SHP1 Targeted Inhibition by Stibogluconate for Melanoma

葡萄糖酸锑对黑色素瘤的 SHP1 靶向抑制

• 批准号: 7278666
• 负责人: ERNEST C BORDEN
• 金额: $ 23.97万
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7278666
• 关键词: Advanced Malignant Neoplasm; Antimony; Blood Cells; Cells; Chemicals; Clinical; Country; Cytokine Signaling; Data; Development; Disease; Dose; Drug Kinetics; Effectiveness; Evaluation; Face; Growth; HC phosphatase; Immune; Immune Cell Activation; In Vitro; Interferons; Interleukin 2 Receptor; Interleukin-2; Interleukins; Janus kinase; Leishmania; Malignant - descriptor; Metastatic Melanoma; NR0B2 gene; Natural Killer Cells; PTPN11 gene; PTPN6 gene; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase III Clinical Trials; Protein Tyrosine Phosphatase; Safety; Signal Transduction; Signal Transduction Inhibitor; Stibogluconate Sodium; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Visceral Leishmaniasis; base; concept; cytokine; gene induction; gluconate; improved; in vivo; inhibitor/antagonist; kinase inhibitor; macrophage; melanoma; mouse model; novel; response; small molecule; success; therapeutic target; tumor

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）：该申请将支持开发首个用于治疗恶性疾病的PTPase抑制剂stiboglconate （SSG）。锑（Sb）偶联葡萄糖酸是一种抗利什曼原虫的药物，需要细胞因子和免疫细胞才能发挥作用。在我们最近的研究中，它已被确定为PTPases， SHP-1和SHP-2的有效和特异性抑制剂。与这种靶向治疗的活性一致，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。在小鼠模型中，SSG与IFN-a2或IL-2联合使用可产生疗效。在不发达国家，SSG已在临床上用于治疗数千名内脏利什曼病患者，其剂量远远大于预期抑制PTPases的剂量。这一数据为SSG作为SHP-1和SHP-2的药效载体的I期试验提供了理论依据。我们选择了转移性黑色素瘤作为初始肿瘤进行评估。在拟议的I期试验中，IFN-a2或IL-2与SSG的II期和III期研究将证实安全性和增强细胞因子信号传导。我们假设通过SSG靶向SHP- 1和SHP-2可以提高IFN-a2或IL-2抗黑色素瘤活性。我们将通过追求以下具体目标来验证我们的假设：1)在黑色素瘤患者中启动SSG/ IFN-a2联合的I期试验，以确定联合的安全性、SSG的药代动力学、患者外周血中SHP-1的抑制以及随后由IFN-a2激活的信号的增强。2)在黑色素瘤患者中开展SSG/IL-2联合的I期试验，以确定该联合的安全性以及SSG对IL-2诱导的免疫细胞活化的活性。这些研究将阐明SSG作为一种新型抗黑色素瘤药物的潜力，为靶向SHP-1和SHP-2改善基于IFN-a2或il -2的晚期黑色素瘤治疗提供概念证明，并显著促进PTPase抑制剂作为靶向治疗药物的开发进展。