PREVENZIONE DELLA RESISTENZA A FARMACI CHEMIOTERAPICI: IL GLIOBLASTOMA COME PARADIGMA

Chemoresistance in Glioblastoma (GBM) is one of the major pitfalls which concurs to the treatment failure in glioblastoma patients. KDMs family is an enzymatic class of “epigenetic erasers” which are involved in chemoresistance and their expression is higher in glioblastoma cells resistant to Temozolomide (TMZ), the chemotherapic drug utilized in standard clinical protocols. We have determined the biological and functional effects of JIB 04 and CPI-455, two KDM inhibitors, on glioblastoma cells in an in vitro and in vivo experimental plan. According to our results, both molecules are particularly effective against TMZ-resistant fraction of glioblastoma cells respect to the native ones. JIB 04, in particular, has as its main target KDM5A, a KDMs member, and activates autophagic and apoptotic pathways, interferes with cell cycle progression, inhibits clonogenicity and dephosphorylation of Akt in PI3K pathway. The in vitro treatments combining Temozolomide and JIB 04 showed that these molecules have a synergistic effect. Finally, we studied, in vivo, the permeability of JIB 04 through the blood-brain barrier and found that this molecule reaches the brain with bioactive concentrations. Besides, an in vivo pilot experiment in an orthotopic GBM xenograft model indicated a trend towards greater survival in mice treated with JIB04 (HR = 0.5). We hypothesized that the combination of cytotoxic drugs like TMZ and molecules that act on the epigenome could offer the opportunity to develop new therapies for this invariably lethal disease.