Chemical biology reprogramming epigenetic aberration in malignant brain tumors

2011 Fiscal Year Final Research Report

• Project/Area Number: 21390408
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Nagoya University
• Principal Investigator: NATSUME Atsushi 名古屋大学, 大学院・医学系研究科, 准教授 (30362255)
• Co-Investigator(Kenkyū-buntansha): WAKABAYASHI Toshihiko 名古屋大学, 大学院・医学系研究科, 教授 (50220835) ; SUZUKI Masaaki 独立行政法人理化学研究所, 分子イメージング科学研究センター, 副センター長 (90093046) ; KOYAMA Hiroko 岐阜大学, 大学院・医学系研究科, 助教 (50402160)
• Co-Investigator(Renkei-kenkyūsha): KONDO Yutaka 愛知県がんセンター研究所, 室長 (00419897) ; TAKEUCHI Ichiro 名古屋工業大学, 工学研究科, 准教授 (40335146)
• Project Period (FY): 2009 – 2011
• Keywords: 創薬

Research Abstract

Almost all cancer cells have multiple epigenetic abnormalities, which combine with genetic changes to affect many cellular processes, including cell proliferation and apoptosis, by silencing tumor-suppressor genes. In this study, we focused on the epigenetic mechanisms of DNA hypomethylation and CpG island hypermethylation in gliomas. Aberrant hypermethylation in promoter CpG islands has been recognized as a key mechanism involved in the silencing of cancer-associated genes and occurs at genes with diverse functions related to tumorigenesis and tumor progression. Such promoter hypermethylation can modulate the sensitivity of glioblastomas to drugs and radiotherapy. As an example, the methylation of the MGMT promoter is a specific predictive biomarker of tumor responsiveness to chemotherapy with alkylating agents. Finally, we also evaluated the potential of NY-ESO-1, the most immunogenic cancer/testis antigen(CTA) discovered thus far, as an immunotherapy target. The use of potent epigenetics-based therapy for cancer cells might restore the abnormally regulated epigenomes to a more normal state through epigenetic reprogramming. Thus, epigenetic therapy may be a promising and potent treatment for human neoplasia.

Research Products

• [Journal Article] Epigenetic subclassification of meningiomas based on genome-wide DNA methylation analyses (2011)
  • Author(s): Kishida Y, Natsume A, Kondo Y, Takeuchi I, An B, Okamoto Y, Shinjo K, Saito K, AndoH, Ohka F, Sekido Y, Wakabayashi T
  • Journal Title: Carcinogenesis
• [Journal Article] Girdin maintains the stemness of glioblastoma stem cells (2011)
  • Author(s): Natsume A, Kato T, Kinjo S, Enomoto A, TodaH, Shimato S, Ohka F, Motomura K, Kondo Y, Miyata T, Takahashi M, Wakabayashi T
  • Journal Title: Oncogene
• [Journal Article] A multicenter phase I trial of combination therapy with interferon-beta and temozolomide for high-grade gliomas(INTEGRA study) (2011)
  • Author(s): Wakabayashi, T., Kayama, T., Nishikawa, R., Takahashi, H., Hashimoto, N., Takahashi, J., Aoki, T., Sugiyama, K., Ogura, M., Natsume, A., and Yoshida, J
  • Journal Title: J Neurooncol Volume: 104 Pages: 573-577
• [Journal Article] The global DNA methylati on surrogate LINE-1 methylation is correlated with MGMT promoter methylation and is a better prognostic factor for glioma (2011)
  • Author(s): Ohka, F., Natsume, A., Motomura, K., Kishida, Y., Kondo, Y., Abe, T., Nakasu, Y., Namba, H., Wakai, K., Fukui, T
  • Journal Title: PLoS One Volume: 6 Pages: 23332
• [Journal Article] Glioma-initiating cells and molecular pathology : implications for therapy (2011)
  • Author(s): Natsume, A., Kinjo, S., Yuki, K., Kato, T., Ohno, M., Motomura, K., Iwami, K., andWakabayashi, T
  • Journal Title: Brain Tumor Pathol Volume: 28 Pages: 1-12
• [Journal Article] Intravenousad ministration of temozolomide as a useful alternative over oral treatment with temozolomide capsules in patients with gliomas (2011)
  • Author(s): Motomura, K., Natsume, A., andWakabayashi, T
  • Journal Title: J Neurooncol Volume: 106 Pages: 209-211
• [Journal Article] Benefits of interferon-bet a and temozolomide combination therapy for newly diagnosed primary glioblastoma with the unmethylated MGMT promoter (2011)
  • Author(s): Motomura, K., Natsume, A., Kishida, Y., Higashi, H., Kondo, Y., Nakasu, Y., Abe, T., Namba, H., Wakai, K., and Wakabayashi, T
  • Journal Title: Amulticenter study Volume: 117 Pages: 1721-1730
• [Journal Article] Long-term survival in patients with newly diagnosed primary central nervous system lymphoma treated with dexamethasone, etoposide, if osfamide and carboplatin chemotherapy and whole-brain radiation therapy (2011)
  • Author(s): Motomura, K., Natsume, A., Fujii, M., Ito, M., Momota, H., and Wakabayashi, T
  • Journal Title: Leuk Lymphoma Volume: 52 Pages: 2069-75
• [Journal Article] Rhabdoid glioblastoma in a child : case report and literature review (2011)
  • Author(s): Momota, H., Iwami, K., Fujii, M., Motomura, K., Natsume, A., Ogino, J., Hasegawa, T., and Wakabayashi, T
  • Journal Title: Brain Tumor Pathol Volume: 28 Pages: 65-70
• [Journal Article] Cytokine networks in glioma (2011)
  • Author(s): Iwami, K., Natsume, A., and Wakabayashi, T
  • Journal Title: Neurosurg Rev Volume: 34 Pages: 253-263, 263-254
• [Journal Article] Retro virally engineered T-cell-based immunotherapy targeting type III variant epidermal growth factor receptor, a glioma-associated antigen (2010)
  • Author(s): Ohno, M., Natsume, A., Ichiro Iwami, K., Iwamizu, H., Noritake, K., Ito, D., Toi, Y., Ito, M., Motomura, K., Yoshida, J
  • Journal Title: Cancer Sci Volume: 101 Pages: 2518-2524
• [Journal Article] Epigenetic aberrations and therapeutic implications in gliomas (2010)
  • Author(s): Natsume, A., Kondo, Y., Ito, M., Motomura, K., Wakabayashi, T., and Yoshida, J
  • Journal Title: Cancer Sci Volume: 101 Pages: 1331-1336
• [Journal Article] A free-radical scavenger protects the neural progenitor cells in the dentate subgranular zone of the hippocampus from cell death after X-irradiation (2010)
  • Author(s): Motomura, K., Ogura, M., Natsume, A., Yokoyama, H., and Wakabayashi, T
  • Journal Title: Neurosci Lett Volume: 485 Pages: 65-70
• [Journal Article] Benefits of interferon-beta and temozolomide combination therapy for newly diagnosed primary glioblastoma with the unmethylated MGMT promoter : a multicenter study (2010)
  • Author(s): Motomura, K., Natsume, A., Kishida, Y., Higashi, H., Kondo, Y., Nakasu, Y., Abe, T., Namba, H., Wakai, K., and Wakabayashi, T
  • Journal Title: Cancer Volume: 117 Pages: 1721-30
• [Journal Article] Efficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells (2010)
  • Author(s): Kato, T., Natsume, A., Toda, H., Iwamizu, H., Sugita, T., Hachisu, R., Watanabe, R., Yuki, K., Motomura, K., Bankiewicz, K., and Wakabayashi, T
  • Journal Title: Gene Ther Volume: 17 Pages: 1363-1371
• [Journal Article] Gene therapy for high-grade glioma (2010)
  • Author(s): Iwami, K., Natsume, A.
  • Journal Title: Neurol Med Chir Volume: 50 Pages: 727-736
• [Journal Article] Human neural stem cells transduced with IFN-beta and cytosine deaminase genes intensify bystander effect in experimental glioma (2010)
  • Author(s): Ito, S., Natsume, A., Shimato, S., Ohno, M., Kato, T., Chansakul, P., Wakabayashi, T., and Kim, S. U
  • Journal Title: Cancer Gene Ther Volume: 17 Pages: 299-306
• [Journal Article] Induction of oligodendrogenesis in glioblastoma-initiating cells by IFN-mediated activation of STAT3 signaling (2009)
  • Author(s): Yuki, K., Natsume, A., Yokoyama, H., Kondo, Y., Ohno, M., Kato, T., Chansakul, P., Ito, M., Kim, S. U., and Wakabayashi, T
  • Journal Title: Cancer Lett Volume: 284 Pages: 71-79
• [Journal Article] p16 promoter methylation in the serum as a basis for the molecular diagnosis of gliomas (2009)
  • Author(s): Wakabayashi, T., Natsume, A., Hatano, H., Fujii, M., Shimato, S., Ito, M., Ohno, M., Ito, S., Ogura, M., and Yoshida, J
  • Journal Title: Neurosurgery Volume: 64 Pages: 455-461, 461-452
• [Journal Article] Advanced new neurosurgical procedure using integrated system of intraoperative MRI and neuronavigation with multimodal neuroradiological images (2009)
  • Author(s): Wakabayashi, T., Fujii, M., Kajita, Y., Natsume, A., Maezawa, S., and Yoshida, J
  • Journal Title: Nagoya J Med Sci Volume: 71 Pages: 101-107
• [Journal Article] Synergistic induction of NY-ESO-1 antigen expression by a novel histone deacetylase inhibitor, valproic acid, with 5-aza-2'-deoxycytidine in glioma cells (2009)
  • Author(s): Oi, S., Natsume, A., Ito, M., Kondo, Y., Shimato, S., Maeda, Y., Saito, K., andWakabayashi, T
  • Journal Title: J Neurooncol Volume: 92 Pages: 15-22
• [Journal Article] The modulation of microRNAs by type I IFN through the activation of signal transducers and activators of transcription 3 in human glioma (2009)
  • Author(s): Ohno, M., Natsume, A., Kondo, Y., Iwamizu, H., Motomura, K., Toda, H., Ito, M., Kato, T., and Wakabayashi, T
  • Journal Title: Mol Cancer Res Volume: 7 Pages: 2022-2030
• [Journal Article] Interferon-beta, MCNU, and conventional radiotherapy for pediatric patients with brainstem glioma (2009)
  • Author(s): Ohno, M., Natsume, A., Fujii, M., Ito, M., and Wakabayashi, T
  • Journal Title: Pediatr Blood Cancer Volume: 53 Pages: 37-41
• [Journal Article] Type I interferon inhibits astrocytic gliosis and promotes functional recovery after spinal cord injury by deactivation of the MEK/ERK pathway (2009)
  • Author(s): Ito, M., Natsume, A., Takeuchi, H., Shimato, S., Ohno, M., Wakabayashi, T., and Yoshida, J
  • Journal Title: J Neurotrauma Volume: 26 Pages: 41-53
• [Presentation] Regulation of heterogeneity by Epigenetic modifications in GBM stem cells (2011)
  • Author(s): Natsume, A
  • Organizer: IARC Seminar
  • Place of Presentation: Lyon, France
  • Year and Date: 2011-03-29
• [Presentation] Immuno-therepay usingretrovirally engineered T cells expressing chimeric antigen receptors specific to glioma-associated antigens (2010)
  • Author(s): Natsume, A
  • Organizer: International Society of Cell Therapy
  • Place of Presentation: Miyazaki, Japan
  • Year and Date: 2010-10-20
• [Presentation] A Multicenter Phase I Trial of Combination Therapy with Interferon-βand Temozolomide for High-grade Gliomas(INTEGRA study): The Final Report (2010)
  • Organizer: 9th annualmeeting of Asian Clinical Oncology Society
  • Place of Presentation: Gifu, Japan
  • Year and Date: 2010-08-26
• [Presentation] Epigenetic plasticity regulated bypolycomb repressive complex inGBM-initiating cells (2010)
  • Organizer: 7th Meeting of Asian Society for Neuro-Oncology
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2010-06-12
• [Presentation] A clinical trial of interleukin-13receptor alpha 2 peptide-pulsed DCvaccine for malignant gliomas (2010)
  • Organizer: World Congress of Vaccine-2010
  • Place of Presentation: Beijing, China
  • Year and Date: 2010-03-25
• [Presentation] Regulation of heterogeneity by Epigenetic modifications in GBMstem cells (2009)
  • Organizer: Seoul National University Seminar
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2009-11-06
• [Book] 脳腫瘍取扱い規約(第3版) (2010)
  • Author(s): 夏目敦至
  • Total Pages: 50-55
  • Publisher: 金原出版
• [Book] 新時代の脳腫瘍学.脳腫瘍におけるエピジェネティクス (2010)
  • Author(s): 夏目敦至
  • Total Pages: 34-42
  • Publisher: 日本臨床
• [Book] 遺伝子診療学.脳腫瘍.ゲノム異常の最新アトラス (2010)
  • Author(s): 夏目敦至
  • Total Pages: 56-62
  • Publisher: 日本臨床
• [Book] 脳腫瘍臨床病理カラーアトラス第3版 (2009)
  • Author(s): 夏目敦至
  • Total Pages: 34-37
  • Publisher: 医学書院