Radioisotope Therapy Targeting the Somatostatin Receptor

针对生长抑素受体的放射性同位素治疗

• 批准号: 6626018
• 负责人: Gina G Chung
• 金额: $ 29.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-21 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6626018
• 关键词: cell line; clinical trial phase I; combination cancer therapy; drug resistance; endocrine neoplasm; human subject; human therapy evaluation; indium; irinotecan; neoplasm /cancer genetics; neoplasm /cancer radionuclide therapy; nervous system neoplasms; neuropeptide receptor; patient oriented research; peptide hormone analog; pharmacokinetics; polymerase chain reaction; radiation resistance; radionuclides; receptor expression; somatostatin

DESCRIPTION (provided by applicant): We have developed a novel radiopeptide therapy using the somatostatin analog, 111-In-pentetreotide, to treat malignancies that have a high level of expression of somatostatin receptors. This targeted biologic approach offers several advantages: somatostatin receptors are found in high density in many tumors, 111-In-pentetreotide binds with high affinity to its receptor and is internalized into the cancer cell, 111-In-pentetreotide is minimally immunogenic, and compared to larger, bulkier antibodies, there is better tumor penetration despite an unfavorable hydrostatic gradient. We treated 39 patients with 111-In-pentetreotide and observed therapeutic activity and minimal toxicity. In cloning assays, we established that the combination of 111-In-pentetreotide and camptothecin are additive/synergistic. Camptothecin binds topoisomerase I, stabilize the topoisomerase I:DNA complex as a protein-linked DNA break (PLDB) and produce double strand (ds) DNA breaks that lead to apoptosis. Our research group has established a unique cell model and used this model to characterize several specific mechanisms of resistance to camptothecin. In this proposal, we will conduct a clinical trial to determine the optimal dose of the camptothecin analog, irinotecan, that can be given with 111-In-pentetreotide. We will correlate the pharmacokinetics of the radioisotope and dosimetry with clinical toxicity and response. We will obtain serial biopsies and fully characterize the expression of somatostatin receptors in the tumors of the patients treated in this study. In cell lines that express somatostatin receptors, we will study mechanisms of resistance to radioisotope therapy and to camptothecin. These preclinical studies will identify potentially important mechanisms of in vivo resistance that will be analyzed in the tumor biopsies taken from patients in this study and subequent studies of 111-In-pentetreotide therapy. These translational studies will serve as the basis for expanding a novel therapeutic modality for neuroendocrine cancers.

描述（申请人提供）：我们开发了一种新型放射性肽 使用生长抑素类似物111-In-喷替曲肽治疗 具有高水平生长抑素受体表达的恶性肿瘤。 这种有针对性的生物方法提供了几个优点：生长抑素 在许多肿瘤中发现高密度的111-In-喷曲肽受体， 与其受体具有高亲和力并被内化到癌细胞中， 111-In-喷曲肽具有最低免疫原性，与体积较大、体积较大的 抗体，有更好的肿瘤渗透，尽管不利的 流体静力梯度我们用111-In-喷曲肽治疗了39例患者， 观察到治疗活性和最小毒性。在克隆试验中，我们 确定了111-In-喷曲肽和喜树碱的组合是 加和/协同。喜树碱结合拓扑异构酶I，稳定 拓扑异构酶I：DNA复合物作为蛋白质连接的DNA断裂（PLDB）并产生 双链（ds）DNA断裂导致细胞凋亡。我们的研究小组 建立了一个独特的细胞模型，并用这个模型来表征几个 喜树碱耐药的具体机制。在本提案中，我们将 进行临床试验以确定喜树碱的最佳剂量 类似物伊立替康，可与111-In-喷曲肽一起给药。我们将 将放射性同位素的药代动力学和剂量测定与临床 毒性和反应。我们将进行一系列的活检， 治疗患者肿瘤中生长抑素受体的表达 本研究在表达生长抑素受体的细胞系中，我们将研究 对放射性同位素疗法和喜树碱的抗性机制。这些 临床前研究将确定潜在的重要机制， 将在从患者中采集的肿瘤活检中分析耐药性， 本研究和随后的111-In-喷替曲肽治疗研究。这些 转化研究将作为扩展一种新的治疗方法的基础， 神经内分泌癌的治疗方法。