Annual Report 2018
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, Nobuyoshi Sasaki, Mutsumi Takadera, Kenji Fujimoto, Eita Uchida, Shun Yamamuro, Tatsuya Kobayashi, Tomoyuki Nakano, Ayana Nakajima, Sakura ShimizuKuzuoka
Introduction
Our laboratory focuses on translational research into various types of malignant brain tumors to improve diagnostic accuracy, identify novel molecular markers and develop new treatment. To meet the molecular criteria defined by the WHO Classification published in 2016 and being recommended by cIMPACTNOW, we develop robust molecular tests and perform molecular diagnostics for brain tumors through a number of nationwide multi-center collaborative initiatives. We also develop novel targeted therapies, perform preclinical studies and conduct clinical trials 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 patients operated on at the Department of Neurosurgery and Neurooncology 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 181 pediatric brain tumors in 2018.
Research activities
1. Molecular diagnosis of pediatric brain tumors
Among the various pediatric brain tumors collected through JCCG and JPMNG as well as other collaborations, we conduct targeted hot-spot mutation screening as well as other known recurrent fusions depending on the tumor types involved. For those tumors without characteristic mutations/fusions, targeted sequencing, genome-wide DNA methylation analysis and RNA sequencing are performed to investigate their molecular pathogenesis. We also published molecular profiling of supratentorial and posterior fossa ependymoma as a JPMNG study. This is the first nationwide molecular epidemiological study of ependymoma, to help underpin molecular diagnostics for pediatric brain tumors in Japan.
2. Molecular 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. Development 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. Based on this result, an investigator-initiated clinical trial to test the efficacy of eribulin against therapyrefractory GBM was launched in a program for which patients are being enrolled. We have also published results showing that a combination of eribulin and radiation outperformed eribulin or radiation alone to suppress the growth of glioblastoma cells in vivo.
4. Genomic analysis of central nervous system germ cell tumors (CNS GCT)
We are developing a novel targeted therapy against CNS GCT using a patient-derived yolk sac tumor cell line, which we established at the National Cancer Center. A single cell transcriptomic study in CNS GCTs is also being conducted.
Clinical trials
We are performing molecular analysis for the BIOMARK clinical trial, in which the efficacy of Bevacizumab is evaluated, alongside the Stupp regimen on glioblastomas. The patient enrollment was completed in January 2017 and 112 tumor specimens were collected and are being analyzed for DNA methylation, targeted sequencing and RNA sequencing. The two-year follow-up was completed in January 2019 and the outcome of the clinical trial is being analyzed.
Education
Five postgraduate students (PhD) did research work between April 2018 and March 2019 at the Division of Brain Tumor Translational Research, one of whom successfully obtained a PhD.
Future prospects
We continue to organize nationwide and international collaboration and conduct research on all types of malignant brain tumors as the leading translational research center on 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 the 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 substantively contribute 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 2018
Journal
1. Nakano Y, Tomiyama A, Kohno T, Yoshida A, Yamasaki K, Ozawa T, Fukuoka K, Fukushima H, Inoue T, Hara J, Sakamoto H, Ichimura K. Identification of a novel KLC1-ROS1 fusion in a case of pediatric low-grade localized glioma. Brain Tumor Pathol, 36:14-19, 2019
2. Yoshida A, Satomi K, Ohno M, Matsushita Y, Takahashi M, Miyakita Y, Hiraoka N, Narita Y, Ichimura K. Frequent false-negative immunohistochemical staining with IDH1 (R132H)-specific H09 antibody on frozen section control slides: a potential pitfall in glioma diagnosis. Histopathology, 74:350-354, 2019
3. Ichimura K. TERT promoter mutation as a diagnostic marker for diffuse gliomas. Neuro-oncology, 21:417-418, 2019
4. Tomiyama A, Kobayashi T, Mori K, Ichimura K. Protein Phosphatases-A Touchy Enemy in the Battle Against Glioblastomas: A Review. Cancers (Basel), 11:2019
5. Tomiyama A, Ichimura K. Signal transduction pathways and resistance to targeted therapies in glioma. Semin Cancer Biol, 2019
6. Nakamura T, Fukuoka K, Nakano Y, Yamasaki K, Matsushita Y, Yamashita S, Ikeda J, Udaka N, Tanoshima R, Shiba N, Tateishi K, Yamanaka S, Yamamoto T, Hirato J, Ichimura K. Genome-wide DNA methylation profiling shows molecular heterogeneity of anaplastic pleomorphic xanthoastrocytoma. Cancer Sci, 110:828- 832, 2019
7. Arita H, Kinoshita M, 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. Lesion location implemented magnetic resonance imaging radiomics for predicting IDH and TERT promoter mutations in grade II/III gliomas. Sci Rep, 8:11773, 2018
8. Yamauchi T, Ohno M, Matsushita Y, Takahashi M, Miyakita Y, Kitagawa Y, Kondo E, Tsushita N, Satomi K, Yoshida A, Ichimura K, Narita Y. Radiological characteristics based on isocitrate dehydrogenase mutations and 1p/19q codeletion in grade II and III gliomas. Brain Tumor Pathol, 35:148-158, 2018
9. Yamamoto Y, Sasaki N, Kumagai K, Takeuchi S, Toyooka T, Otani N, Wada K, Narita Y, Ichimura K, Namba H, Mori K, Tomiyama A. Involvement of Intracellular Cholesterol in Temozolomide-Induced Glioblastoma Cell Death. Neurol Med Chir (Tokyo), 58:296-302, 2018
10. Otani R, Uzuka T, Higuchi F, Matsuda H, Nomura M, Tanaka S, Mukasa A, Ichimura K, Kim P, Ueki K. IDH-mutated astrocytomas with 19q-loss constitute a subgroup that confers better prognosis. Cancer Sci, 109:2327-2335, 2018
11. Miyazaki M, Otomo R, Matsushima-Hibiya Y, Suzuki H, Nakajima A, Abe N, Tomiyama A, Ichimura K, Matsuda K, Watanabe T, Ochiya T, Nakagama H, Sakai R, Enari M. The p53 activator overcomes resistance to ALK inhibitors by regulating p53-target selectivity in ALK-driven neuroblastomas. Cell Death Discov, 4:56, 2018
12. Morita S, Nitta M, Muragaki Y, Komori T, Masui K, Maruyama T, Ichimura K, Nakano Y, Sawada T, Koriyama S, Tsuzuki S, Yasuda T, Hashimoto K, Niwa A, Kawamata T. Brainstem pilocytic astrocytoma with H3 K27M mutation: case report. J Neurosurg, 129:593-597, 2018
13. Shimoi T, Yoshida M, Kitamura Y, Yoshino T, Kawachi A, Shimomura A, Noguchi E, Yunokawa M, Yonemori K, Shimizu C, Kinoshita T, Ichimura K, Fukuda T, Fujiwara Y, Tamura K. TERT promoter hotspot mutations in breast cancer. Breast Cancer, 25:292-296, 2018
14. Miki S, Imamichi S, Fujimori H, Tomiyama A, Fujimoto K, Satomi K, Matsushita Y, Matsuzaki S, Takahashi M, Ishikawa E, Yamamoto T, Matsumura A, Mukasa A, Nishikawa R, Masutomi K, Narita Y, Masutani M, Ichimura K. Concomitant administration of radiation with eribulin improves the survival of mice harboring intracerebral glioblastoma. Cancer Sci, 109:2275-2285, 2018
15. Masui K, Komori T, Kato Y, Masutomi K, Ichimura K, Ogasawara S, Kaneko MK, Oki H, Suzuki H, Nitta M, Maruyama T, Muragaki Y, Kawamata T, Sawada T, Shibata N. Elevated TERT Expression in TERT-Wildtype Adult Diffuse Gliomas: Histological Evaluation with a Novel TERT-Specific Antibody. Biomed Res Int, 2018:7945845, 2018
16. Fukuoka K, Kanemura Y, Shofuda T, Fukushima S, Yamashita S, Narushima D, Kato M, Honda-Kitahara M, Ichikawa H, Kohno T, Sasaki A, Hirato J, Hirose T, Komori T, Satomi K, Yoshida A, Yamasaki K, Nakano Y, Takada A, Nakamura T, Takami H, Matsushita Y, Suzuki T, Nakamura H, Makino K, Sonoda Y, Saito R, Tominaga T, Matsusaka Y, Kobayashi K, Nagane M, Furuta T, Nakada M, Narita Y, Hirose Y, Ohba S, Wada A, Shimizu K, Kurozumi K, Date I, Fukai J, Miyairi Y, Kagawa N, Kawamura A, Yoshida M, Nishida N, Wataya T, Yamaoka M, Tsuyuguchi N, Uda T, Takahashi M, Nakano Y, Akai T, Izumoto S, Nonaka M, Yoshifuji K, Kodama Y, Mano M, Ozawa T, Ramaswamy V, Taylor MD, Ushijima T, Shibui S, Yamasaki M, Arai H, Sakamoto H, Nishikawa R, Ichimura K. Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors. Acta Neuropathol Commun, 6:134, 2018