Fimepinostat is a dual inhibitor of tumor and angiogenesis in glioblastoma and synergizes with temozolomide through suppressing MYC

Glioblastoma, an aggressive brain tumor that largely depends on angiogenesis, has limited treatment options and poor prognosis. This study explores the therapeutic potential of fimepinostat, a dual HDAC/PI3K inhibitor, as a single agent alone and in combination of temozolomide in glioblastoma using preclinical tumor and angiogenesis models. We show that fimepinostat at nanomolar concentrations inhibited proliferation and induced apoptosis in a panel of glioblastoma cell lines. In addition, fimepinostat inhibited capillary network formation of microvascular endothelial cells derived from patients, indicating that fimepinostat inhibits glioblastoma angiogenesis. Combination index analysis indicates that fimepinostat and temozolomide is synergistic in inhibiting glioblastoma. Consistent with the <i>in vitro</i> findings, fimepinostat significantly inhibited glioblastoma growth in mice without causing any toxicity. The combination of fimepinostat and temozolomide significantly inhibited tumor growth and prolonged survival compared to monotherapy or control. Mechanism studies confirmed that fimepinostat acts on glioblastoma cells through suppressing Akt/MYC. Our findings suggest that dual targeting of tumor and angiogenesis by fimepinostat may provide an alternative approach for anti-glioblastoma therapy.