EXTH-19. A COMBINATION OF PALBOCICLIB AND RADIOTHERAPY IMPROVES SURVIVAL IN GLIOBLASTOMA

New treatments are urgently needed for patients diagnosed with MGMT unmethylated glioblastoma. Palbociclib (Pfizer) is a CDK4/6 inhibitor. The aim of this study was to assess efficacy of palbociclib as a monotherapy and in combination with radiotherapy on glioblastoma patient derived cell lines (PDCLs) and xenografts that were MGMT unmethylated and RB1 proficient. A panel of 6 PDCLs were treated with different concentrations of palbociclib alone, and with radiotherapy (4Gy). We assessed the effect of treatment using clonogenic assays (the ability to form tumor colonies). We also measured expression of RB1, CDK4, CDK6, H2AX and cleaved-PARP (a measure of apoptosis). The PDCL, RN1 was intracranially injected into the brains of Nod Skid gamma mice and treated in vivo with palbociclib (75mg/kg; gavage) and Radiotherapy (4Gy). Palbociclib alone was effective in inhibition of tumor cell proliferation in all 6 PDCLs with concentrations ranging from 11uM to 22uM. We found significant synergy when palbociclib was administered with radiotherapy. Protein expression levels of RB1, CDK4 and CDK6 were significantly inhibited with the combination treatment and H2AX and cleaved PARP were induced. In vivo, significantly longer survival was observed in mice treated with the combination of palbociclib and radiotherapy. The median survival was 100.5 days (combination treatment) compared to 93 days (control); 83 days (radiotherapy only) and 92 days (Palbociclib only) (p value=0.0488). The combination of palbociclib and radiotherapy significantly improves overall survival in our xenografts models. In mice, the combination is safe and crosses the blood brain barrier. A phase I/II clinical trial for glioblastoma patients with MGMT unmethylated and RB1 proficient tumors is currently in development.