Synthetic lethality with FTD and CHK1 inhibitor for esophageal squamous cell carcinoma

• Project/Area Number: 19K08369
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kyoto University
• Principal Investigator: OHASHI SHINYA 京都大学, 医学研究科, 特定准教授 (20435556)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 食道扁平上皮癌 / CHK1シグナル阻害 / DNA修復応答 / トリフルリジン / 放射線感受性 / 合成致死 / CHK1阻害剤 / 放射線治療 / DNA傷害 / DNA修復 / DNA障害 / Synthetic lethality / トリフルリジン（FTD) / TAS-102

Outline of Research at the Start

本研究では、トリフルリジン（FTD）投与により誘導されるDNA修復シグナル(CHK1シグナル)を、CHK1阻害剤で遮断する「二重標的治療」が食道癌細胞に対し有効な抗腫瘍効果を発揮するかin vitro, in vivoの実験系で検討する。さらに、本治療が放射線感受性の増強作用を有するかどうかについても検討する。本研究は予後不良な食道扁平上皮がんに対する新たな治療戦略開発の基盤となる基礎研究である。

Outline of Final Research Achievements

In this study, we revealed the DNA damage response when esophageal squamous cell carcinoma (ESCC) cells was treated with FTD, and found that FTD strongly induces CHK1 phosphorylation in ESCC cells. CHK1 inhibitors enhanced the FTD-induced DNA damage and/or cytotoxic effects in vitro. Furthermore, combination treatment with FTD and CHK1 inhibitors showed an efective antitumor effects on ESCC xenograft tumors as well as PDX tumors. Moreover, we showed that drug treatment with FTD and CHK1 inhibitors significantly enhances radiosensitivity, and the combination treatment with FTD, CHK1 inhibitor and radiotherapy showed a potent antitumor effects on ESCC.

Academic Significance and Societal Importance of the Research Achievements

食道扁平上皮癌は集学的治療を行っても依然死亡率の高い難治性癌であり、食道扁平上皮癌の予後改善のためには有効性の高い抗がん剤治療の開発が急務である。本研究成果により、トリフルリジンとCHK1阻害剤の併用治療が食道扁平上皮癌細胞に対する新たな治療法となりうる可能性が示唆された。今後、臨床応用へ向けたさらなる研究開発が期待される。

Research Products

• [Journal Article] Visceral fat obesity is the key risk factor for the development of reflux erosive esophagitis in 40-69-years subjects (2021)
  • Author(s): Shinya Ohashi, Takahisa Maruno, Keita Fukuyama, Osamu Kikuchi, Tomohiko Sunami, Ｙuki Ｋondo, Ｓeiichiro Ｉmai, Ｍatsushima Ａki, Ｋimiyo Ｓuzuki, Ｆumika Ｕsui, Ｍasahiro Ｙakami, Ａtsushi Yamada, Hiroyoshi Isoda, Shigemi Matsumoto, Hiroshi Seno, Manabu Muto, Mayumi Inoue
  • Journal Title: Esophagus Volume: 18 Issue: 4 Pages: 889-899
  • DOI: 10.1007/s10388-021-00859-5
  • Peer Reviewed / Open Access
• [Journal Article] Cancer of unknown primary with EGFR mutation successfully treated with targeted therapy directed by clinical next-generation sequeincing: a case report (2020)
  • Author(s): Mitani Y, Kanai M, Kou T, Kataoka S, Doi K, Matsubara J, Ohashi S, Matsumoto S, Muto M.
  • Journal Title: BMC Cancer Volume: 20 Issue: 1 Pages: 1177-1177
  • DOI: 10.1186/s12885-020-07640-4
  • Peer Reviewed / Open Access
• [Journal Article] Autophagy migrates ethanol-induced mitochondrial dysfunction and oxidative stress in esophageal keratinocytes (2020)
  • Author(s): Chandranouleeswaran PM, Guha M, Shimonosono M, Whealan KA, Ruthel G, Mukherjee S, Gonzalez MV, Garifallou J, Amesaros C, Blair IA, Pellegrino R, Noguchi E, Hakonarson H, Baur JA, Engel N, Maekawa H, Sachdeva UM, Ohashi S, Klein-Szanto A, Nakagawa H,
  • Journal Title: PLOS One Volume: 15 Issue: 9 Pages: e0239625-e0239625
  • DOI: 10.1371/journal.pone.0239625
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] E487K-induced disorder in functionally relevant dynamics of mitochondrial aldehyde dehydrogenase 2 (2020)
  • Author(s): Matsumoto S, Araki M, Isaka Y, Ono F, Hirohashi K, Ohashi S, Muto M, Okuno Y
  • Journal Title: Biophysical Journal Volume: 119 Issue: 3 Pages: 628-637
  • DOI: 10.1016/j.bpj.2020.07.002
  • Peer Reviewed / Open Access
• [Journal Article] Experimental model for the irradiation-mediated abscopal effect and factors influencing this effect (2020)
  • Author(s): Baba K, Nomura M, Ohashi S, Hiratsuka T, Nakai Y, Saito T, Kondo Y, Fukuyama K, Kikuchi O, Yamada A, Matsubara J, Hirohashi K, Mitani Y, Mizumoto A, Muto M
  • Journal Title: American Journal of Cancer Research Volume: 10 Pages: 440-453
  • Peer Reviewed / Open Access
• [Journal Article] Protective effects of Alda-1, an ALDH2 activator, on alcohol-derived DNA damage in the esophagus of human ALDH2*2(Glu504Lys) knock-in mice (2019)
  • Author(s): Kenshiro Hirohashi, Shinya Ohashi, Yusuke Amanuma, Yukie Nakai, Tomomi Ida, Kiichiro Baba, Yosuke Mitani, Ayaka Mizumoto, Yoshihiro Yamamoto, Osamu Kikuchi, Junichi Matsubara, Atsushi Yamada, Shin'ichi Miyamoto, Hiroshi Seno, Tomonori Matsuda, Manabu Muto
  • Journal Title: Carcinogenesis Volume: ― Issue: 2 Pages: 194-202
  • DOI: 10.1093/carcin/bgz091
  • NAID: 120006649578
  • Peer Reviewed / Open Access
• [Journal Article] Patient-derived tumor models of esophageal cancer (2019)
  • Author(s): Tomoki Saito, Shinya Ohashi, Ayaka Mizumoto, Manabu Muto
  • Journal Title: Enzymes Volume: 46 Pages: 97-111
  • DOI: 10.1016/bs.enz.2019.10.003
  • Peer Reviewed
• [Journal Article] Combination treatment with highly bioavailable curcumin and NQO1 inhibitor exhibits potent antitumor effects on esophageal squamous cell carcinoma. (2019)
  • Author(s): Mizumoto A, Ohashi S, Kamada M, Saito T, Nakai Y, Baba K, Hirohashi K, Mitani Y, Kikuchi O, Matsubara J, Yamada A, Takahashi T, Lee H, Okuno Y, Kanai M, Muto M.
  • Journal Title: Journal of Gastroenterology Volume: ― Issue: 8 Pages: 687-698
  • DOI: 10.1007/s00535-019-01549-x
  • Peer Reviewed / Open Access
• [Journal Article] Recent Advances from Basic and Clinical Studies of Esophageal Squamous Cell Carcinoma. (2015)
  • Author(s): Ohashi S, Miyamoto S, Kikuchi O, Goto T, Amanuma Y, Muto M.
  • Journal Title: Gastroenterology Volume: 149 Issue: 7 Pages: 1700-1715
  • DOI: 10.1053/j.gastro.2015.08.054
  • NAID: 120005848418
  • Peer Reviewed / Open Access
• [Presentation] Synthetic lethalityによる食道扁平上皮癌に対する新たな治療戦略の確立 (2022)
  • Author(s): 大橋真也、菊池理、武藤学
  • Organizer: 第18回日本消化管学会総会学術集会
• [Presentation] HER2-G776S mutation triggers colorectal cancer progression through loss of APC function. (2020)
  • Author(s): 三谷洋介、大橋真也、菊池理、中村英二郎、武藤学
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] The chick chorioallantoic membrane tumor model retaining a series of histological features of the parental tumor. (2020)
  • Author(s): 齋藤伴樹、真辺綾佳、菊池理、大橋真也、吉岡正博、武藤学
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 4-ニトロキノン-オキシド(4NQO)を用いた食道扁平上皮発がんモデルの検討 (2020)
  • Author(s): 近藤 雄紀、大橋真也 山本佳宏、貴島孝、下ノ薗将貴、田中晃司、原豪男、長沼誠二、中川裕、武藤学
  • Organizer: 第74回日本食道学会学術集会
• [Presentation] 頭頚部・食道における発癌メカニズム (2020)
  • Author(s): 武藤 学、横山顕礼、大橋真也
  • Organizer: 第44回日本頭頚部癌学会
• [Presentation] トリフルリジン・チピラシルおよびプレキサセルティブ（CHK1阻害剤）併用による食道扁平上皮癌に対する新たな治療戦略 (2019)
  • Author(s): 大橋真也、菊池理、齋藤伴樹、近藤雄紀、三谷洋介、武藤学
  • Organizer: 第78回日本癌学会学術総会