SHPI Targeted Inhibition by Stibogluconate for Melanoma

描述(申请人提供)：这项申请将支持开发第一个临床PTPase抑制剂，硫代葡萄糖酸盐(SSG)，治疗恶性疾病。SSG，即锑(Sb)结合葡萄糖酸，是一种抗利什曼药物，需要吡啶和免疫细胞才能发挥疗效。在我们最近的研究中，它被确定为一种有效的和特异的PTPase抑制物，SHP-1和SHP-2。作为一种靶向治疗，SSG在体外增强了干扰素诱导的信号和生长抑制，增强了IL-2诱导的T细胞增殖，并在体外增强了T细胞、NK细胞和巨噬细胞的活性。SSG联合干扰素-α2或IL-2对小鼠模型有明显的治疗作用。SSG已在欠发达国家用于治疗数千名内脏利什曼病患者，其剂量大大高于预期的抑制PTPase的剂量。这一数据为SSG作为SHP-1和SHP-2的药库的第一阶段试验提供了理论基础。我们选择转移性黑色素瘤作为初始肿瘤进行评估。在拟议的第一阶段试验中确认安全性并证明增强的细胞因子信号将导致使用SSG进行干扰素-a2或白介素2的第二阶段和第三阶段研究。我们推测，通过SSG靶向SHP-1和SHP-2，可以增加干扰素-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验证我们的假设：1)在黑色素瘤患者中启动SSG/干扰素-a2组合的I期试验，以确定该组合的安全性、SSG的药代动力学、抑制患者外周血细胞中的SHP-1以及随后增强由干扰素-a2激活的信号。2)在黑色素瘤患者中进行SSG/IL-2联合治疗的I期试验，以确定该联合治疗的安全性以及SSG对IL-2诱导的免疫细胞激活的作用。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以改进基于干扰素-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发展。

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.