Division of Brain Tumor Translational Research

Koichi Ichimura, Tatsuya Ozawa, Shintaro Fukushima, Kohei Fukuoka, Kai Yamasaki, Yoshiko Nakano, Yuko Matsushita, Mai Kitahara, Sanae Matsuzaki, Yuki Yomoda, Yumi Miyamoto, Hirokazu Takami, Shunichiro Miki, Mutsumi Takadera, Nobuyoshi Sasaki, Sakura Shimizu-Kuzuoka, Sae Ishimaru, Hideyuki Arita

Introduction

Our laboratory focuses on translational research on various types of malignant brain tumors. Extensive genomic studies in recent years dramatically improved our understanding of the molecular mechanisms of brain tumors. As a result, the newly published WHO Classification for Central Nervous System Tumours (Revised 4th edition) has incorporated molecular diagnostics as a part of criteria in some tumors. In order to meet the new diagnostic requirement, we are standardizing a robust molecular classification and a diagnostic system through a number of nation-wide multi-center collaborations. We conduct a thorough genome analysis on brain tumors and conduct preclinical studies of novel targeted therapies.

Our team and what we do

We are the team of neurosurgeons, pediatric neuro-oncologists, and laboratory technicians, including those who are working on their PhD dissertation. One of our main activities is to provide a molecular diagnostic service to the Department of Neurosurgery and Neuro-oncology at the National Cancer Center Hospital (NCCH) as well as a number of external centers as a part of either collaboration, clinical trials or agreed services. For brain tumors operated at the NCCH, fresh frozen tumor tissues are subjected to molecular analysis each week. The results are reported back to the clinicians and pathologists within two weeks after the operation to help them to make diagnosis.

Research activities

1.Development of a novel molecular classification and optimal molecular tests for adult gliomas

We examined a total of 951 newly diagnosed adult gliomas collected through a multicenter study of 18 centers to validate current molecular classification. We found that the combination of IDH and TERT promoter mutation status is compatible with the 1p/19q-based classification and identifies subsets of gliomas that have significantly different prognosis (Arita, Acta Neuropathol Commun 2016).

2.Development of a novel targeted therapy for glioblastoma

We conducted a preclinical trial for a novel targeted therapy against TERT for glioblastoma in collaboration with the Division of Cancer Stem Cell at the NCC Research Institute (NCCRI). The results showed that glioblastoma cell lines that have TERT mutations are highly sensitive to the TERT inhibitor, and the survival of mice transplanted with TERT-mutated glioblastoma cell lines in the brain was significantly prolonged. Based on the above preclinical test, an investigator-initiated clinical trial is expected to be launched in 2017.

3.Genomic analysis of central nervous system germ cell tumors (CNS GCT)

We established the Intracranial Germ Cell Tumor Consortium (iGCT Consortium), through which tumor samples of more than 270 cases from 28 centers have been collected. We performed a whole exome and targeted sequencing in 197 germ cell tumors of CNS or testis, the results of which showed a high prevalence of mutations affecting the MAPK and/or PI3K pathway (Ichimura, Acta Neuropathol 2016). We then analyzed the genome-wide DNA methylation status of CNS GCTs and found that germinomas were characterized by a global hypomethylation which resembled that of primordial germ cells, suggesting their origin.

4.Molecular diagnosis of pediatric brain tumors

We analyzed more than 100 ependymomas collected through JPMNG and have successfully classified ependymomas into 4 groups, PFA and PFB for posterior fossa ependymomas, and RELA(+) and RELA(-) for ST-ependymomas. We found that RELA-negative ST ependymomas are molecularly heterogeneous group of tumors. We contributed these results at the 2nd Ependymoma Consensus Conference and agreed upon the Consensus Statements (Pajtler, Acta Neuropathol, 2016). We are now offering a central molecular diagnostic service for pediatric brain tumors (gliomas, ependymomas, and GCTs) as a part of the JCCG central diagnostics and a patient registry system. A total of 67 cases were analyzed in 2016.

Clinical trials

We continue to offer an MGMT methylation test for the patients enrolled in the EGGTRIAL, a clinical trial for elderly glioblastoma patients. We are in charge of molecular analysis for the BIOMARK trial, in which the efficacy of Bevacizumab together with the Stupp regimen on glioblastomas is evaluated. The first 32 tumors have been analyzed. A novel TERT-targeted therapy is going to be tested in an investigator-initiated clinical trial. We are also in charge of molecular tests in a number of other clinical trials including JCOG1016, 1303, and 1308, as well as the newly launched phase I study of a novel mutant-IDH1 inhibitor.

Education

Five postgraduate students, three research residents, and one clinical chief resident from the NCCH did research work during 2016 at the Division of Brain Tumor Translational Research. One of the postgraduate students successfully defended his thesis and obtained a PhD degree.

Future prospects

As one of the leading translational research centers on malignant brain tumors in Japan, we continue to organize nationwide collaboration and perform research. We offer a central molecular diagnostic service of brain tumors. We develop novel targeted therapies, conduct rigorously validated in pre-clinical studies, and contribute to clinical trials. We also support young dedicated clinician investigators and help them with their PhD projects. Our goal is to be able to offer better patient care and treatment for brain tumor sufferers, and help develop world-class neuro-oncology research in Japan.

List of papers published in 2016

Journal

1.Arita H, Yamasaki K, Matsushita Y, Nakamura T, Shimokawa A, Takami H, Tanaka S, Mukasa A, Shirahata M, Shimizu S, Suzuki K, Saito K, Kobayashi K, Higuchi F, Uzuka T, Otani R, Tamura K, Sumita K, Ohno M, Miyakita Y, Kagawa N, Hashimoto N, Hatae R, Yoshimoto K, Shinojima N, Nakamura H, Kanemura Y, Okita Y, Kinoshita M, Ishibashi K, Shofuda T, Kodama Y, Mori K, Tomogane Y, Fukai J, Fujita K, Terakawa Y, Tsuyuguchi N, Moriuchi S, Nonaka M, Suzuki H, Shibuya M, Maehara T, Saito N, Nagane M, Kawahara N, Ueki K, Yoshimine T, Miyaoka E, Nishikawa R, Komori T, Narita Y, Ichimura K. A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas. Acta Neuropathol Commun, 4:79, 2016

2.Komori K, Yanagisawa R, Miyairi Y, Sakashita K, Shiohara M, Fujihara I, Morita D, Nakamura T, Ogiso Y, Sano K, Shirahata M, Fukuoka K, Ichimura K, Shigeta H. Temozolomide Treatment for Pediatric Refractory Anaplastic Ependymoma with Low MGMT Protein Expression. Pediatr Blood Cancer, 63:152-155, 2016

3.Ichimura K, Fukushima S, Totoki Y, Matsushita Y, Otsuka A, Tomiyama A, Niwa T, Takami H, Nakamura T, Suzuki T, Fukuoka K, Yanagisawa T, Mishima K, Nakazato Y, Hosoda F, Narita Y, Shibui S, Yoshida A, Mukasa A, Saito N, Kumabe T, Kanamori M, Tominaga T, Kobayashi K, Shimizu S, Nagane M, Iuchi T, Mizoguchi M, Yoshimoto K, Tamura K, Maehara T, Sugiyama K, Nakada M, Sakai K, Kanemura Y, Nonaka M, Asai A, Yokogami K, Takeshima H, Kawahara N, Takayama T, Yao M, Kato M, Nakamura H, Hama N, Sakai R, Ushijima T, Matsutani M, Shibata T, Nishikawa R. Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy. Acta Neuropathol, 131:889-901, 2016

4.Ohno M, Narita Y, Miyakita Y, Matsushita Y, Arita H, Yonezawa M, Yoshida A, Fukushima S, Takami H, Ichimura K, Shibui S. Glioblastomas with IDH1/2 mutations have a short clinical history and have a favorable clinical outcome. Jpn J Clin Oncol, 46:31-39, 2016

5.Ogasawara S, Fujii Y, Kaneko MK, Oki H, Sabit H, Nakada M, Suzuki H, Ichimura K, Komori T, Kato Y. Establishment of Anti-Human ATRX Monoclonal Antibody AMab-6. Monoclon Antib Immunodiagn Immunother, 35:254-258, 2016

6.Nakamura T, Tateishi K, Niwa T, Matsushita Y, Tamura K, Kinoshita M, Tanaka K, Fukushima S, Takami H, Arita H, Kubo A, Shuto T, Ohno M, Miyakita Y, Kocialkowski S, Sasayama T, Hashimoto N, Maehara T, Shibui S, Ushijima T, Kawahara N, Narita Y, Ichimura K. Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas. Neuropathol Appl Neurobiol, 42:279-290, 2016

7.Fukumura K, Kawazu M, Kojima S, Ueno T, Sai E, Soda M, Ueda H, Yasuda T, Yamaguchi H, Lee J, Shishido-Hara Y, Sasaki A, Shirahata M, Mishima K, Ichimura K, Mukasa A, Narita Y, Saito N, Aburatani H, Nishikawa R, Nagane M, Mano H. Genomic characterization of primary central nervous system lymphoma. Acta Neuropathol, 131:865-875, 2016

Book

1.Rosenblum MK, Nakazato Y, Matsutani M, Ichimura K, Leuschner I, Huse JT. "Germ cell tumours" in Louis DN et al. ed. "WHO Classification of Tumours of the Central Nervous System" Revised 4th Edition, International Agency for Research on Cancer (IARC), Lyon, 2016