Abstract 816: Antitumor efficacy of a novel anthracycline derivative aldoxorubicin in an orthotopic mouse model of glioblastoma

Abstract

Abstract Background: Glioblastoma multiforme (GBM) is the most common and most malignant of all primary brain tumors with a median survival of only 12-15 months despite standard-of-care, including surgical resection, radiotherapy, and temozolomide. In this study, we evaluated the preclinical efficacy of a novel albumin-binding prodrug of doxorubicin, aldoxorubicin, for the treatment of GBM in a murine model, and compared its antitumor effect with doxorubicin. Methods: U87MG human glioma cells (5 x 105) expressing firefly luciferase (U87-luc) were stereotactically injected into the left striatum of nude mice. After 12 days, mice (n=8 in each group) received either vehicle or a single intravenous injection of 24 mg/kg [3/4 maximum tolerated dose (MTD)] aldoxorubicin, or 6 mg/kg (3/4 MTD) of doxorubicin once a week. Tumor growth was monitored weekly using in vivo quantitative bioluminescence imaging (photons/sec), and survival compared using Kaplan-Meier curves. Aldoxorubicin concentrations in the tumors and uninvolved brain tissues harvested from these mice were quantified by HPLC. Results: All animals in the control and doxorubicin groups developed large tumors (median tumor size 5.0 x 108 photons/sec) by day 22 and died within 34 days after tumor implantation. During the same period, animals treated with aldoxorubicin displayed significant tumor regression (median tumor size 1.6 x 108 photons/sec) and remained alive with a median survival of more than 60 days. Fluorescence microscopy showed selective accumulation of aldoxorubicin, but not doxorubicin, in the tumor tissues resected from tumor-bearing mice 24h following intravenous injection of these drugs. HPLC analysis revealed 3- to 4-fold higher aldoxorubicin retention in the tumor tissues than in the surrounding brain tissues. Immunohistochemical evaluation of aldoxorubicin-treated tumors showed that the drug significantly decreased the number of dividing cells stained with the nuclear-localized Ki67 proliferation marker, and activated the apoptosis effector cleaved caspase-3. Conclusion: Our preliminary findings indicate that aldoxorubicin, but not doxorubicin, administered intravenously induces tumor regression and significantly increases survival in an in vivo xenograft tumor model employing intracranial injection and growth of human GBM cells. Preferential accumulation and prolonged retention in the tumor tissues, combined with its safety profile, provide significant rationale for the assessment of aldoxorubicin in the treatment of patients with GBM tumors. Citation Format: Om Prakash, Albero E. Musto, Dorota Wyczechowska, Luis Marrero, Adriana Zapata, Chelsey P. Walker, Christopher Parsons, Scott Wieland, Daniel Levitt, Krzysztof Reiss. Antitumor efficacy of a novel anthracycline derivative aldoxorubicin in an orthotopic mouse model of glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 816. doi:10.1158/1538-7445.AM2014-816