SHPI Targeted Inhibition by Stibogluconate for Melanoma

描述（由申请人提供）：本申请将支持开发第一种用于恶性疾病的临床PTR抑制剂葡萄糖酸锑（SSG）。SSG，锑（Sb）共轭葡萄糖酸，是一种抗利什曼原虫药物，需要细胞因子和免疫细胞的疗效。在我们最近的研究中，它已被鉴定为PTPases，SHP-1和SHP-2的有效和特异性抑制剂。与作为靶向治疗剂的这种活性一致，SSG在体外增强IFN诱导的信号传导和生长抑制，在体外增强IL-2诱导的T细胞增殖以及T细胞、NK细胞和巨噬细胞的活性。SSG与IFN-a2或IL-2的组合在小鼠模型中产生疗效。SSG已在不发达国家临床上用于数千名内脏利什曼病患者，剂量大大高于预期抑制PTPases的剂量。该数据为SSG作为SHP-1和SHP-2的药效团的I期试验提供了依据。我们选择转移性黑色素瘤作为初始肿瘤进行评估。在所提议的I期试验中安全性的确认和增强的细胞因子信号传导的证明将导致IFN-α 2或IL-2与SSG的II期和III期研究。我们假设，IFN-α 2或IL-2抗黑色素瘤活性可以通过用SSG靶向SHP- 1和SHP-2来增加。我们将通过追求以下具体目标来测试我们的假设：1）在黑色素瘤患者中启动SSG/IFN-α 2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IFN-α 2激活的信号传导的增强。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和SSG对IL-2诱导的免疫细胞活化的活性。拟议的研究将阐明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以改善晚期黑色素瘤的基于IFN-α 2或IL-2的治疗提供概念证明，并显着提高PTSD抑制剂作为靶向治疗剂的开发进展。

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.