Identification of compounds to suppress post-chemotherapeutic cancer relapse using drug-tolerant cancer subpopulations

• Project/Area Number: 25462034
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Iwate Medical University
• Principal Investigator: Nishizuka Satoshi 岩手医科大学, 医学部, 講師 (50453311)
• Co-Investigator(Kenkyū-buntansha): Kume Kohei 岩手医科大学, 医歯薬総合研究所・神経科学研究部門, 助教 (10609663) ; 前沢 千早 岩手医科大学, 医学部, 教授 (10326647) ; 若林 剛 岩手医科大学, 医学部, 教授 (50175064)
• Co-Investigator(Renkei-kenkyūsha): Iwaya Takeshi 岩手医科大学, 医学部外科, 講師 (70405801)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 化学療法 / 薬剤耐性 / RNAポリメラーゼ

Outline of Final Research Achievements

Post-chemotherapeutic cancer relapse has been considered a result of population selection of drug-tolerant colonies (DTCs).The originally developed CoLA technology revealed that DTCs are of two distinct subpopulations expressing either stem cell- or epithelia-associated proteins. The TAF15 gene was identified as one of the uniquely expressed genes in DTCs. Subsequent TAF15 gene knockdown demonstrated a similar morphological change that was seen when RNA polymerase inhibitors were administered. An RNA polymerase inhibitor, alpha-amanitin (alpha-AMA) was identified for suppression of DTCs in vitro. Concurrent administration of alpha-AMA/CDDP suppressed peritoneal dissemination and prolonged survival in a mouse model.

Research Products

• [Int'l Joint Research] National Institutes of Health(米国)
• [Journal Article] Aipha-Amanitin restrains cancer relapse from drug-tolerant cell subpopulations via TAF-15 (2016)
  • Author(s): Kume K, Ikeda M, Miura S, Ito K, Sato KA, Ohmori Y, Endo F, Katagiri H, Ishida K, Ito C, Iwaya T, Nishizuka SS
  • Journal Title: Sci Rep. Volume: 6 Pages: 25895-25895
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Intracorporeal reconstruction after laparoscopic pylorus-preserving gastrectomy for middle-third early gastric cancer: a hybrid technique using linear stapler and manual suturing. (2016)
  • Author(s): Koeda K, Chiba T, Noda H, Nishinari Y, Segawa T, Akiyama Y, Iwaya T, Nishizuka S, Nitta H, Otsuka K, Sasaki A.
  • Journal Title: Langenbecks Arch Surg Volume: 401 Issue: 3 Pages: 397-402
  • DOI: 10.1007/s00423-016-1378-3
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Systematic Protein Level Regulation via Degradation Machinery Induced by Genotoxic Drugs (2016)
  • Author(s): Kume K, Ishida K, Ikeda M, Takemoto K, Shimura T, Young L, Nishizuka SS.
  • Journal Title: J Proteome Res Volume: 15 Issue: 1 Pages: 205-15
  • DOI: 10.1021/acs.jproteome.5b00759
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Individualized Mutation Detection in Circulating Tumor DNA for Monitoring Colorectal Tumor Burden Using a Cancer-Associated Gene Sequencing Panel. (2016)
  • Author(s): Sato KA, Hachiya T, Iwaya T, Kume K, Matsuo T, Kawasaki K, Abiko Y, Akasaka R, Matsumoto T, Otsuka K, Nishizuka SS
  • Journal Title: PLoS One Volume: 11 Issue: 1 Pages: e0146275-e0146275
  • DOI: 10.1371/journal.pone.0146275
  • Peer Reviewed / Open Access
• [Journal Article] New era of integrated cancer biomarker discovery using reverse-phase protein arrays (2016)
  • Author(s): Nishizuka SS, Mills GB
  • Journal Title: Drug Metab Pharmacokinet. Volume: 31 Issue: 1 Pages: 35-45
  • DOI: 10.1016/j.dmpk.2015.11.009
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A compensatory role of NF-κB to p53 in response to 5-FU-based chemotherapy for gastric cancer cell lines (2014)
  • Author(s): Endo et al.
  • Journal Title: PLoS ONE Volume: 27
• [Journal Article] Contrasting expression patterns of histone mRNA and microRNA 760 in patients with gastric cancer (2013)
  • Author(s): Iwaya et al.
  • Journal Title: Clin Cancer Res Volume: 19 Pages: 6438-6449
• [Presentation] Prevention of peritonitis carcinomatosa after adjuvant chemotherapy by the inhibition of RNA polymerase in drug-tolerant subpopulations (2015)
  • Author(s): Nishizuka SS, Kume K, Sato K, Wakabayashi G
  • Organizer: 2015 American Association for Cancer Research
  • Place of Presentation: 米国
  • Year and Date: 2015-04-22
  • Int'l Joint Research
• [Presentation] Differential Anticancer Drug Response by High-Dimensional Protein Monitori ng
  • Author(s): Nishizuka et al.
  • Organizer: American Association for Cancer Research
  • Place of Presentation: Washington DC
• [Presentation] 薬剤寛容性コロニーを用いた癌再発予防へ向けた基礎的研究
  • Author(s): 西塚哲ほか
  • Organizer: 制癌剤適応研究会
  • Place of Presentation: 名古屋
• [Presentation] がんの定義とがん遺伝子診断
  • Author(s): 西塚哲ほか
  • Organizer: 次世代シークエンサー現場の会 第三回研究会
  • Place of Presentation: 神戸
• [Presentation] 抗癌剤耐性コロニー 由来細胞集団の分子生物学的プロファイル
  • Author(s): 西塚哲ほか
  • Organizer: 日本外科学会
  • Place of Presentation: 福岡
• [Patent(Industrial Property Rights)] 腫瘍の再発を抑制する医薬 (2015)
  • Inventor(s): 西塚 哲、久米浩平
  • Industrial Property Rights Holder: 西塚 哲、久米浩平
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-09-04
• [Patent(Industrial Property Rights)] 腫瘍の再発を抑制するための標的分子としてのTAF15遺伝子およびその産物 (2015)
  • Inventor(s): 西塚 哲、久米浩平
  • Industrial Property Rights Holder: 西塚 哲、久米浩平
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-09-04
• [Patent(Industrial Property Rights)] 微小細胞集団の発現プロファイル方法 (2015)
  • Inventor(s): 西塚 哲、久米浩平
  • Industrial Property Rights Holder: 西塚 哲、久米浩平
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-09-04