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

基本信息

批准号：
8850628
负责人：
DAVID L BUSHNELL
金额：
$ 25.59万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850628
关键词：
90Y Adult Adverse effects Affinity Alternative Therapies Apoptotic Basic Science Binding Biological Assay Bone Marrow Carcinoid Tumor Cell surface Cells Characteristics Child Clinical Clinical Trials Competitive Binding Data Development Dopamine Dopamine Receptor Dose Dose-Limiting Drug Prescriptions Drug resistance Effectiveness Europe Fibroblasts Future G Protein-Coupled Receptor Genes G-Protein-Coupled Receptors GTP-Binding Proteins Goals Human Image In complete remission Incidence Kidney Label Lead Length Life Ligands Malignant Neoplasms Marrow Metastatic Neoplasm to the Liver Midgut Modeling Molecular Molecular Target Necrosis Neoplasm Metastasis 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 Radio Radioisotopes Radiolabeled Radionuclide therapy Radiopharmaceuticals Rare Diseases Receptor Cell Relative (related person)Research Resources Secure Small Intestines Somatostatin Somatostatin Receptor Specialized Program of Research Excellence Staging Survival Rate Symptoms Systemic Therapy Testing Therapeutic Time Toxic effect Translating Treatment Protocols United States Work base chemotherapy cohort design dimer disorder control effective therapy evidence base falls image guided improved in vitro testing innovation interest metaiodobenzylguanidine molecular imaging mortality neoplastic cell novel novel strategies radiotracer receptor response trial design tumor

项目摘要

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，在以下地区发病率较低（<10000/年）美国。因此，事实证明，获得实现这一目标所需的利益或资源非常困难。针对这些患者的临床领域提供了新的治疗方法。虽然前期进展缓慢，但一旦 NETs发生转移，目前5年生存率<30%。更新、更有效的治疗形式是急需。使用 131I-间碘苄胍等单一药物进行靶向放射性核素治疗 (131I MIBG) 和 90Y-DOTA-tyr3-奥曲肽 (90Y-DOTATOC) 已显示出治疗小肠的前景 NET 的回复率为 20-40%。不幸的是，完整的反应非常罕见，发生在不到 10% 的患者，而且反应持续时间也常常令人失望。我们建议进行 I 期临床结合 90Y-DOTATOC 和 131I MIBG 的试验应增加递送至患者的辐射剂量肿瘤不超过正常肾脏和骨髓的安全限度。本次试验设计，基于强有力的初步成像数据和辐射剂量模型，有可能提供持久的治疗益处适用于其他治疗策略无法达到的小肠 NET 患者。在进一步的基础科学中研究中，我们提出了一种针对独特 G 蛋白偶联受体异二聚体的创新策略，例如在 NET 中表达的生长抑素受体/多巴胺受体缀合物。初步数据证明这些新的靶向剂与肿瘤细胞具有高亲和力结合；他们预计将是由于异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治疗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。