Annual Report 2019
Division of Brain Tumor Translational Research
Koichi Ichimura, Tatsuya Ozawa, Arata Tomiyama, Yoshiko Nakano, Yuko Matsushita, Mai Kitahara, Yuko Hibiya, Sanae Matsuzaki, Yuki Yomoda, Kaishi Satomi, Masamichi Takahashi, Mutsumi Takadera, Eita Uchida, Shun Yamamuro, Tatsuya Kobayashi, Tomoyuki Nakano, Yuki Yamagishi, Yui Kimura, Daisuke Kawauchi, Takaki Omura
Introduction
Our laboratory focuses on translational research on various types of malignant brain tumors to improve diagnostic accuracy, identify novel molecular markers and develop new treatment. In order to meet the molecular criteria defined by the WHO Classification published in 2016 and being recommended by cIMPACT-NOW, we develop robust molecular tests and perform molecular diagnostics for brain tumors through a number of nationwide multi-center collaboration initiatives. We also develop novel targeted therapies, perform preclinical studies and conduct clinical trial in collaboration with clinicians.
The Team and What We Do
We are a team of neurosurgeons, pediatric neuro-oncologists, postgraduate students and laboratory technicians who are dedicated to researching brain tumors. We provide molecular analysis for the patients operated on at the Department of Neurosurgery and Neuro-Oncology at the National Cancer Center Hospital as well as a number of external collaborators. We also oversee molecular tests for the JCCG (Japan Children’s Cancer Group) central diagnostic service, which saw us examine 157 pediatric brain tumors in 2019.
Research activities
1. olecular diagnosis of pediatric brain tumors
Among the various pediatric brain tumors collected through the JCCG and iGCT (Intracranial Germ Cell Tumor Consortium) as well as other collaborations, we conduct targeted hot-spot mutation screening and other known recurrent fusions depending on the tumor types. For those tumors that do not have characteristic mutations/fusions, targeted sequencing, genome-wide DNA methylation analysis and RNA sequencing are performed to investigate their molecular pathogenesis, and the results are published as molecular case reports.
2. olecular analysis for adult gliomas
We have developed a novel in vitro diagnostic kit to determine 1p/19q codeletion to facilitate molecular diagnostics of adult gliomas in collaboration with Leica Microsystems. We are investigating molecular markers using tumor specimens collected from patients enrolled in several other ongoing clinical trials for brain tumors.
3. evelopment of a novel targeted therapy for glioblastoma
Our preclinical experiments in collaboration with the Division of Cancer Stem Cell successfully demonstrated the anti-tumor effect of eribulin against glioblastoma in a series of mouse brain tumor models in which human PDXs were transplanted into the brain. The results were published. A series of preclinical studies for other molecular targeted drugs or anticancer agents was also performed.
4. enomic analysis of central nervous system germ cell tumors (CNS GCTs)
We published a large scale clinico-molecular study on CNS GCTs as well as an immune cell profiling in germinomas. We are developing a novel targeted therapy against CNS GCTs using a patient-derived yolk sac tumor cell line which we established at the National Cancer Center. A single cell transcriptomic study and a whole genome sequencing in CNS GCTs are also being conducted.
Clinical trials
We analyzed the two-year follow-up data of the BIOMARK clinical trial, in which the efficacy of Bevacizumab together with the Stupp regimen on glioblastomas was evaluated. We compared the results with molecular data and gave a report in the Annual Meeting of the Society for Neuro-Oncology. An investigator-initiated clinical trial to test the efficacy of eribulin against therapy-refractory GBM was conducted (ENIGMA), and enrolment of 38 patients was successfully completed. A molecular analysis of tumor samples from the patients enrolled in ENIGMA is being conducted.
Education
Eleven clinician-scientists including seven postgraduate students (PhD) did research work between April 2019 and March 2020 at the Division of Brain Tumor Translational Research and presented the results at the Japan Society for Neuro-Oncology Annual Meeting.
Future prospects
We continue to organize nationwide and international collaborations and conduct research on all types of malignant brain tumors as the leading translational research center for malignant brain tumors in Japan. We will continue to offer a molecular diagnostic service for brain tumors, including the central diagnostic system provided through JCCG. Novel targeted therapies are being developed, and we will continue to perform a thorough genomic analysis to investigate molecular pathogenesis of brain tumors. Our lab acts as a hub for young dedicated clinician investigators to meet, collaborate and collectively push neuro-oncological research forward. Our goal is to improve the diagnosis and treatment of brain tumor patients in Japan, and make significant scientific contributions to the international neuro-oncological community through publication, international collaboration and organizing the 19th International Symposium on Pediatric Neuro-Oncology in 2020.
List of papers published in 2019
Journal
1. Takami H, Perry A, Graffeo CS, Giannini C, Narita Y, Nakazato Y, Saito N, Nishikawa R, Matsutani M, Ichimura K, Daniels DJ. Comparison on epidemiology, tumor location, histology, and prognosis of intracranial germ cell tumors between Mayo Clinic and Japanese consortium cohorts. J Neurosurg, 1-11, 2020
2. Yamasaki K, Nakano Y, Nobusawa S, Okuhiro Y, Fukushima H, Inoue T, Murakami C, Hirato J, Kunihiro N, Matsusaka Y, Honda-Kitahara M, Ozawa T, Shiraishi K, Kohno T, Ichimura K, Hara J. Spinal cord astroblastoma with an EWSR1-BEND2 fusion classified as a high-grade neuroepithelial tumour with MN1 alteration. Neuropathol Appl Neurobiol, 46:190-193, 2020
3. Li BK, Vasiljevic A, Dufour C, Yao F, Ho BLB, Lu M, Hwang EI, Gururangan S, Hansford JR, Fouladi M, Nobusawa S, Laquerriere A, Delisle MB, Fangusaro J, Forest F, Toledano H, Solano-Paez P, Leary S, Birks D, Hoffman LM, Szathmari A, Faure-Conter C, Fan X, Catchpoole D, Zhou L, Schultz KAP, Ichimura K, Gauchotte G, Jabado N, Jones C, Loussouarn D, Mokhtari K, Rousseau A, Ziegler DS, Tanaka S, Pomeroy SL, Gajjar A, Ramaswamy V, Hawkins C, Grundy RG, Hill DA, Bouffet E, Huang A, Jouvet A. Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study. Acta Neuropathol, 139:223-241, 2020
4. 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
5. Takami H, Fukushima S, Aoki K, Satomi K, Narumi K, Hama N, Matsushita Y, Fukuoka K, Yamasaki K, Nakamura T, Mukasa A, Saito N, Suzuki T, Yanagisawa T, Nakamura H, Sugiyama K, Tamura K, Maehara T, Nakada M, Nonaka M, Asai A, Yokogami K, Takeshima H, Iuchi T, Kanemura Y, Kobayashi K, Nagane M, Kurozumi K, Yoshimoto K, Matsuda M, Matsumura A, Hirose Y, Tokuyama T, Kumabe T, Ueki K, Narita Y, Shibui S, Totoki Y, Shibata T, Nakazato Y, Nishikawa R, Matsutani M, Ichimura K. Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance. Neuropathol Appl Neurobiol, 46:111-124, 2020
6. Fukuma R, Yanagisawa T, Kinoshita M, Shinozaki T, Arita H, Kawaguchi A, Takahashi M, Narita Y, Terakawa Y, Tsuyuguchi N, Okita Y, Nonaka M, Moriuchi S, Takagaki M, Fujimoto Y, Fukai J, Izumoto S, Ishibashi K, Nakajima Y, Shofuda T, Kanematsu D, Yoshioka E, Kodama Y, Mano M, Mori K, Ichimura K, Kanemura Y, Kishima H. Prediction of IDH and TERT promoter mutations in low-grade glioma from magnetic resonance images using a convolutional neural network. Sci Rep, 9:20311, 2019
7. Inada M, Sato A, Shindo M, Yamamoto Y, Akasaki Y, Ichimura K, Tanuma SI. Anticancer Non-narcotic Opium Alkaloid Papaverine Suppresses Human Glioblastoma Cell Growth. Anticancer Res, 39:6743-6750, 2019
8. Ohno M, Matsuzaki J, Kawauchi J, Aoki Y, Miura J, Takizawa S, Kato K, Sakamoto H, Matsushita Y, Takahashi M, Miyakita Y, Ichimura K, Narita Y, Ochiya T. Assessment of the Diagnostic Utility of Serum MicroRNA Classification in Patients With Diffuse Glioma. JAMA Netw Open, 2:e1916953, 2019
9. Kadota T, Saito R, Kumabe T, Mizusawa J, Katayama H, Sumi M, Igaki H, Kinoshita M, Komori T, Ichimura K, Narita Y, Nishikawa R. A multicenter randomized phase III study for newly diagnosed maximally resected glioblastoma comparing carmustine wafer implantation followed by chemoradiotherapy with temozolomide with chemoradiotherapy alone; Japan Clinical Oncology Group Study JCOG1703 (MACS study). Jpn J Clin Oncol, 49:1172-1175, 2019
10. Ohno M, Miyakita Y, Takahashi M, Igaki H, Matsushita Y, Ichimura K, Narita Y. Survival benefits of hypofractionated radiotherapy combined with temozolomide or temozolomide plus bevacizumab in elderly patients with glioblastoma aged ≧ 75 years. Radiat Oncol, 14:200, 2019
11. Guerreiro Stucklin AS, Ryall S, Fukuoka K, Zapotocky M, Lassaletta A, Li C, Bridge T, Kim B, Arnoldo A, Kowalski PE, Zhong Y, Johnson M, Li C, Ramani AK, Siddaway R, Nobre LF, de Antonellis P, Dunham C, Cheng S, Boué DR, Finlay JL, Coven SL, de Prada I, Perez-Somarriba M, Faria CC, Grotzer MA, Rushing E, Sumerauer D, Zamecnik J, Krskova L, Garcia Ariza M, Cruz O, Morales La Madrid A, Solano P, Terashima K, Nakano Y, Ichimura K, Nagane M, Sakamoto H, Gil-da-Costa MJ, Silva R, Johnston DL, Michaud J, Wilson B, van Landeghem FKH, Oviedo A, McNeely PD, Crooks B, Fried I, Zhukova N, Hansford JR, Nageswararao A, Garzia L, Shago M, Brudno M, Irwin MS, Bartels U, Ramaswamy V, Bouffet E, Taylor MD, Tabori U, Hawkins C. Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas. Nat Commun, 10:4343, 2019
12. Tsurubuchi T, Nakano Y, Hirato J, Yoshida A, Muroi A, Sakamoto N, Alexander Z, Matsuda M, Ishikawa E, Kohno T, Yoshioka T, Honda-Kitahara M, Ichimura K, Yamamoto T, Matsumura A. Subependymal giant cell astrocytoma harboring a PRRC2B-ALK fusion: A case report. Pediatr Blood Cancer, 66:e27995, 2019
13. Sakaguchi M, Nakano Y, Honda-Kitahara M, Kinoshita M, Tanaka S, Oishi M, Noguchi K, Fukuda M, Maeba H, Watanabe T, Hayashi Y, Ikeda H, Minato H, Ichimura K, Nojima T, Nakada M. Two cases of primary supratentorial intracranial rhabdomyosarcoma with DICER1 mutation which may belong to a “spindle cell sarcoma with rhabdomyosarcoma-like feature, DICER1 mutant”. Brain Tumor Pathol, 36:174-182, 2019
14. Takami H, Fukuoka K, Fukushima S, Nakamura T, Mukasa A, Saito N, Yanagisawa T, Nakamura H, Sugiyama K, Kanamori M, Tominaga T, Maehara T, Nakada M, Kanemura Y, Asai A, Takeshima H, Hirose Y, Iuchi T, Nagane M, Yoshimoto K, Matsumura A, Kurozumi K, Nakase H, Sakai K, Tokuyama T, Shibui S, Nakazato Y, Narita Y, Nishikawa R, Matsutani M, Ichimura K. Integrated clinical, histopathological, and molecular data analysis of 190 central nervous system germ cell tumors from the iGCT Consortium. Neuro Oncol, 21:1565-1577, 2019
15. Fukushima H, Nakano Y, Ishii N, Nozuchi N, Okuno T, Yamasaki K, Okada K, Fujisaki H, Kunihiro N, Matsusaka Y, Sakamoto H, Honda-Kitahara M, Ichimura K, Hara J, Inoue T. Histological and genetic analysis of anaplastic pleomorphic xanthoastrocytoma suspected of malignant progression over a 12-year clinical course. Pathol Int, 69:608-613, 2019
16. Yoshida K, Nakano Y, Honda-Kitahara M, Wakai S, Motoi T, Ogura K, Sano N, Shibata T, Okuma T, Iwata S, Kawai A, Ichimura K, Yoshida A. “Absence of H3F3A mutation in a subset of malignant giant cell tumor of bone” Mod Pathol. 2019 Dec;32:1751-1761
17. Nakano Y, Hasegawa D, Stewart DR, Schultz KAP, Harris AK, Hirato J, Uemura S, Tamura A, Saito A, Kawamura A, Yoshida M, Yamasaki K, Yamashita S, Ushijima T, Kosaka Y, Ichimura K, Dehner LP, Hill DA. Presacral malignant teratoid neoplasm in association with pathogenic DICER1 variation. Mod Pathol, 32:1744-1750, 2019
18. Nakano Y, Yamasaki K, Sakamoto H, Matsusaka Y, Kunihiro N, Fukushima H, Inoue T, Honda-Kitahara M, Hara J, Yoshida A, Ichimura K. A long-term survivor of pediatric midline glioma with H3F3A K27M and BRAF V600E double mutations. Brain Tumor Pathol, 36:162-168, 2019
19. Takahashi M, Miki S, Fujimoto K, Fukuoka K, Matsushita Y, Maida Y, Yasukawa M, Hayashi M, Shinkyo R, Kikuchi K, Mukasa A, Nishikawa R, Tamura K, Narita Y, Hamada A, Masutomi K, Ichimura K. Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts. Cancer Sci, 110:2247-2257, 2019
20. Inada M, Shindo M, Kobayashi K, Sato A, Yamamoto Y, Akasaki Y, Ichimura K, Tanuma SI. Anticancer effects of a non-narcotic opium alkaloid medicine, papaverine, in human glioblastoma cells. PLoS One, 14:e0216358, 2019
21. Tateishi K, Nakamura T, Juratli TA, Williams EA, Matsushita Y, Miyake S, Nishi M, Miller JJ, Tummala SS, Fink AL, Lelic N, Koerner MVA, Miyake Y, Sasame J, Fujimoto K, Tanaka T, Minamimoto R, Matsunaga S, Mukaihara S, Shuto T, Taguchi H, Udaka N, Murata H, Ryo A, Yamanaka S, Curry WT, Dias-Santagata D, Yamamoto T, Ichimura K, Batchelor TT, Chi AS, Iafrate AJ, Wakimoto H, Cahill DP. PI3K/AKT/mTOR Pathway Alterations Promote Malignant Progression and Xenograft Formation in Oligodendroglial Tumors. Clin Cancer Res, 25:4375-4387, 2019
22. Sasaki A, Hirato J, Hirose T, Fukuoka K, Kanemura Y, Hashimoto N, Kodama Y, Ichimura K, Sakamoto H, Nishikawa R. Review of ependymomas: assessment of consensus in pathological diagnosis and correlations with genetic profiles and outcome. Brain Tumor Pathol, 36:92-101, 2019
23. Tomiyama A, Ichimura K. Signal transduction pathways and resistance to targeted therapies in glioma. Semin Cancer Biol, 58:118-129, 2019