Radioisotope Therapy Targeting the Somatostatin Receptor

描述(申请人提供)：我们开发了一种新的放射性多肽 使用生长抑素类似物111 in-戊四氮治疗 生长抑素受体高表达的恶性肿瘤。 这种有针对性的生物学方法提供了几个优点：生长抑素 在许多肿瘤中发现了高密度的受体，111-in-戊四核苷酸与之结合 与其受体有很高的亲和力，并内化到癌细胞中， 111-in-戊四核苷酸的免疫原性最低，而且与更大、更大的 抗体，有较好的肿瘤穿透性，尽管不利 静水压梯度。我们治疗了39例患者，使用111 in-喷曲肽和 观察到治疗活性和最低毒性。在克隆测试中，我们 确定了111-in-喷曲肽和喜树碱的组合是 添加剂/增效剂。喜树碱结合拓扑异构酶I，稳定 拓扑异构酶I：DNA复合体作为蛋白质连锁的DNA断裂(PLDB)并产生 双链(DS)DNA断裂导致细胞凋亡。我们的研究小组已经 建立了一个独特的细胞模型，并用该模型描述了几个 喜树碱耐药的具体机制。在这项提案中，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，可以用111英寸的戊四肽给药。我们会 放射性同位素的药代动力学和剂量学与临床的关系 毒性和反应。我们会做一系列的活组织检查并充分描述 生长抑素受体在治疗后肿瘤中的表达 在这项研究中。在表达生长抑素受体的细胞系中，我们将研究 对放射性同位素治疗和喜树碱耐药的机制。这些 临床前研究将确定体内潜在的重要机制 将在#年从患者的肿瘤活检中分析耐药性 这项研究和111 in-戊四肽治疗的后续研究。这些 翻译研究将成为扩展一种新疗法的基础 神经内分泌癌的治疗方法。

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.