A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model.

Yukino Machida,Tomoki Imaoka,Yutaka Shima,Yoko Ogawara,Masato Itoh,Issay Kitabayashi,Kanae Suzuki,Takahiko Seki,Makoto Suzuki,Takuo Katsumoto,Masayuki Yamaguchi,Koichi Ichimura,Daichi Baba,Oltea Sampetrean,Makoto Nakagawa,Hironori Matsunaga,Hideyuki Saya,Ayuna Hattori,Kazuya Yamagata ,Yoshiaki Nishiya ,Kōichi Nakamura

doi:10.1158/1535-7163.mct-18-1349

Abstract

Gliomas are the second most common primary brain tumors in adults. They are treated with combination therapies, including surgery, radiotherapy, and chemotherapy. There are currently limited treatment options for recurrent gliomas, and new targeted therapies need to be identified, especially in glioblastomas, which have poor prognosis. Isocitrate dehydrogenase (IDH) mutations are detected in various tumors, including gliomas. Most patients with IDH mutant glioma harbor the IDH1R132H subtype. Mutant IDH catalyzes the conversion of α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), which induces aberrant epigenetic status and contributes to malignant progression, and is therefore a potential therapeutic target for IDH mutant tumors. The present study describes a novel, orally bioavailable selective mutant IDH1 inhibitor, DS-1001b. The drug has high blood-brain barrier (BBB) permeability and inhibits IDH1R132H. Continuous administration of DS-1001b impaired tumor growth and decreased 2-HG levels in subcutaneous and intracranial xenograft models derived from a patient with glioblastoma with IDH1 mutation. Moreover, the expression of glial fibrillary acidic protein was strongly induced by DS-1001b, suggesting that inhibition of mutant IDH1 promotes glial differentiation. These results reveal the efficacy of BBB-permeable DS-1001b in orthotopic patient-derived xenograft models and provide a preclinical rationale for the clinical testing of DS-1001b in recurrent gliomas.

Highlights

Gliomas are the second most common primary brain tumors in adults and comprise three major histologic subtypes: astrocytomas, oligodendrogliomas, and glioblastomas (GBM)
Cell-free enzymatic assays conducted without any preincubation of the enzyme and compound in the absence of substrate demonstrated that DS-1001b strongly inhibited mutant IDH1, but not wild-type IDH1 or mutant IDH2 (Table 1)
We developed a novel blood–brain barrier (BBB)-permeable mutant IDH1 inhibitor, DS-1001b, and investigated its effect in mutant IDH1 GBM using subcutaneous and intracranial patient-derived xenograft (PDX) models

Summary

A Potent Blood–Brain Barrier-Permeable Mutant IDH1

Yukino Machida1,2, Makoto Nakagawa1,3,4, Hironori Matsunaga5, Masayuki Yamaguchi6, Yoko Ogawara1, Yutaka Shima1, Kazutsune Yamagata1, Takuo Katsumoto1, Ayuna Hattori1, Masato Itoh5, Takahiko Seki5, Yumi Nishiya7, Koichi Nakamura7, Kanae Suzuki7, Tomoki Imaoka7, Daichi Baba8, Makoto Suzuki9, Oltea Sampetrean10, Hideyuki Saya10, Koichi Ichimura11, and Issay Kitabayashi1

Introduction

Materials and Methods

Results

Discussion

Disclosure of Potential Conflicts of Interest