Repurposing Oxaliplatin for the Treatment of Glioblastoma

Abstract

Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults, accounting for approximately 40% of primary brain tumors. Even with the most aggressive therapy, the mean survival for patients with GBM is still less than 18 months, highlighting the critical need for new therapeutic strategies for this deadly cancer. Among the strategies under consideration is a repurposing of platinum-based chemotherapeutics. Traditionally considered DNA damaging cytotoxic agents, recent findings suggest that platinum-based chemotherapeutics, especially oxaliplatin (OXA), can induce multi-faceted anti-tumor effects, including modulation of cytokines, transcription factors, and tumor immunosuppressive mechanisms, even at lower concentrations that are not directly cytotoxic. Data suggests that a major alternative effect of OXA is the inhibition of signal transducer and activator of transcription 3 (STAT3), a transcription factor at the core of GBM pathobiology. STAT3 signaling is constitutively active in many gliomas and dictates diverse aspects of glioma biology including angiogenesis, invasion, chemotherapeutic resistance, and immunosuppression. STAT3 also controls and co-opts the primary gliomainfiltrating immune cell, the macrophage, which composes up to 40% of the tumor mass. OXA treatment may overcome the pleiotropic glioma-supporting functions of STAT3. It is likely that OXA therapeutic formulations designed to maximize the multi-faceted effects of OXA, including STAT3 inhibition, will have potent anti-GBM effects, including reprogramming of the tumor microenvironment. Although high-dose platinum-based chemotherapeutics have been investigated for CNS tumors, systemic and direct neuronal toxicity at high doses has thus far limited their use. However, new therapeutic delivery strategies including polymeric nanoparticle formulations capable of improving drug delivery to tumor cells, providing a sustained release of chemotherapeutic at the target site, and significantly reducing toxicity are facilitating the adaptation of these compounds in the CNS. We sought to investigate the multi-faceted anti-tumor effects of low-dose OXA in glioma cells and macrophages, with a particular focus on STAT3 modulation. We hypothesized that OXA will reduce STAT3 activity in glioma cells as well as macrophages and that OXA nanoparticle formulations will sustain STAT3 inhibition in vivo, thereby enabling the use of OXA as a biomaterial inhibitor of STAT3 for the treatment of glioma.