P11.51 Repurposing the antipsychotic chlorpromazine for the treatment of glioblastoma multiforme

Abstract

Abstract BACKGROUND Background Glioblastoma multiforme (GBM) is characterized by short survival rates, thus generating a compelling need for more effective therapeutic schemes. Therapeutic approaches involving novel drugs must travel a long and expensive way in order to reach the bedside; drug repurposing and repositioning are viable strategies to develop therapies, involving shorter timelines and lower costs. Here we analyzed the activity of the antipsychotic drug chlorpromazine (CPZ) in hindering GBM growth in vitro and in vivo. The safety of this drug springs from six decades of clinical use as an antipsychotic. CPZ has been very recently identified as an inhibitor of the mitotic kinesin KSP/Eg5 and the AKT/mTOR pathway in human glioma cells. MATERIAL AND METHODS To explore CPZ pharmacodynamic properties, we assayed the effects of CPZ on several GBM cell lines growing in an anchorage-dependent manner or as neurospheres (cancer stem cells). Further experimentation using high-throughput proteomic and metabolomic platforms is underway. RESULTS In our hands CPZ, in the low micromolar range, strongly reduced GBM cell viability after 48 h in both anchorage-dependent cells (IC50=10 microM) and neurospheres (IC50=16 microM), cloning efficiency after 15 d (IC 50=4 and 9 microM, respectively), inducing also, at the respective IC50 concentrations for viability, spindle aberrations up to mitotic catastrophe in almost all cells, as highlighted by means of alpha-tubulin immunofluorescent staining. A Phase II clinical trial involving CPZ, in addition to the adjuvant phase of the Stupp protocol, in GBM patients carrying a hypo-methylated MGMT gene is now ongoing. CONCLUSION We proved the effectiveness of CPZ in potently hindering GBM cell growth, without sparing cancer stem cells. This last characteristic is important in order to overcome disease relapse and drug resistance. Recently, many drugs have been repositioned as potentially useful in GBM and for many of these, such as metformin, disulfiram, chloroquine, sirolimus and others, there are clinical trials that challenge them individually combined with the Stupp protocol. On the basis on our results, we consider the choice to undertake a Phase II clinical trial adding CPZ to TMZ in the adjuvant phase of the Stupp protocol as a rational and ethical option to be pursued