EXTH-54. In vivo characterization of preclinical efficacy of brincidofovir against glioblastoma

Brincidofovir (BCV) is lipid-conjugated cidofovir characterized by a lack of nephrotoxicity and superior activity compared to cidofovir. BCV exerts antitumor effects on glioblastoma (GBM) in vitro, regardless of MGMT status. BCV and its active metabolite were detected in the animal brain following peripheral treatment with BCV. This study examined the preclinical activity of BCV against GBM in vivo. The efficacy of BCV monotherapy was tested in patient-derived xenograft (PDX) models using GBM6, GBM14, GBM16, GBM39, and GBM43 cells. The combinatory effects of BCV with the standard of care for GBM were tested in a xenograft model using U87MG cells. METHODS Nude mice were orthotopically implanted with firefly luciferase-transfected human GBM cells. In the monotherapy study, mice were administered vehicle or BCV (10 or 20 mg/kg i.p.) twice weekly (BIW). In the combination study, mice were administered temozolomide 2 mg/kg p.o. (TMZ) once daily for 5 days, whole brain radiotherapy (WBRT) of 1.5 Gy for 5 days plus TMZ, or bevacizumab 5 mg/kg i.p. BIW alone or concomitant with BCV 10 mg/kg. Bioluminescence imaging was performed BIW after i.p. injection of D-Luciferin to evaluate intracerebral tumor growth. Survival was evaluated using the Kaplan-Meier method. RESULTS BCV alone at 10 or 20 mg/kg caused significant tumor suppression and significant prolongation of survival in all PDX models except GBM14 tumor growth. TMZ alone or WBRT plus TMZ significantly inhibited tumor growth and enhanced survival compared to vehicle; both of which were significantly augmented by the addition of BCV 10 mg/kg. Monotherapy with bevacizumab or BCV 10 mg/kg significantly increased survival compared to the vehicle control and, though significance was not reached, their combination further prolonged median survival. CONCLUSIONS BCV monotherapy suppressed tumor growth and prolonged survival in PDX models of GBM and improved the efficacy of the standard of care for GBM.