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. ? ? ?
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