitive Binding; Data; Development; Dopamine; Dopamine Receptor; Dose; Drug Prescriptions; Drug resistance; Effectiveness; Europe; Fibroblasts; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Human; Image; In complete remission; Incidence; Individual; Kidney; Label; Lead; Length; Life; Ligands; Malignant Neoplasms; Marrow; Metastatic Neoplasm to the Liver; Midgut; Modeling; Molecular; Molecular Target; Necrosis; Neoplasm Metastasis; Neuroendocrine Therapy; Neuroendocrine Tumors; Non-Malignant; Normal tissue morphology; Octreotide; Opioid; Organ; Pancreas; Pathway interactions; Patients; Peptides; Pharmacodynamics; Phase I Clinical Trials; Property; Quality of life; Radiation; Radiation therapy; Radioisotopes; Radiolabeled; Radionuclide therapy; Radiopharmaceuticals; Rare Diseases; Research; Resources; SSTR2 gene; Secure; Small Intestines; Somatostatin; Somatostatin Receptor; Specialized Program of Research Excellence; Survival Rate; Systemic Therapy; Testing; Therapeutic; Time; Toxic effect; Translating; Treatment Protocols; United States; base; chemotherapy; cohort; design; dimer; disorder control; effective therapy; evidence base; falls; image guided; imaging approach; improved; in vitro testing; innovation; interest; metaiodobenzylguanidine; mortality; neoplastic cell; novel; novel strategies; patient response; receptor; reduce symptoms; response; targeted agent; trial design; tumor

Neuroendocrine tumors (NETs) are considered an Orphan Disease with a low incidence (<10000/yr) in the United States. Consequently, it has proven very difficult to secure the interest or resources needed to bring newer treatments to the clinical arena for these patients. Although slow to progress in the early stages, once NETs metastasize, the current 5-year survival rate is <30%. Newer, more effective forms of therapy are urgently needed. Targeted radionuclide therapies using single agents such as 131I-metaiodobenzylguanidine (131I MIBG) and 90Y-DOTA-tyr3-Octreotide (90Y-DOTATOC) have shown promise for therapy of small bowel NETs with response rates of 20-40%. Unfortunately, complete responses are notably uncommon, occurring in less than 10% of patients and response duration is often disappointing as well. We propose a Phase I clinical trial combining 90Y-DOTATOC and 131I MIBG that should provide an increase in the radiation dose delivered to tumors without exceeding safe limits for normal kidney and bone marrow. This trial design, based on strong preliminary imaging data and radiation dose modeling, has the potential to provide durable therapeutic benefit for patients with small bowel NETs where other therapeutic strategies fall short. In further basic science studies, we propose an innovative strategy targeting unique G-protein coupled receptor hetero-dimers such as somatostatin receptor/dopamine receptor conjugates that are expressed in NETs. Preliminary data demonstrate that these new targeting agents have high affinity binding to tumor cells; they are predicted to be highly specific for tumor cells as the hetero-dimeric receptors are rarely expressed in normal tissues. Successful development of these unique radionuclide therapies will provide a new paradigm for molecular targeting and image-guided radionuclide therapy that will likely be translated to other malignancies.

神经内分泌肿瘤（NET）被认为是一种孤儿病，在美国发病率低（<10000/年）， 美国的因此，事实证明，很难获得必要的利益或资源， 为这些患者的临床竞技场提供新的治疗方法。虽然在早期阶段进展缓慢，但一旦 NET转移，目前5年生存率<30%。更新，更有效的治疗形式是 迫切需要。使用单一药剂如131 I-间碘苄胍的靶向放射性核素疗法 (131I MIBG）和90 Y-DOTA-tyr 3-奥曲肽（90 Y-DOTATOC）已经显示出用于治疗小肠疾病的前景。 NET的响应率为20- 40%。不幸的是，完全反应是非常罕见的，发生在 不到10%的患者，反应持续时间也常常令人失望。我们提出了一个I期临床 联合90 Y-DOTATOC和131 I MIBG的试验，应增加输送至 肿瘤，而不超过正常肾脏和骨髓的安全限度。本试验设计，基于强大的 初步成像数据和辐射剂量建模，有可能提供持久的治疗益处 对于其他治疗策略不足的小肠NETs患者。在进一步的基础科学中 研究，我们提出了一种创新的策略，针对独特的G蛋白偶联受体异源二聚体，如 在NET中表达的促生长素抑制素受体/多巴胺受体缀合物。初步数据 证明这些新的靶向剂具有与肿瘤细胞的高亲和力结合;它们被预测为 由于异源二聚体受体很少在正常组织中表达，因此对肿瘤细胞具有高度特异性。 这些独特的放射性核素疗法的成功开发将为分子生物学提供新的范例。 靶向和图像引导的放射性核素治疗可能会转化为其他恶性肿瘤。