10024- TB-2 COMBINATION THERAPY OF NOVEL MDM4 INHIBITOR CEP-1347 AND IONIZING RADIATION FOR MALIGNANT BRAIN TUMORS

Abstract Radiation therapy represents the cornerstone treatment for malignant brain tumors, the majority of which express wild-type p53. Identification of drugs that promote ionizing-radiation (IR) induced activation of p53, therefore, is expected to help increase the efficacy of radiation therapy for these tumors. The growth inhibitory effects of CEP-1347, a known inhibitor of MDM4 expression, on malignant brain tumor cell lines expressing wild-type p53 were examined, alone or in combination with IR, by dye exclusion and/or colony formation assays. The effects of CEP-1347 on the p53 pathway, alone or in combination with IR, were examined by RT-PCR and Western blot analyses. The combination of CEP-1347 and IR activated p53 in malignant brain tumor cells and inhibited their growth more effectively than either alone. Mechanistically, CEP-1347 and IR each reduced MDM4 expression, but their combination did not result in further reduction. Instead, CEP-1347 promoted IR-induced Chk2 phosphorylation and increased p53 expression in concert with IR in a Chk2-dependent manner. Our findings show that CEP-1347 is capable of promoting Chk2-mediated p53 activation by IR besides inhibiting the expression of MDM4 and thus identify CEP-1347 as a promising radiosensitizer for malignant brain tumors expressing wild-type p53.