DDRE-35. PRE-CLINICAL ASSESSMENT OF PPRX-1701, A NANOPARTICLE FORMULATION OF 6-BROMO-ACETOXIME, FOR THE TREATMENT OF GLIOBLASTOMA

Abstract

Abstract We previously showed that derivatives of the Chinese traditional medicine indirubin promote survival in murine glioblastoma models (Williams et al. Cancer Research 2011). However, poor drug solubility hampered further development of this approach. Here we introduce PPRX-1701, a 6’-bromoindirubin acetoxime (BiA) containing drug/polymer nanoparticle formulation which can be injected intravenously at relatively high concentrations. Mechanistically, BiA is thought to act as a broadly selective serine-threonine protein kinase inhibitor, with activity against Src family kinases, GSK-3 and JAK2. Our preliminary data show that intravenous administration of PPRX-1701 is well-tolerated and can reach intracranial murine glioblastoma as assessed by luminescent reporter assays. PPRX-1701 administration leads to improved survival in the GL261 glioblastoma mouse model (median survival 30 days (control), 47 days (treated), p < 0.0001). Treatment with PPRX-1701 was associated with alterations in the tumor immune microenvironment, with reduced Tregs and pro-tumor macrophages, and increased CD8+ T cells. Further preliminary mechanistic studies have shown that PPRX-1701/BiA blocks the expression multiple immunosuppressive molecules in GBM downstream of interferon-g (IFNg) including PD-L1 and indoleamine 2,3-dioxygenase 1 (IDO1) - a key enzyme in the tryptophan–kynurenine–aryl hydrocarbon receptor (Trp–Kyn–AhR) immunosuppressive pathway. BiA promoted more effective T-cell mediated tumor cell killing using patient derived glioblastoma ex vivo co-culture models. This data supports further development of PPRX-1701 is a candidate immunotherapeutic agent for glioblastoma treatment. Ongoing pre-clinical studies are investigating combination with other relevant therapies.