Elucidation of in vivo-like signal regulated by mutated KRAS in colorectal cancer spheroid and development of inhibitor.

• Project/Area Number: 18K07215
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Fukuoka University
• Principal Investigator: Tsunoda Toshiyuki 福岡大学, 医学部, 准教授 (70444817)
• Co-Investigator(Kenkyū-buntansha): 白澤 専二 福岡大学, 医学部, 教授 (10253535)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: KRAS / 3次元培養 / 低分子化合物 / 免疫逃避 / 大腸癌 / 細胞内小器官 / 免役チェックポイント / 免疫チェックポイント

Outline of Final Research Achievements

KRAS　mutation promotes the immune evasion other than the proliferation of cells. We have developed the lead compounds (STAR2) that suppresses the in vivo-like signal regulated by mutated (mt) KRAS and applied for patent. We also have succeeded to find the STAR2 targets, VDAC and KDELR. VDAC is localized in the outer membrane of mitochondria and KDELR is localized in endoplasmic reticulm. These results suggest the novel pathway that is regulated by mtKRAS in microorganism.

Academic Significance and Societal Importance of the Research Achievements

変異KRASは全癌の30%占めるが近年KRASのG12C変異を標的とする分子標的薬が開発されつつあり、臨床治験で効果を示している。しかしG12Cは全KRAS変異の中でも3％であり、依然として変異KRASを制御することは困難である。又、従来の抗癌剤は副作用が強く、最近の生物学的製剤などは一部の腫瘍に効果は認めるものの、薬剤耐性や高価である事などの問題点が多い。我々の開発している薬剤は安価な低分子化合物であり、癌特異的な変異KRASのシグナルを特異的に抑え、下流のハブ分子を抑えるために耐性化も認められない。二人に一人が癌を罹患する世の中において副作用の少ない抗腫瘍化合物は非常に意義がある。

Research Products

• [Int'l Joint Research] University of Glasgow(英国)
• [Int'l Joint Research] University of Glasgow(英国)
• [Journal Article] Mutant KRAS Promotes NKG2D+ T Cell Infiltration and CD155 Dependent Immune Evasion (2020)
  • Author(s): NISHI KENSUKE、ISHIKURA SHUHEI、UMEBAYASHI MASAYO、MORISAKI TAKASHI、INOZUME TAKASHI、KINUGASA TETSUSHI、AOKI MIKIKO、NIMURA SATOSHI、SWAIN ANTHONY、YOSHIDA YOICHIRO、HASEGAWA SUGURU、NABESHIMA KAZUKI、SAKATA TOSHIFUMI、SHIRASAWA SENJI、TSUNODA TOSHIYUKI
  • Journal Title: Anticancer Research Volume: 40 Issue: 8 Pages: 4663-4674
  • DOI: 10.21873/anticanres.14465
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MK615 Suppresses Hypoxia Tolerance by Up-regulation of E-cadherin in Colorectal Cancer Cells With Mutant KRAS (2020)
  • Author(s): NISHI KENSUKE、TSUNODA TOSHIYUKI、UCHIDA YOSHINORI、SUETA TAKAYUKI、SAWATSUBASHI MOTOHIRO、YAMANO TAKAFUMI、HASHIGUCHI YASUKO、SWAIN ANTHONY、SHIRASAWA SENJI、SAKATA TOSHIFUMI
  • Journal Title: Anticancer Research Volume: 40 Issue: 8 Pages: 4687-4694
  • DOI: 10.21873/anticanres.14468
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptional and metabolic rewiring of colorectal cancer cells expressing the oncogenic KRASG13D mutation (2019)
  • Author(s): Charitou Theodosia、Srihari Sriganesh、Lynn Miriam A.、Jarboui Mohamed-Ali、Fasterius Erik、Moldovan Max、Shirasawa Senji、Tsunoda Toshiyuki、Ueffing Marius、Xie Jianling、Xin Jin、Wang Xuemin、Proud Christopher G.、Boldt Karsten、Al-Khalili Szigyarto Cristina、Kolch Walter、Lynn David J.
  • Journal Title: British Journal of Cancer Volume: 121 Issue: 1 Pages: 37-50
  • DOI: 10.1038/s41416-019-0477-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Zfat Is Indispensable for the Development of Erythroid Cells in the Fetal Liver (2019)
  • Author(s): DOI KEIKO、TSUNODA TOSHIYUKI、KOYANAGI MIDORI、TANAKA YOKO、YAMANO SHIORI、FUJIKANE AYA、NISHI KENSUKE、ISHIKURA SHUHEI、SHIRASAWA SENJI
  • Journal Title: Anticancer Research Volume: 39 Issue: 8 Pages: 4495-4502
  • DOI: 10.21873/anticanres.13625
  • Peer Reviewed / Open Access
• [Journal Article] A novel compound, ferulic acid-bound resveratrol, induces the tumor suppressor gene p15 and inhibits the three-dimensional proliferation of colorectal cancer cells (2019)
  • Author(s): Sawata Yuuga、Matsukawa Taiji、Doi Satoshi、Tsunoda Toshiyuki、Arikawa Nagisa、Matsunaga Natsumi、Ohnuki Koichiro、Shirasawa Senji、Kotake Yojiro
  • Journal Title: Molecular and Cellular Biochemistry Volume: 462 Issue: 1-2 Pages: 25-31
  • DOI: 10.1007/s11010-019-03606-8
  • Peer Reviewed / Open Access
• [Journal Article] Zfat expression in ZsGreen reporter gene knoc;in mice: Implications for a novel function of Zfat in definitive erythropoiesis. (2018)
  • Author(s): Tsunoda T, Doi K, Ishikura S, Luo H, Nishi K, Matsuzaki H, Koyanagi M, Tanaka Y, Okamura T, Shirasawa S
  • Journal Title: Int J Mol Med. Volume: 42 Pages: 2595-2603
  • DOI: 10.3892/ijmm.2018.3806
  • Peer Reviewed / Open Access
• [Journal Article] Growth suppression of human colorectal cancer cells with mutated KRAS by 3-deaza-cytarabine in 3d floating culture (2018)
  • Author(s): Luo, H.; Nishi, K.; Ishikura, S.; Swain, A.; Morishige, N.; Yazaki, R.; Ohshima, T.; Shirasawa, S.; Tsunoda, T.
  • Journal Title: Anticancer research Volume: 38 Issue: 7 Pages: 4247-4256
  • DOI: 10.21873/anticanres.12721
  • Peer Reviewed / Open Access
• [Journal Article] A novel resveratrol derivative selectively inhibits the proliferation of colorectal cancer cells with KRAS mutation. (2018)
  • Author(s): Okamoto H, Matsukawa T, Doi S, Tsunoda T, Sawata Y, Naemura M, Ohnuki K, Shirasawa S, Kotake Y
  • Journal Title: Molecular and Cellular Biochemistry Volume: 442(1-2) Issue: 1-2 Pages: 39-45
  • DOI: 10.1007/s11010-017-3191-x
  • Peer Reviewed / Open Access
• [Journal Article] The Long Noncoding RNA OIP5-AS1 Is Involved in the Regulation of Cell Proliferation. (2018)
  • Author(s): Naemura M, Kuroki M, Tsunoda T, Arikawa N, Sawata Y, Shirasawa S, Kotake Y.
  • Journal Title: Anticancer Res Volume: 38 Pages: 77-81
  • Peer Reviewed / Open Access
• [Journal Article] Acquisition of resistance to vemurafenib leads to interleukin-10 production through an aberrant activation of Akt in a melanoma cell line (2018)
  • Author(s): Inozume T, Tsunoda T, Morisaki T, Harada K, Shirasawa S, Kawamura T
  • Journal Title: Journal of Dermatology Volume: 45 Issue: 12 Pages: 1434-1439
  • DOI: 10.1111/1346-8138.14651
  • Peer Reviewed / Open Access
• [Presentation] 変異KRAS関連シグナルが活性化した癌細胞の増殖はVDAC1およびKDELR1の2重調節剤により抑制される． (2020)
  • Author(s): 角田俊之, 西憲祐, 白澤専二
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] VDACおよびKDELRを標的とする低分子化合物STAR2は変異KRAS関連シグナルを抑制する． (2020)
  • Author(s): 角田俊之, 橋本小百合, 永井正義, 西憲祐, 石倉周平,白澤専二．
  • Organizer: 第24回バイオ治療法研究会学術集会
• [Presentation] 難治性腫瘍に対する副作用の少ない抗がん剤 (2020)
  • Author(s): 角田俊之,
  • Organizer: 2020イノベーションジャパン
• [Presentation] 難治性腫瘍に対する副作用のない抗がん剤 (2019)
  • Author(s): 角田 俊之
  • Organizer: 2019イノベーションジャパン
• [Presentation] 変異KRAS関連シグナルが活性化した癌細胞株の増殖を抑制する低毒性化合物 (2019)
  • Author(s): 角田俊之, 西憲祐, 白澤専二
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 変異KRASはTNK細胞の腫瘍内浸潤とCD155依存的な免疫逃避を誘導する． (2019)
  • Author(s): 角田俊之, 西憲祐, 石倉周平, 梅林雅代, 森崎隆, 猪爪隆史, 衣笠哲史, 青木光希子, 二村聡, スウェイン・アンソニー, 吉田陽一郎, 長谷川傑, 鍋島一樹, 坂田俊文, 白澤専二．
  • Organizer: 第23回バイオ治療法研究会学術集会
• [Presentation] Inhibition of PDE4 Triggers Luminal Apoptosis in Human Colorectal Cancer Spheroids. (2018)
  • Author(s): Toshiyuki Tsunoda.
  • Organizer: Gordon Research Conference: Cyclic Nucleotide Phosphodiesterases. Newry, ME, US. June 10-15
  • Int'l Joint Research
• [Presentation] 3-deaza-cytarabineは3次元浮遊培養において変異KRAS陽性大腸癌細胞塊の増殖を抑制する (2018)
  • Author(s): 角田俊之, 西憲祐, 白澤専二
  • Organizer: 第77回日本癌学会学術総会，大阪，9月27-29日
• [Presentation] KRAS変異大腸癌細胞塊とCytokine-activated killer細胞の共培養系におけるCD155/TIGIT経路の役割の解析 (2018)
  • Author(s): 角田俊之, 西憲祐, 羅昊, 梅林雅代, 森崎隆, 白澤専二
  • Organizer: 第22回バイオ治療法研究会学術集会，東京，12月8日
• [Remarks] Institute of Cardiovascular & Medical Sciences
  • URL: https://www.gla.ac.uk/researchinstitutes/icams/staff/georgebaillie/
• [Patent(Industrial Property Rights)] ピラゾール誘導体及び医薬組成物 (2020)
  • Inventor(s): 白澤専二、角田俊之、大嶋孝志、矢崎亮、末永正彦
  • Industrial Property Rights Holder: 白澤専二、角田俊之、大嶋孝志、矢崎亮、末永正彦
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-017307
  • Filing Date: 2020
• [Patent(Industrial Property Rights)] フェニルテトラヒドロピリドインドール誘導体及び医薬組成物 (2018)
  • Inventor(s): 白澤 専二、角田 俊之、大嶋 孝志、矢崎 亮
  • Industrial Property Rights Holder: 白澤 専二、角田 俊之、大嶋 孝志、矢崎 亮
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-147801
  • Filing Date: 2018