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Cancer Sci. 2019 Jul;110(7):2247-2257. doi: 10.1111/cas.14067. Epub 2019 Jun 10.

Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts.

Author information

1
Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan.
2
Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.
3
Division of Cancer Stem Cell, National Cancer Center Research Institute, Tokyo, Japan.
4
Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, Japan.
5
Tsukuba Research Laboratory, Eisai, Tsukuba, Japan.
6
Department of Neurosurgery, The University of Tokyo, Tokyo, Japan.
7
Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Hidaka, Japan.
8
Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.

Abstract

Glioblastoma is one of the most devastating human malignancies for which a novel efficient treatment is urgently required. This pre-clinical study shows that eribulin, a specific inhibitor of telomerase reverse transcriptase (TERT)-RNA-dependent RNA polymerase, is an effective anticancer agent against glioblastoma. Eribulin inhibited the growth of 4 TERT promoter mutation-harboring glioblastoma cell lines in vitro at subnanomolar concentrations. In addition, it suppressed the growth of glioblastoma cells transplanted subcutaneously or intracerebrally into mice, and significantly prolonged the survival of mice harboring brain tumors at a clinically equivalent dose. A pharmacokinetics study showed that eribulin quickly penetrated brain tumors and remained at a high concentration even when it was washed away from plasma, kidney or liver 24 hours after intravenous injection. Moreover, a matrix-assisted laser desorption/ionization mass spectrometry imaging analysis revealed that intraperitoneally injected eribulin penetrated the brain tumor and was distributed evenly within the tumor mass at 1 hour after the injection whereas only very low levels of eribulin were detected in surrounding normal brain. Eribulin is an FDA-approved drug for refractory breast cancer and can be safely repositioned for treatment of glioblastoma patients. Thus, our results suggest that eribulin may serve as a novel therapeutic option for glioblastoma. Based on these data, an investigator-initiated registration-directed clinical trial to evaluate the safety and efficacy of eribulin in patients with recurrent GBM (UMIN000030359) has been initiated.

KEYWORDS:

TERT ; RdRP; eribulin; glioblastoma; mass spectrometry imaging

PMID:
31099446
PMCID:
PMC6609810
DOI:
10.1111/cas.14067
[Indexed for MEDLINE]
Free PMC Article

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