PHASE I EVALUATION OF SODIUM STIBOGLUICONATE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 SSG，锑（Sb）共轭葡萄糖酸，是一种抗利什曼原虫药物，已知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。作为一种有针对性的治疗，SSG增强IFN诱导的信号传导和体外生长抑制，IL-2诱导的T细胞增殖和T细胞，NK细胞和巨噬细胞在体外的活动，和抗肿瘤活性的IFN-？2和IL-2在小鼠模型中的表达。 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。 在拟议的I期试验中，安全性的确认和增强细胞因子信号传导的证明将导致IFN-？2或IL-2与SSG。 我们假设IFN-？2或IL-2的抗黑色素瘤活性可以通过用SSG或该PTR的类似物抑制剂靶向SHP-1和SHP-2来增加。 我们将通过以下具体目标来检验我们的假设：1）启动SSG/ IFN-？2组合在黑色素瘤患者中，以确定组合的安全性，SSG的药代动力学，抑制患者外周血细胞中的SHP-1，随后增强IFN-γ激活的信号传导。2. 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。 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提高IFN-？2或IL-2为基础的治疗晚期黑色素瘤，并显着提高进展的PTK抑制剂作为靶向治疗。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. SSG, antimony (Sb) conjugated gluconic acid, is an anti-leishmania drug known to require cytokines 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 activities of T cells, NK cells and macrophages in vitro, and antitumor activity of IFN-?2 and IL-2 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-?2 or IL-2 with SSG. We hypothesize that IFN-?2 or IL-2 anti-melanoma activity can be increased by targeting SHP-1 and SHP-2 with SSG or analog inhibitors of this PTPase. We will test our hypothesis by pursuing the following specific aims: 1) Initiate a Phase I trial of SSG/ IFN-?2 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-?2. 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 a proof of concept for targeting SHP-1 and SHP-2 to improve IFN-?2 or IL-2-based therapy for advanced melanoma, and significantly enhance progress of PTPase inhibitors as targeted therapeutics.