KRAS/BRAF変異大腸癌に対するマイクロRNAを利用した新規治療法の開発

2015 Fiscal Year Annual Research Report

• Project/Area Number: 25462057
• Research Institution: Okayama University
• Principal Investigator: 田澤 大 岡山大学, 大学病院, 助教 (90415513)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: マイクロRNA / 大腸癌 / KRAS / BRAF / EGFR

Outline of Annual Research Achievements

本研究では、KRAS/BRAF変異型大腸癌の治療抵抗性におけるEGFRシグナルの活性化を検証し、EGFRシグナル抑制性マイクロRNAを誘導するウイルス製剤を用いた新しい治療法の開発を目指す事を目的とした。

平成27年度は、KRAS/BRAF正常型大腸癌細胞株、KRAS変異型大腸癌細胞株、BRAF変異型大腸癌細胞株に対する2種類の腫瘍融解アデノウイルス製剤OBP-301、OBP-702のEGFR-KRAS/BRAF-ERKシグナルに対する抑制効果をウェスタンブロット法で検証した。OBP-301はKRAS/BRAF正常型大腸癌細胞株とKRAS変異型大腸癌細胞株におけるEGFR-KRAS-ERKシグナルの抑制を示したが、BRAF変異型大腸癌細胞株のEGFR-BRAF-ERKシグナルの抑制を示さなかった。一方、p53発現誘導能を有するOBP-702は全ての細胞株においてEGFR-KRAS/BRAF-ERKシグナルの抑制を示した。次に、OBP-301が誘導するマイクロRNA-7とOBP-702が誘導するマイクロRNA-34がKRAS/BRAF変異型大腸癌細胞の生存率に対する抑制効果を検討した。マイクロRNA-7はKRAS変異型大腸癌の生存率を低下させ、マイクロRNA-34はBRAF変異型大腸癌細胞の生存率を低下させた。以上の結果から、KRAS/BRAF正常型大腸癌細胞やKRAS変異型大腸癌細胞に対して、腫瘍融解アデノウイルス製剤OBP-301はマイクロRNA-7によるEGFR-KRAS-ERKシグナルの抑制を介して抗腫瘍効果を示す事が示唆された。一方、BRAF変異型大腸癌細胞に対して、p53発現誘導能を有する腫瘍融解アデノウイルス製剤OBP-702はマイクロRNA-34によるEGFR-BRAF-ERKシグナルの抑制を介して抗腫瘍効果を示す可能性が示唆された。

Research Products

• [Journal Article] Biological ablation of sentinel lymph node metastasis in submucosally invaded early gastrointestinal cancer (2015)
  • Author(s): Kikuchi S, Kishimoto H, Tazawa H, Hashimoto Y, Kuroda S, Nishizaki M, Nagasaka T, Shirakawa Y, Kagawa S, Urata Y, Hoffman RM, Fujiwara T
  • Journal Title: Mol Ther Volume: 23 Pages: 501-509
  • DOI: 10.1038/mt.2014.244.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Fluorescence virus-guided capturing system of human colorectal circulating tumor cells for non-invasive companion diagnostics (2015)
  • Author(s): Shigeyasu K, Tazawa H, Hashimoto Y, Mori Y, Nishizaki M, Kishimoto H, Nagasaka T, Kuroda S, Urata Y, Goel A, Kagawa S, Fujiwara T
  • Journal Title: Gut Volume: 64 Pages: 627-635
  • DOI: 10.1136/gutjnl-2014-306957.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Viral transduction of HER2-extracellular domain expands trastuzumab-based photoimmunotherapy for HER2 negative breast cancer cells (2015)
  • Author(s): Shimoyama K, Kagawa S, Ishida M, Watanabe M, Noma K, Takehara K, Tazawa H, Hashimoto Y, Matsuoka J, Kobayashi H, Fujiwara T
  • Journal Title: Breast Cancer Res Treat Volume: 149 Pages: 597-605
  • DOI: 10.1007/s10549-015-3265-y.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cancer cells mimic in vivo spatial-temporal cell-cycle phase distribution and chemosensitivity in 3-dimensional gelfoam histoculture but not 2-dimensional culture as visualized with real-time FUCCI imaging (2015)
  • Author(s): Yano S, Miwa S, Mii S, Hiroshima Y, Uehara F, Kishimoto H, Tazawa H, Zhao M, Bouvet M, Fujiwara T, Hoffman RM
  • Journal Title: Cell Cycle Volume: 14 Pages: 808-819
  • DOI: 10.1080/15384101.2014.1000685
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Experimental curative fluorescence-guided surgery of highly-invasive glioblastoma multiforme selectively labeled with a killer-reporter adenovirus (2015)
  • Author(s): Yano S, Miwa S, Kishimoto H, Toneri M, Hiroshima Y, Yamamoto M, Bouvet M, Urata Y, Tazawa H, Kagawa S, Fujiwara T, Hoffman RM
  • Journal Title: Mol Ther Volume: 23 Pages: 1182-1188
  • DOI: 10.1038/mt.2015.63.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Targeting tumors with a killer-reporter adenovirus for curative fluorescence-guided surgery of soft-tissue sarcoma (2015)
  • Author(s): Yano S, Miwa S, Kishimoto H, Uehara F, Tazawa H, Toneri M, Hiroshima Y, Yamamoto M, Urata Y, Kagawa S, Bouvet M, Fujiwara T
  • Journal Title: Oncotarget Volume: 6 Pages: 13133-13148
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Color-coding cancer and stromal cells with genetic reporters in a patient-derived orthotopic xenograft (PDOX) model of pancreatic cancer enhances fluorescence-guided surgery (2015)
  • Author(s): Yano S, Hiroshima Y, Maawy A, Kishimoto H, Suetsugu A, Miwa S, Toneri M, Yamamoto M, Katz M, Fleming J, Urata Y, Tazawa H, Kagawa S, Bouvet M, Fujiwara T
  • Journal Title: Cancer Gene Ther Volume: 22 Pages: 344-350
  • DOI: 10.1038/cgt.2015.26.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genetic and epigenetic alterations of netrin-1 receptors in gastric cancer with chromosomal instability (2015)
  • Author(s): Toda K, Nagasaka T, Umeda Y, Tanaka T, Kawai T, Fuji T, Taniguchi F, Yasui K, Kubota N, Takehara Y, Tazawa H, Kagawa S, Sun DS, Nishida N, Goel A, Fujiwara T
  • Journal Title: Clin Epigenetics Volume: 7 Pages: 73
  • DOI: 10.1186/s13148-015-0096-y.
  • Peer Reviewed / Int'l Joint Research
• [Presentation] KRAS/BRAF変異を持つ大腸癌に対する新たな腫瘍融解ウイルス療法の開発 (2015)
  • Author(s): 田村周太、田澤 大、堀 直人、國府島 健、菊地覚次、黒田新士、岸本浩行、永坂岳司、西崎正彦、浦田泰生、香川俊輔、藤原俊義
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08 – 2015-10-10
• [Presentation] Preclinical evaluation of tumor-specific oncolytic virotherapy against human colorectal cancer cells with different KRAS/BRAF mutation and microsatellite stability (2015)
  • Author(s): Tamura S, Tazawa H, Hori N, Koujima T, Kikuchi S, Kuroda S, Kishimoto H, Nagasaka T, Nishizaki M, Urata Y, Kagawa S, Fujiwara T
  • Organizer: 第21回日本遺伝子治療学会
  • Place of Presentation: 大阪
  • Year and Date: 2015-07-24 – 2015-07-26
• [Presentation] Companion diagnostics-based telomerase-specific oncolytic virotherapy: preclinical evaluation in human colorectal cancer cell lines differentially affected in the RAS/RAF/MEK signaling pathway (2015)
  • Author(s): Tamura S, Tazawa H, Hori N, Koujima T, Kikuchi S, Kuroda S, Kishimoto H, Nagasaka T, Nishizaki M, Urata Y, Kagawa S, Fujiwara T
  • Organizer: 106th Annual Meeting of the American Association for Cancer Research
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-18 – 2015-04-22
  • Int'l Joint Research