Clarification of mechanisms for inhibition of retinoblastoma growth by CEP-1347

• Project/Area Number: 19K18870
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Yamagata University
• Principal Investigator: Keita Togashi 山形大学, 医学部, 病院助教 (80810796)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 網膜芽細胞腫 / CEP1347 / MDM4 / p53 / CEP-1347 / 細胞増殖抑制能 / 増殖抑制 / 細胞死

Outline of Research at the Start

小児がんの代表の１つである網膜芽細胞腫に対する治療は進歩しているが、治療に伴う副作用の回避、視機能温存、二次性発がん予防など、克服すべき急務な課題となっている。申請者は、c-Jun N-terminal kinase (JNK)の上流因子であるmixed lineage kinase（MLK）阻害剤CEP-1347が、ヒト網膜芽細胞腫細胞株に対し増殖抑制を示すことを確認した。
本研究では細胞実験や動物実験を用いてCEP-1347が網膜芽細胞腫細胞株に対してどのような機序で増殖抑制をもたらすのかを解明し、CEP-1347が網膜芽細胞腫の新規分子標的治療薬となりうるか検証することを目的としている。

Outline of Final Research Achievements

Retinoblastoma is the most common pediatric intraocular malignancy. Although retinoblastoma has become one of the malignant tumors with a good prognosis due to the development of various treatment methods, the rate of eye preservation in severe cases is still low. In addition, chemotherapy and radiotherapy involve the risk of secondary cancer development, and novel therapies that are safe and preserve visual function are strongly needed.
The present study revealed that CEP1347, a drug developed for the Parkinson's disease, has a potent growth inhibitory effect on retinoblastoma cells in which p53, a representative tumor suppressor gene, is wild-type and the MDM4 gene, a p53 suppressor gene, is amplified.
Furthermore, we found that one of the molecular mechanisms of the inhibitory effect of CEP1347 on retinoblastoma cells is the activation of p53 by suppressing MDM4 expression.

Academic Significance and Societal Importance of the Research Achievements

網膜芽細胞腫は幼少期に発症するため患児の長い人生において著しい視機能障害ひいてはQOLの低下をもたらす疾患である。多くの網膜芽細胞腫において、代表的ながん抑制遺伝子p53が野生型であることが知られており、加えてp53の抑制因子の一つであるMDM4遺伝子は約65%の症例において増幅しているとの報告もある。本研究ではCEP1347がp53野生型かつMDM4高発現している網膜芽細胞腫症例において抗腫瘍効果を持つことを明らかにし、近い未来、多くの網膜芽細胞腫患者に対して有用な新規分子標的治療の1選択肢となる可能性を提言した。

Research Products

• [Journal Article] Gemcitabine Cooperates with Everolimus to Inhibit the Growth of and Sensitize Malignant Meningioma Cells to Apoptosis Induced by Navitoclax, an Inhibitor of Anti-Apoptotic BCL-2 Family Proteins (2022)
  • Author(s): Yamamoto Masahiro、Suzuki Shuhei、Togashi Keita、Sugai Asuka、Okada Masashi、Kitanaka Chifumi
  • Journal Title: Cancers Volume: 14 Issue: 7 Pages: 1706-1706
  • DOI: 10.3390/cancers14071706
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of the Lipid Droplet-Peroxisome Proliferator-Activated Receptor α Axis Suppresses Cancer Stem Cell Properties. (2021)
  • Author(s): Kuramoto K, Yamamoto M, Suzuki S, Togashi K, Sanomachi T, Kitanaka C, Okada M.
  • Journal Title: Genes (Basel) Volume: 12(1) Issue: 1 Pages: 99-99
  • DOI: 10.3390/genes12010099
  • Peer Reviewed / Open Access
• [Journal Article] Roles for hENT1 and dCK in gemcitabine sensitivity and malignancy of meningioma (2021)
  • Author(s): Yamamoto Masahiro、Sanomachi Tomomi、Suzuki Shuhei、Uchida Hiroyuki、Yonezawa Hajime、Higa Nayuta、Takajo Tomoko、Yamada Yuki、Sugai Asuka、Togashi Keita、Seino Shizuka、Okada Masashi、Sonoda Yukihiko、Hirano Hirofumi、Yoshimoto Koji、Kitanaka Chifumi
  • Journal Title: Neuro-Oncology Volume: XX Issue: 6 Pages: 1-10
  • DOI: 10.1093/neuonc/noab015
  • Peer Reviewed / Open Access
• [Journal Article] Metastatic Orbital Tumor From Breast Ductal Carcinoma With Neuroendocrine Differentiation Initially Presenting as Ocular Symptoms: A Case Report and Literature Review (2021)
  • Author(s): Togashi Keita、Nishitsuka Koichi、Hayashi Shion、Namba Hiroyuki、Goto Sakiko、Takeda Yusuke、Suzuki Shuhei、Kato Tomoya、Yamada Yuki、Konno Eriko、Yoshioka Takashi、Yamakawa Mitsunori、Sonoda Yukihiko、Suzuki Tamio、Yamashita Hidetoshi
  • Journal Title: Frontiers in Endocrinology Volume: 12
  • DOI: 10.3389/fendo.2021.625663
  • Peer Reviewed / Open Access
• [Journal Article] Lurasidone Sensitizes Cancer Cells to Osimertinib by Inducing Autophagy and Reduction of Survivin (2021)
  • Author(s): SUZUKI SHUHEI、YAMAMOTO MASAHIRO、SANOMACHI TOMOMI、TOGASHI KEITA、SEINO SHIZUKA、SUGAI ASUKA、YOSHIOKA TAKASHI、OKADA MASASHI、KITANAKA CHIFUMI
  • Journal Title: Anticancer Research Volume: 41 Issue: 9 Pages: 4321-4331
  • DOI: 10.21873/anticanres.15237
  • Peer Reviewed
• [Journal Article] Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction (2021)
  • Author(s): Suzuki Shuhei、Yamamoto Masahiro、Sanomachi Tomomi、Togashi Keita、Sugai Asuka、Seino Shizuka、Yoshioka Takashi、Okada Masashi、Kitanaka Chifumi
  • Journal Title: Life Volume: 11 Issue: 9 Pages: 885-885
  • DOI: 10.3390/life11090885
  • Peer Reviewed / Open Access
• [Journal Article] Gemcitabine radiosensitization primes irradiated malignant meningioma cells for senolytic elimination by navitoclax (2021)
  • Author(s): Yamamoto Masahiro、Sanomachi Tomomi、Suzuki Shuhei、Togashi Keita、Sugai Asuka、Seino Shizuka、Sato Atsushi、Okada Masashi、Kitanaka Chifumi
  • Journal Title: Neuro-Oncology Advances Volume: 3 Issue: 1 Pages: 1-11
  • DOI: 10.1093/noajnl/vdab148
  • Peer Reviewed / Open Access
• [Journal Article] Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts (2021)
  • Author(s): Okada Masashi、Suzuki Shuhei、Togashi Keita、Sugai Asuka、Yamamoto Masahiro、Kitanaka Chifumi
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 21 Pages: 11633-11633
  • DOI: 10.3390/ijms222111633
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of Retinoblastoma Cell Growth by CEP1347 Through Activation of the P53 Pathway. (2020)
  • Author(s): Togashi K, Okada M, Suzuki S, Sanomachi T, Seino S, Yamamoto M, Yamashita H, Kitanaka C.
  • Journal Title: Anticancer Res. Volume: 40(9) Issue: 9 Pages: 4961-4968
  • DOI: 10.21873/anticanres.14499
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Therapeutic targeting of pancreatic cancer stem cells by dexamethasone modulation of the MKP-1?JNK axis (2020)
  • Author(s): Suzuki Shuhei、Okada Masashi、Sanomachi Tomomi、Togashi Keita、Seino Shizuka、Sato Atsushi、Yamamoto Masahiro、Kitanaka Chifumi
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 52 Pages: 18328-18342
  • DOI: 10.1074/jbc.ra120.015223
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells (2020)
  • Author(s): Kuramoto Kenta、Yamamoto Masahiro、Suzuki Shuhei、Sanomachi Tomomi、Togashi Keita、Seino Shizuka、Kitanaka Chifumi、Okada Masashi
  • Journal Title: The FEBS Journal Volume: Epub ahead of print Issue: 10 Pages: 2023-2036
  • DOI: 10.1111/febs.15187
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In vitro and in vivo anti-tumor effects of brexpiprazole, a newly-developed serotonin-dopamine activity modulator with an improved safety profile (2019)
  • Author(s): Suzuki S, Togashi K et al.
  • Journal Title: Oncotarget Volume: 10 Pages: 3547-3558
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction (2019)
  • Author(s): Suzuki S, Togashi K et al.
  • Journal Title: Cancers (Basel) Volume: 11 Pages: 947-959
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Brexpiprazole Reduces Survivin and Reverses EGFR Tyrosine Kinase Inhibitor Resistance in Lung and Pancreatic Cancer (2019)
  • Author(s): Sanomachi T, Togashi K et al.
  • Journal Title: Anticancer Res Volume: 39 Pages: 4817-4828
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Spironolactone, a Classic Potassium-Sparing Diuretic, Reduces Survivin Expression and Chemosensitizes Cancer Cells to Non-DNA-Damaging Anticancer Drugs (2019)
  • Author(s): Sanomachi T, Togashi K et al.
  • Journal Title: Cancers (Basel) Volume: 11 Pages: 1550-1566
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 眼球摘出に至った脈絡膜悪性黒色腫症例の腫瘍検体の初代培養による細胞株樹立の試み (2020)
  • Author(s): 冨樫 敬太, 林 思音, 岡田 雅司, 大江 倫太郎, 髙村 浩, 今野 伸弥 , 難波 広幸, 赤羽 梢, 西塚 弘一, 山川 光徳, 北中 千史, 山下 英俊
  • Organizer: 第124回日本眼科学会総会
• [Presentation] 眼球突出を契機として原発巣が判明した神経内分泌型乳管癌の眼窩転移の1例 (2019)
  • Author(s): 冨樫敬太, 林思音, 後藤早紀子, 武田祐介, 鈴木修平, 加藤智也, 山田裕樹, 紺野恵理子, 吉岡孝志, 山川光徳, 園田順彦, 鈴木民夫, 西塚弘一, 山下英俊
  • Organizer: 第137回山形眼科研究会