A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model
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 glio...
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| Veröffentlicht in: | Molecular cancer therapeutics 2020-02, Vol.19 (2), p.375-383 |
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| creator | Machida, Yukino Nakagawa, Makoto Matsunaga, Hironori Yamaguchi, Masayuki Ogawara, Yoko Shima, Yutaka Yamagata, Kazutsune Katsumoto, Takuo Hattori, Ayuna Itoh, Masato Seki, Takahiko Nishiya, Yumi Nakamura, Koichi Suzuki, Kanae Imaoka, Tomoki Baba, Daichi Suzuki, Makoto Sampetrean, Oltea Saya, Hideyuki Ichimura, Koichi Kitabayashi, Issay |
| description | 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. |
| doi_str_mv | 10.1158/1535-7163.MCT-18-1349 |
| format | Article |
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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.</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.MCT-18-1349</identifier><identifier>PMID: 31727689</identifier><language>eng</language><publisher>United States</publisher><subject>Administration, Oral ; Animals ; Blood-Brain Barrier - metabolism ; Brain Neoplasms - drug therapy ; Brain Neoplasms - enzymology ; Brain Neoplasms - pathology ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacokinetics ; Enzyme Inhibitors - pharmacology ; Glioblastoma - drug therapy ; Glioblastoma - enzymology ; Glioblastoma - pathology ; Humans ; Isocitrate Dehydrogenase - antagonists & inhibitors ; Isocitrate Dehydrogenase - genetics ; Isocitrate Dehydrogenase - metabolism ; Isoxazoles - chemistry ; Isoxazoles - pharmacokinetics ; Isoxazoles - pharmacology ; Male ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mutation ; Random Allocation ; Xenograft Model Antitumor Assays</subject><ispartof>Molecular cancer therapeutics, 2020-02, Vol.19 (2), p.375-383</ispartof><rights>2019 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-3ee42aa9bc3f83a6f3e5a262a233b426d849f7339f451e7addb77467cfdfbded3</citedby><cites>FETCH-LOGICAL-c408t-3ee42aa9bc3f83a6f3e5a262a233b426d849f7339f451e7addb77467cfdfbded3</cites><orcidid>0000-0002-9474-1154</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3342,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31727689$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Machida, Yukino</creatorcontrib><creatorcontrib>Nakagawa, Makoto</creatorcontrib><creatorcontrib>Matsunaga, Hironori</creatorcontrib><creatorcontrib>Yamaguchi, Masayuki</creatorcontrib><creatorcontrib>Ogawara, Yoko</creatorcontrib><creatorcontrib>Shima, Yutaka</creatorcontrib><creatorcontrib>Yamagata, Kazutsune</creatorcontrib><creatorcontrib>Katsumoto, Takuo</creatorcontrib><creatorcontrib>Hattori, Ayuna</creatorcontrib><creatorcontrib>Itoh, Masato</creatorcontrib><creatorcontrib>Seki, Takahiko</creatorcontrib><creatorcontrib>Nishiya, Yumi</creatorcontrib><creatorcontrib>Nakamura, Koichi</creatorcontrib><creatorcontrib>Suzuki, Kanae</creatorcontrib><creatorcontrib>Imaoka, Tomoki</creatorcontrib><creatorcontrib>Baba, Daichi</creatorcontrib><creatorcontrib>Suzuki, Makoto</creatorcontrib><creatorcontrib>Sampetrean, Oltea</creatorcontrib><creatorcontrib>Saya, Hideyuki</creatorcontrib><creatorcontrib>Ichimura, Koichi</creatorcontrib><creatorcontrib>Kitabayashi, Issay</creatorcontrib><title>A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>Gliomas are the second most common primary brain tumors in adults. 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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. 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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.</abstract><cop>United States</cop><pmid>31727689</pmid><doi>10.1158/1535-7163.MCT-18-1349</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-9474-1154</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Molecular cancer therapeutics, 2020-02, Vol.19 (2), p.375-383 |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Administration, Oral Animals Blood-Brain Barrier - metabolism Brain Neoplasms - drug therapy Brain Neoplasms - enzymology Brain Neoplasms - pathology Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Glioblastoma - drug therapy Glioblastoma - enzymology Glioblastoma - pathology Humans Isocitrate Dehydrogenase - antagonists & inhibitors Isocitrate Dehydrogenase - genetics Isocitrate Dehydrogenase - metabolism Isoxazoles - chemistry Isoxazoles - pharmacokinetics Isoxazoles - pharmacology Male Mice Mice, Inbred NOD Mice, SCID Mutation Random Allocation Xenograft Model Antitumor Assays |
| title | A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model |
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