Annual Report 2019
Division of Hematological Malignancy
Issay Kitabayashi, Kazutsune Yamagata, Takuo Katsumoto, Ayuna Hattori, Haruka Shinohara, Junpei Ito, Yukiko Aikawa, Tomoko Shoji
Introduction
Isocitrate dehydrogenase (IDH) mutations are frequently detected in various cancers including acute myeloid leukemia, glioma and chondrosarcoma, and contribute to malignant transformation. Mutant IDH inhibitors are therefore potential novel anticancer drugs for IDH mutant tumors. Mutant IDH catalyzes the conversion of α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), which induces an aberrant epigenetic status and contributes to malignant progression. It is therefore a potential therapeutic target for IDH mutant tumors.
The Team and What We Do
Our research purpose involves establishing new therapeutic methods by identifying molecular targets that are essential for maintaining hematological malignancies, especially AML stems.
Research activities
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 for glioblastomas, which have poor prognosis. We developed 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.
Chondrosarcoma is the second most common malignant bone tumor. It is characterized by low vascularity and an abundant extracellular matrix, which confer these tumors resistance to chemotherapy and radiotherapy. There are currently no effective treatment options for relapsed or dedifferentiated chondrosarcoma, and new targeted therapies need to be identified. We examined the efficacy of the inhibition of mutant IDH1 as an antitumor approach in chondrosarcoma cells in vitro and in vivo, and investigated the association between the IDH mutation and chondrosarcoma cells. DS-1001b, a novel, orally bioavailable, selective mutant IDH1 inhibitor, impaired the proliferation of chondrosarcoma cells with IDH1 mutations in vitro and in vivo, and decreased 2-HG levels. RNA-seq analysis showed that inhibition of mutant IDH1 promoted chondrocyte differentiation in the conventional chondrosarcoma L835 cell line and caused cell cycle arrest in the dedifferentiated JJ012 cell line. Mutant IDH1-mediated modulation of SOX9 and CDKN1C expression regulated chondrosarcoma tumor progression, and DS-1001b upregulated the expression of these genes via a common mechanism involving the demethylation of H3K9me3. DS-1001b treatment reversed the epigenetic changes caused by aberrant histone modifications. The present data strongly suggest that inhibition of mutant IDH1 is a promising therapeutic approach in chondrosarcoma, particularly for the treatment of relapsed or dedifferentiated chondrosarcoma.
Clinical trials
Phase II clinical trials for the mIDH1 inhibitor and EZH1/2 dual inhibitor are ongoing at the National Cancer Center Hospital and elsewhere.
Education
A post-doctoral fellow and a graduate student were trained for research.
Future prospects
Based on our research, we are developing anti-cancer therapies for cancer patients.
List of papers published in 2019
Journal
1. Machida Y, Nakagawa M, Matsunaga H, Yamaguchi M, Ogawara Y, Shima Y, Yamagata K, Katsumoto T, Hattori A, Itoh M, Seki T, Nishiya Y, Nakamura K, Suzuki K, Imaoka T, Baba D, Suzuki M, Sampetrean O, Saya H, Ichimura K, Kitabayashi I. A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model. Mol Cancer Ther, 19:375-383, 2020
2. Nakagawa M, Fujita S, Katsumoto T, Yamagata K, Ogawara Y, Hattori A, Kagiyama Y, Honma D, Araki K, Inoue T, Kato A, Inaki K, Wada C, Ono Y, Yamamoto M, Miura O, Nakashima Y, Kitabayashi I. Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma. Cancer Sci, 110:194-208, 2019
3. Tanaka M, Ishige A, Yaguchi M, Matsumoto T, Shirouzu M, Yokoyama S, Ishikawa F, Kitabayashi I, Takemori T, Harada M. Development of a simple new flow cytometric antibody-dependent cellular cytotoxicity (ADCC) assay with excellent sensitivity. J Immunol Methods, 464:74-86, 2019
4. Hayashi Y, Harada Y, Kagiyama Y, Nishikawa S, Ding Y, Imagawa J, Shingai N, Kato N, Kitaura J, Hokaiwado S, Maemoto Y, Ito A, Matsui H, Kitabayashi I, Iwama A, Komatsu N, Kitamura T, Harada H. NUP98-HBO1-fusion generates phenotypically and genetically relevant chronic myelomonocytic leukemia pathogenesis. Blood Adv, 3:1047-1060, 2019
5. Nakagawa M, Nakatani F, Matsunaga H, Seki T, Endo M, Ogawara Y, Machida Y, Katsumoto T, Yamagata K, Hattori A, Fujita S, Aikawa Y, Ishikawa T, Soga T, Kawai A, Chuman H, Yokoyama N, Fukushima S, Yahiro K, Kimura A, Shimada E, Hirose T, Fujiwara T, Setsu N, Matsumoto Y, Iwamoto Y, Nakashima Y, Kitabayashi I. Selective inhibition of mutant IDH1 by DS-1001b ameliorates aberrant histone modifications and impairs tumor activity in chondrosarcoma. Oncogene, 38:6835-6849, 2019