Tumor specific siRNA delivery for KRAS mutant colorectal cancer

• Project/Area Number: 18K07979
• 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: Nagoya City University
• Principal Investigator: Shimura Takaya 名古屋市立大学, 医薬学総合研究院(医学), 講師 (90405192)
• Co-Investigator(Kenkyū-buntansha): 田上 辰秋 名古屋市立大学, 医薬学総合研究院(薬学), 准教授 (10609887) ; 尾関 哲也 名古屋市立大学, 医薬学総合研究院(薬学), 教授 (60277259)
• Project Period (FY): 2018-04-01 – 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: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 大腸癌 / 膵癌 / KRAS変異 / ドラッグデリバリー / DDS

Outline of Final Research Achievements

Glut1 is a membrane-binding protein that overexpresses in cell membranes of KRAS-mutated colorectal cancer and pancreatic cancer. We newly established anti-Glut1 antibody conjugated liposome containing siRNA of KRAS gene inside　(siKRAS-Glut1-LP) in this study. This novel delivery system of nucleic acids (siKRAS-Glut1-LP) accumulated cell membranes of KRAS-mutated colorectal cancer and pancreatic cancer cells and inhibited cancer cell growth through suppressing KRAS expression.

Academic Significance and Societal Importance of the Research Achievements

これまでKRAS変異型大腸癌に対しては特異的な治療薬がなかった。本研究により開発した、ドラッグデリバリーシステムは、KRAS変異を有する大腸癌・膵癌組織へ特異的にsiRNAをデリバリーすることによりdriver oncogeneであるKRAS発現を阻害する新規治療法である。本研究成果は、予後不良であるKRAS変異型大腸癌・膵癌の新規治療法として注目される。しかしながら、薬剤の安定性にはまだ課題があり、今後の組成の工夫を加え、動物実験による有効性と安全性の評価を加えることにより画期的な新規治療となる可能性がある。

Research Products

• [Journal Article] A Novel Urinary miRNA Biomarker for Early Detection of Colorectal Cancer. (2022)
  • Author(s): Iwasaki H, Shimura T, Kitagawa M, Yamada T, Nishigaki R, Fukusada S, Okuda Y, Katano T, Horike SI, Kataoka H.
  • Journal Title: Cancers Volume: 14 Issue: 2 Pages: 461-461
  • DOI: 10.3390/cancers14020461
  • Peer Reviewed / Open Access
• [Journal Article] The Risk Analyses of Lymph Node Metastasis and Recurrence for Submucosal Invasive Colorectal Cancer: Novel Criteria to Skip Completion Surgery (2022)
  • Author(s): Ozeki T, Shimura T, Ozeki T, Ebi M, Iwasaki H, Kato H, Inaguma S, Okuda Y, Katano T, Nishie H, Takahashi S, Kataoka H
  • Journal Title: Cancers Volume: 14 Issue: 3 Pages: 822-822
  • DOI: 10.3390/cancers14030822
  • Peer Reviewed / Open Access
• [Journal Article] Novel and Simple Criteria for Predicting Mortality of Peptic Ulcer Disease (2021)
  • Author(s): Iwasaki H, Shimura T, Yamada T, Nishigaki R, Okuda Y, Fukusada S, Ozeki T, Kitagawa M, Katano T, Tanaka M, Nishie H, Ozeki K, Kubota E, Tanida S, Kataoka H.
  • Journal Title: Internal Medicine Volume: 60 Issue: 15 Pages: 2349-2356
  • DOI: 10.2169/internalmedicine.6945-20
  • NAID: 130008070675
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-08-01
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between gene mutations and clinicopathological features in nonampullary duodenal epithelial tumors. (2021)
  • Author(s): Fukusada S, Shimura T, Iwasaki H, Okuda Y, Katano T, Ozeki T, Kitagawa M, Nishie H, Tanaka M, Ozeki K, Kubota E, Tanida S, Kataoka H.
  • Journal Title: Dig Liver Dis. Volume: Dec 24 Issue: 7 Pages: 905-910
  • DOI: 10.1016/j.dld.2021.12.004
  • Peer Reviewed / Open Access
• [Journal Article] Urinary microRNA biomarkers for detecting the presence of esophageal cancer. (2021)
  • Author(s): Okuda Y, Shimura T, Iwasaki H, Fukusada S, Nishigaki R, Kitagawa M, Katano T, Okamoto Y, Yamada T, Horike SI, Kataoka H.
  • Journal Title: Sci Rep. Volume: 11 Issue: 1 Pages: 8508-8508
  • DOI: 10.1038/s41598-021-87925-1
  • Peer Reviewed / Open Access
• [Journal Article] 5-aminolaevulinic acid (5-ALA) accumulates in GIST-T1 cells and photodynamic diagnosis using 5-ALA identifies gastrointestinal stromal tumors (GISTs) in xenograft tumor models. (2021)
  • Author(s): Sasaki M, Tanaka M, Ichikawa H, Suzuki T, Nishie H, Ozeki K, Shimura T, Kubota E, Tanida S, Kataoka H
  • Journal Title: PLoS One Volume: 16 Issue: 4 Pages: e0249650-e0249650
  • DOI: 10.1371/journal.pone.0249650
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between Immunophenotype and Clinicopathological Findings for Superficial Nonampullary Duodenal Epithelial Tumor (2021)
  • Author(s): Fukusada S, Shimura T, Iwasaki H, Okuda Y, Katano T, Nishigaki R, Ozeki T, Kitagawa M, Nishie H, Tanaka M, Ozeki K, Kubota E, Tanida S, Kataoka H
  • Journal Title: Digestion Volume: Apr 1 Issue: 6 Pages: 1-8
  • DOI: 10.1159/000514812
  • Peer Reviewed
• [Journal Article] A novel balloon-attached endoscopy-assisted reduction technique for an acute strangulated stoma prolapse (2021)
  • Author(s): Shimura T, Ozeki T, Ushigome H, Hirokawa T, Shiga K, Takahashi H, Kataoka H
  • Journal Title: Endoscopy Volume: Feb 19 Issue: 01 Pages: E36-E37
  • DOI: 10.1055/a-1346-8427
  • Peer Reviewed / Open Access
• [Journal Article] A multicenter, single-blind randomized controlled trial of endoscopic clipping closure for preventing coagulation syndrome after colorectal endoscopic submucosal dissection. (2020)
  • Author(s): Nomura S, Shimura T, Katano T, Iwai T, Mizuno Y, Yamada T, Ebi M, Hirata Y, Nishie H, Mizushima T, Nojiri Y, Togawa S, Shibata S, Kataoka H.
  • Journal Title: Gastrointestinal Endoscopy Volume: 91 Issue: 4 Pages: 859-867
  • DOI: 10.1016/j.gie.2019.11.030
  • Peer Reviewed
• [Journal Article] Omental adipocytes promote peritoneal metastasis of gastric cancer through the CXCL2-VEGFA axis (2020)
  • Author(s): Natsume M, Shimura T, Iwasaki H, Okuda Y, Hayashi K, Takahashi S, Kataoka H.
  • Journal Title: British Journal of Cancer Volume: 123 Issue: 3 Pages: 459-470
  • DOI: 10.1038/s41416-020-0898-3
  • Peer Reviewed
• [Journal Article] Novel urinary protein biomarker panel for early diagnosis of gastric cancer (2020)
  • Author(s): Shimura T, Dayde D, Wang H, Okuda Y, Iwasaki H, Ebi M, Kitagawa M, Yamada T, Yamada T, Hanash SM, Taguchi A, Kataoka H
  • Journal Title: British Journal of Cancer Volume: 123 Issue: 11 Pages: 1656-1664
  • DOI: 10.1038/s41416-020-01063-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The first management using intubation of a nasogastric tube with Gastrografin enterography or long tube for non-strangulated acute small bowel obstruction: a multicenter, randomized controlled trial (2020)
  • Author(s): Katano T, Shimura T, Nishie H, Iwai T, Itoh K, Ebi M, Mizuno Y, Togawa S, Shibata S, Yamada T, Mizushima T, Inagaki Y, Kitagawa M, Nojiri Y, Tanaka Y, Okamoto Y, Sugiura M, Matoya S, Nagura Y, Inagaki Y, Koguchi H, Ono S, Ozeki K, Hayashi N, Takiguchi S, Kataoka H
  • Journal Title: Journal of Gastroenterology Volume: 55 Issue: 9 Pages: 858-867
  • DOI: 10.1007/s00535-020-01708-5
  • Peer Reviewed
• [Journal Article] Serum Exosomal Dicer Is a Useful Biomarker for Early Detection of Differentiated Gastric Adenocarcinoma (2020)
  • Author(s): Okuda Y, Shimura T, Iwasaki H, Katano T, Kitagawa M, Nishigaki R, Fukusada S, Natsume M, Tanaka M, Nishie H, Ozeki K, Yamada T, Kataoka H.
  • Journal Title: Digestion. Volume: Oct 13 Issue: 4 Pages: 1-10
  • DOI: 10.1159/000510993
  • Peer Reviewed / Open Access
• [Journal Article] A novel urinary microRNA biomarker panel for detecting gastric cancer. (2019)
  • Author(s): Iwasaki H, Shimura T, Yamada T, Okuda Y, Natsume M, Kitagawa M, Horike SI, Kataoka H
  • Journal Title: Journal of Gastroenterology Volume: 54 Issue: 12 Pages: 1061-1069
  • DOI: 10.1007/s00535-019-01601-w
  • Peer Reviewed
• [Journal Article] Current status of urinary diagnostic biomarkers for colorectal cancer. (2019)
  • Author(s): Iwasaki H, Shimura T, Kataoka H
  • Journal Title: Clin Chim Acta. Volume: 498 Pages: 76-83
  • DOI: 10.1016/j.cca.2019.08.011
  • Peer Reviewed
• [Journal Article] Urinary Cysteine-Rich Protein 61 and Trefoil Factor 3 as Diagnostic Biomarkers for Colorectal Cancer. (2019)
  • Author(s): Shimura T, Iwasaki H, Kitagawa M, Ebi M, Yamada T, Yamada T, Katano T, Nisie H, Okamoto Y, Ozeki K, Mizoshita T, Kataoka H.
  • Journal Title: Transl Oncol. Volume: 12(3) Issue: 3 Pages: 539-544
  • DOI: 10.1016/j.tranon.2018.12.006
  • Peer Reviewed / Open Access
• [Journal Article] Placental growth factor is a predictive biomarker for ramucirumab treatment in advanced gastric cancer. (2019)
  • Author(s): Natsume M, Shimura T, Iwasaki H, Okuda Y, Kitagawa M, Okamoto Y, Hayashi K, Kataoka H
  • Journal Title: Cancer Chemother Pharmacol. Volume: Mar 21. Issue: 6 Pages: 1037-1046
  • DOI: 10.1007/s00280-019-03817-2
  • Peer Reviewed / Open Access
• [Journal Article] Colorectal obstruction is a potential prognostic factor for stage II colorectal cancer. (2018)
  • Author(s): Okuda Y, Shimura T, Yamada T, Hirata Y, Yamaguchi R, Sakamoto E, Kataoka H.
  • Journal Title: Int J Clin Oncol. Volume: 23(6) Issue: 6 Pages: 1101-1111
  • DOI: 10.1007/s10147-018-1307-2
  • Peer Reviewed
• [Presentation] 癒着性小腸イレウスに対するロングチューブ vs. 経鼻胃管ガストログラフィン造影のランダム化比較試験 (2020)
  • Author(s): 志村 貴也
  • Organizer: 第16回日本消化管学会総会
  • Invited
• [Presentation] 表在性非乳頭部十二指腸腫瘍に対する当院の内視鏡的治療方針とその妥当性の検討 (2020)
  • Author(s): 志村貴也、尾関貴紀、片岡洋望
  • Organizer: 第99回日本消化器内視鏡学会総会
• [Presentation] 大腸がんに対する尿中診断バイオマーカーの開発 (2019)
  • Author(s): 志村貴也、岩崎弘靖、片岡洋望
  • Organizer: 第105回日本消化器病学会総会
• [Presentation] POTENTIAL OF URINARY CYSTEINE-RICH PROTEIN 61 AND TREFOIL FACTOR 3 AS NOVEL BIOMARKERS FOR THE DETECTION OF COLORECTAL CANCER. (2019)
  • Author(s): Shimura T, Iwasaki H, Ebi M, Yamada T, Yamada T, Kataoka H.
  • Organizer: DDW2019
  • Int'l Joint Research
• [Presentation] 十二指腸腫瘍に対する当院での内視鏡治療指針の妥当性の検討 (2019)
  • Author(s): 志村貴也、尾関啓司、片岡洋望．
  • Organizer: 第97回日本消化器内視鏡学会総会．
• [Presentation] Potential of urinary microRNA biomarker panel for the early detection of gastric cancer. (2019)
  • Author(s): Shimura T, Iwasaki H, Yamada T, Kataoka H.
  • Organizer: UEGW2019
  • Int'l Joint Research
• [Presentation] The results of endoscopic resection for superficial non-ampullary duodenal neoplasms. (2019)
  • Author(s): Shimura T, Nishie H, Ozeki K, Takiguchi S, Kataoka H.
  • Organizer: IGCS2019
  • Int'l Joint Research
• [Presentation] Omental fat tissue promotes peritoneal dissemination of gastric cancer. (2019)
  • Author(s): Natsume M, Shimura T, Iwasaki H, Okuda Y, Kataoka H.
  • Organizer: UEGW2019
  • Int'l Joint Research
• [Presentation] The obesity and pancreatic cancer connection: Crosstalk between adipose, tumor, and stroma. (2019)
  • Author(s): Roopali Roy, Takaya Shimura, Adelle Dagher and Marsha A. Moses.
  • Organizer: AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care
  • Int'l Joint Research