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

神经内分泌肿瘤(NETs)被认为是一种低发病率(10000/年)的孤儿疾病。 美国。因此，事实证明，很难获得所需的利益或资源来带来 为这些患者提供更新的临床治疗。虽然在早期阶段进展缓慢，但一旦 肿瘤转移，目前5年存活率为30%。更新、更有效的治疗形式是 急需之物。使用单剂如131I-间碘苯甲基胍的靶向放射性核素治疗 ~(131)I-MIBG和~(90)Y-DOTA-Tyr3-奥曲肽(~(90)Y-DOTATOC)已显示出治疗小肠疾病的前景 应答率为20%-40%的网络。不幸的是，完整的回复非常少见，发生在 不到10%的患者，反应持续时间也经常令人失望。我们建议一期临床 结合90Y-DOTATOC和131I-MIBG的试验，应能增加向 肿瘤不超过正常肾脏和骨髓的安全限度。本试验性设计，基于强大的 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达不到要求的小肠网患者。在进一步的基础科学中 研究中，我们提出了一种针对独特的G蛋白偶联受体异二聚体的创新策略，如 在Net中表达的生长抑素受体/多巴胺受体结合物。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 由于异二聚体受体在正常组织中很少表达，因此对肿瘤细胞具有高度的特异性。 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一个新的范例 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。

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.