SHPI Targeted Inhibition by Stibogluconate for Melanoma

SHPI 葡萄糖酸锑靶向抑制黑色素瘤

• 批准号: 7095014
• 负责人: ERNEST C BORDEN
• 金额: $ 21.94万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-21 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095014
• 关键词: clinical research; clinical trial phase I; cytokine; melanoma

DESCRIPTION (provided by applicant): This application will support the development of the first clinical PTPase inhibitor, stibogluconate (SSG), ttor malignant disease. SSG, antimony (Sb) conjugated gluconic acid, is an anti-leishmania drug requiring pytokines and immune cells for efficacy. It has been identified as a potent and specific inhibitor of PTPases, SHP-1 and SHP-2, in our recent studies. Consistent with this activity as a targeted therapeutic, SSG augments IFN-induced signaling and growth inhibition in vitro, IL-2-induced T-cell proliferation and the activities of T cells, NK cells and macrophages in vitro. In combination, SSG with IFN-a2 or IL-2 resulted in curative effects in mouse models. SSG has been used clinically in underdeveloped countries for thousands of patients with visceral leishmaniasis at doses substantially greater than those expected to inhibit PTPases. This data provides rationale for Phase I trials of SSG as a pharmocophore for SHP-1 and SHP-2. We have selected as an initial tumor for evaluation, metastatic melanoma. Confirmation of safety and demonstration of enhanced cytokine signaling in the proposed Phase I trials will result in Phase II and Phase III studies of either IFN-a2 or IL-2 with SSG. We hypothesize that IFN-a2 or IL-2 anti-melanoma activity can be increased by targeting SHP- 1 and SHP-2 with SSG. We will test our hypothesis by pursuing the following specific aims: 1) Initiate a Phase I trial of SSG/ IFN-a2 combination in melanoma patients to define the safety of the combination, pharmacokinetics of SSG, inhibition of SHP-1 in patients' peripheral blood cells with subsequent augmentation of signaling activated by IFN-a2. 2) Undertake a Phase I trial of SSG/IL-2 combination in melanoma patients to define the safety of this combination and SSG activity on IL-2-induced immune cell activation. The proposed studies will elucidate the potential of SSG as a novel anti-melanoma agent, provide proof of concept for targeting SHP-1 and SHP-2 to improve IFN-a2 or IL-2-based therapy for advanced melanoma, and significantly enhance progress towards development of PTPase inhibitors as targeted therapeutics.

描述（由申请人提供）：本申请将支持第一个临床 PTPase 抑制剂葡萄糖酸锑 (SSG) 的开发，用于治疗恶性疾病。 SSG（锑 (Sb) 缀合葡萄糖酸）是一种抗利什曼原虫药物，需要细胞因子和免疫细胞才能发挥功效。在我们最近的研究中，它已被确定为 PTPase、SHP-1 和 SHP-2 的有效且特异性抑制剂。与作为靶向治疗的这种活性一致，SSG 增强了体外 IFN 诱导的信号传导和生长抑制、IL-2 诱导的 T 细胞增殖以及体外 T 细胞、NK 细胞和巨噬细胞的活性。 SSG 与 IFN-a2 或 IL-2 相结合，在小鼠模型中产生了疗效。 SSG 已在不发达国家临床上用于治疗数千名内脏利什曼病患者，其剂量远高于预期抑制 PTP 酶的剂量。该数据为 SSG 作为 SHP-1 和 SHP-2 药效基团的 I 期试验提供了依据。我们选择转移性黑色素瘤作为初始评估肿瘤。在拟议的 I 期试验中确认安全性并证明细胞因子信号传导增强，将导致 IFN-a2 或 IL-2 与 SSG 的 II 期和 III 期研究。我们假设通过用 SSG 靶向 SHP-1 和 SHP-2 可以增加 IFN-a2 或 IL-2 的抗黑色素瘤活性。我们将通过追求以下具体目标来检验我们的假设：1) 在黑色素瘤患者中启动 SSG/IFN-a2 组合的 I 期试验，以确定组合的安全性、SSG 的药代动力学、患者外周血细胞中 SHP-1 的抑制以及随后由 IFN-a2 激活的信号增强。 2) 在黑色素瘤患者中进行 SSG/IL-2 组合的 I 期试验，以确定该组合的安全性以及 SSG 对 IL-2 诱导的免疫细胞激活的活性。拟议的研究将阐明SSG作为新型抗黑色素瘤药物的潜力，为靶向SHP-1和SHP-2以改善晚期黑色素瘤的基于IFN-a2或IL-2的治疗提供概念证明，并显着促进PTPase抑制剂作为靶向治疗药物的开发进展。