Development of anticancer drug specifically targeting oncogenic driver mutations

• Project/Area Number: 25871150
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical genome science; Tumor therapeutics
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: WATANABE Takayoshi 千葉県がんセンター(研究所), がん遺伝創薬研究室, 研究員 (60526060)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ピロール・イミダゾールポリアミド / KRAS / 変異型ドライバーオンコジーン / PIP / CBI / ドライバーオンコジーン / PIポリアミド / βアラニン / γアミノ酪酸

Outline of Final Research Achievements

We studied novel anticancer drug candidates using alkylating pyrrole imdazole polyamides (PIP) and CBI conjugates which target several mutant deliver oncogene mutations. Based on a candidate agent, KR12 targeting KRAS codon12 mutant DNA sequence, we synthesized a KR12-α derivative of KR12 which also showed antitumor activities as seen in KR12. In addition, PIP-CBIs targeting variable mutant driver oncogenes other than KRAS were designed and synthesized. As a result, these PIP-CBIs have strong toxicity to cancer lines bearing target mutant mutations, such as ALK, PIK3CA and MYCN.
In conclusion, resulting from the study for two years, great progress of PIP-CBI chemical synthesis has been made and discovered multiple drug candidates which target distinct mutant deriver oncogene DNA mutations.

Research Products

• [Journal Article] Preclinical Study of Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Hypertrophic Scars in a Common Marmoset Primate Model. (2015)
  • Author(s): Igarashi J, Fukuda N, Inoue T, Nakai S, Saito K, Fujiwara K, Matsuda H, Ueno T, Matsumoto Y, Watanabe T, Nagase H, Bando T, Sugiyama H, Itoh T, Soma M
  • Journal Title: PLoS One Volume: e0125295
  • NAID: 120005947168
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a novel E-box binding PI polyamide inhibiting MYC-driven cell-proliferation. (2015)
  • Author(s): Mishra R, Watanabe T, Kimura M, Koshikawa N, Ikeda M, Uekusa S, Kawashima H, Wang X, Igarashi J, Choudhury D, Grandori C, Kemp C, Ohira M, Verma N, Kobayashi Y, Takeuchi J, Koshinaga T, Nemoto N, Fukuda N, Soma M, Kusafuka T, Fujiwara K, Nagase H.
  • Journal Title: Cancer Science Volume: 106(4) Issue: 4 Pages: 421-429
  • DOI: 10.1111/cas.12610
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole-imidazole polyamide conjugate. (2014)
  • Author(s): Hiraoka K, Inoue T, Taylor RD, Watanabe T, Koshikawa N, Yoda H, Shinohara K, Takatori A, Sugimoto H, Maru Y, Denda T, Fujiwara K, Balmain A, Ozaki T, Bando T, Sugiyama H, Nagase H.
  • Journal Title: Nat. Commun. Volume: 6 Issue: 1 Pages: 6706-6706
  • DOI: 10.1038/ncomms7706
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pyrrole-imidazole polyamide targeted to break fusion sites in TMPRSS2 and ERG gene fusion represses prostate tumor growth (2014)
  • Author(s): Obinata D, Ito Akiko, Fujiwara K, Takayama K, Ashikari D, Murata Y, Yamaguchi K, Urano T, Fujimura T, Fukuda N, Soma M, Watanabe T, Nagase H, Inoue S, Takahashi S
  • Journal Title: Cancer Sci Volume: 105 Issue: 10 Pages: 1272-1278
  • DOI: 10.1111/cas.12493
  • Peer Reviewed / Open Access
• [Journal Article] A novel gene regulator, pyrrole-imidazole polyamide targeting ABCA1 gene increases cholesterol efflux from macrophages and plasma HDL concentration (2014)
  • Author(s): Tsunemi A, Ueno T, Fukuda N, Watanabe T, Tahira K, Haketa A, Hatanaka Y, Tanaka S, Matsumoto T, Matsumoto Y, Nagase H, Soma M
  • Journal Title: Journal of Molecular Medicine Volume: 92 Pages: 509-521
  • Peer Reviewed
• [Journal Article] A novel gene regulator, pyrrole-imidazole polyamide targeting ABCA1 gene increases cholesterol efflux from macrophages and plasma HDL concentration. (2014)
  • Author(s): Tsunemi A, Ueno T, Fukuda N, Watanabe T, Tahira K, Haketa A, Hatanaka Y, Tanaka S, Matsumoto T, Matsumoto Y, Nagase H, Soma M.
  • Journal Title: J Mol Med Volume: 92 Pages: 509-521
  • Peer Reviewed
• [Journal Article] RNA binding properties of novel gene silencing pyrrole-imidazole polyamides. (2013)
  • Author(s): Iguchi A, Fukuda N, Takahashi T, Watanabe T, Matsuda H, Nagase H, Bando T, Sugiyama H, Shimizu K.
  • Journal Title: Biol Pharm Bull Volume: 36 Pages: 1152-1158
  • NAID: 130003361484
• [Presentation] Efficient Gene Silencing by PI Polyamide with -crossed Formation Targeting MMP-9 Promoter (2014)
  • Author(s): Takayoshi Watanabe, Nobuko Koshikawa, Toshinori Ozaki, Toshikazu Bando, Hiroshi Sugiyama, and Hiroki Nagase
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Precision Medicineを目指したオンコジェニックドライバーを標的とした治療 (2014)
  • Author(s): 永瀬浩喜、平岡桐子、井上隆博、渡部隆義、越川信子、尾崎俊文
  • Organizer: 第23回癌病態治療研究会
  • Place of Presentation: 岐阜
• [Presentation] KRASコドン12変異を標的とした分子標的アルキル化剤 (2014)
  • Author(s): 永瀬 浩喜、平岡桐子、井上隆博、渡部隆義
  • Organizer: 第18回日本がん分子標的治療学会学術集会
  • Place of Presentation: 仙台
• [Presentation] A novel alkylating pyrrole‐imidazole polyamide specifically targeting KRAS codon12 mutations preferentially suppresses the malignant phenotypes in colon cancer cells bearing G12D or G12V mutation. (2014)
  • Author(s): Hiroki Nagase, Kiriko Hiraoka,Takahiro Inoue,Toshinori Ozaki,Takayoshi Watanabe,Ken-ichi Shinohara,Nobuko Koshokawa
  • Organizer: An AACR Special Conference on RAS ONCOGENES:FROM BIOLOGY TO THERAPY
  • Place of Presentation: オーランド 米国
• [Presentation] KRAS G12D and G12V Specific Alkylating Agent (KR12) inhibits growth of colon cancer with those KRA mutations in vitro as well as in vivo (2014)
  • Author(s): Hiroki Nagase, Kiriko Hiraoka, Takahiro Inoue, Takayoshi Watanabe, Ken-Ichi Shinohara, Nobuko Koshikawa, Ozaki Toshinori
  • Organizer: AACR American Association for Cancer Research ANUAL MEETING 2014
  • Place of Presentation: サンディエゴ 米国
• [Presentation] 標的ゲノム配列特異的なヒストンアセチル化の誘導 (2013)
  • Author(s): 永瀬浩喜, 越川信子, 渡部隆義
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] 新規Eボックス認識化合物によるMYC依存性腫瘍の増殖抑制 (2013)
  • Author(s): 永瀬浩喜, 越川信子, 渡部隆義, 藤原恭子, MISHRA Rajeev
  • Organizer: 第55回日本小児血液・がん学会学術集会・第11回日本小児がん看護学会・第18回がんの子供を守る会公開シンポジウム
  • Place of Presentation: 福岡
• [Presentation] 変異型KRASを標的とした塩基配列特異的アルキル化剤によるマウス移植ヒト大腸癌の増殖抑制 (2013)
  • Author(s): 井上貴博, 平岡桐子, 養田裕行, 杉本博一, 篠原憲一, 渡部隆義, 越川信子, 尾崎俊文, 永瀬浩喜, 坂東俊和, 杉山弘
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] 変異型KRASを標的とした塩基配列特異的アルキル化剤による腫瘍細胞の増殖抑制 (2013)
  • Author(s): 平岡桐子, 井上貴博, 養田裕行, 杉本博一, 篠原憲一, 渡部隆義, 越川信子, 尾崎俊文, 永瀬浩喜, 板東俊和, 杉山弘
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] Automatic synthesis of efficient transcription inhibitors as anticancer agents designing sequence-specific DNA-banding molecules (2013)
  • Author(s): Hiroki Nagase, Nobuko Koshikawa, Takayoshi Watanabe
  • Organizer: AACR American Association for Cancer Research AAUAL MEETING 2013
  • Place of Presentation: ワシントンDC 米国