ATPS-84HYDROXYUREA SENSITIZES PATIENT-DERIVED GLIOBLASTOMA TUMORS TO TEMOZOLOMIDE IRRESPECTIVE OF MGMT STATUS

Abstract

Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor. Standard-of-care treatment involves radiation, chemotherapy (temozolomide; TMZ), and maximal surgical resection of the tumor. The 5-year survival rate of patients with GBM is <10%, a colossal failure that has been partially attributed to intrinsic and/or acquired resistance to TMZ through MGMT tumor status. Through drug screening, we identified hydroxyurea (HU), an FDA-approved drug, to sensitize GBM cells to TMZ. HU synergized with TMZ in both newly diagnosed GBM with different MGMT status as well as recurrent, TMZ-resistant, tumors in culture as well as in different quantitative intracranial in vivo models. HU acts specifically on the S-phase of the cell cycle by inhibiting the enzyme ribonucleotide reductase M2. Knockdown of this enzyme using RNA interference and other known inhibitors exerted a similar effect to HU in combination with TMZ both in vitro and in vivo. Although HU has been previously evaluated in malignant gliomas in combination with radiation or cytotoxic chemotherapy, and has shown limited efficacy, it was never evaluated in combination with TMZ. In summary, we demonstrate preclinical efficacy of ribonucleotide reductase inhibition using hydroxyurea in combination with TMZ for the treatment of glioblastoma, which warrant further evaluation in a clinical setting.