Analysis of aberrantly activated receptor tyrosine kinase and development of molecular targeting therapy in small animals with malignancies.

• Project/Area Number: 21580395
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Clinical veterinary science
• Research Institution: Nippon Veterinary and Life Science University
• Principal Investigator: MAKOTO Bonkobara 日本獣医生命科学大学, 獣医学部, 准教授 (50343611)
• Co-Investigator(Renkei-kenkyūsha): TOSHIRO Arai 日本獣医生命科学大学, 獣医学部, 教授 (70184257) ; ONO Kenichiro 日本獣医生命科学大学, 獣医学部, 客員教授 (50111480)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: c-kit / 猫 / 肥満細胞腫 / チロシンキナーゼ / 分子標的療法 / 犬 / 悪性黒色腫 / 分子標的薬 / NFkB / プロテアソーム阻害剤 / c-kit変異 / イマチニブ

Research Abstract

The mutation status of KIT and effects of imatinib on the mutant KIT were investigated in vitro and in clinical cases of cats and dogs with mast cell tumors(MCTs). Mutations in c-kit exon 8 and 9 were identified in tumor cells from cats and dogs with MCTs. These mutations caused constitutive phosphorylation of KIT. Imatinib suppressed the phosphorylation of the mutant KIT. A beneficial response to imatinib was observed in cats and dogs that had a mutation in c-kit exon 8 or 9.MCTs with mutations in c-kit exon 8 and 9 are potentially sensitive to imatinib in dogs and cats.

Research Products

• [Journal Article] Establishment of a PCR analysis method for canine BRCA2 (2012)
  • Author(s): Yoshikawa Y, Morimatsu M, Ochiai K, Okuda K, Taoda T, Chikazawa S, Shimamura A, Omi T, Bonkobara M, Orino K, Watanabe K.
  • Journal Title: BMC Res Notes Volume: (in press) Issue: 1 Pages: 173-173
  • DOI: 10.1186/1756-0500-5-173
  • Peer Reviewed
• [Journal Article] Establishment and Characterization of Canine Rhabdomyosarcoma Cell Line, CMS-C (2011)
  • Author(s): Azakami D, Shibutani H, Dohi M, Takasaki M, Ishioka K, Mori A, Momota Y, Bonkobara M, Washizu T, Michishita M, Hatakeyama H, Ogasawara S, Sako T.
  • Journal Title: Journal of Veterinary Medical Science Volume: 73(8) Pages: 1105-1108
  • NAID: 130000677101
• [Journal Article] Reconstruction of stratum corneum in organotypically cultured canine keratinocyte-derived CPEK cells (2011)
  • Author(s): Yagihara H, Okumura T, Shiomi E, Shinozaki N, Kuroki S, Sasaki Y, Ito K, Ono K, Washizu T, Bonkobara M.
  • Journal Title: Veterinary Research Communications Volume: 35(7) Pages: 433-437
• [Journal Article] Imatinib elicited a favorable response in a dog with a mast cell tumor carrying a c-kit c. 1523A> T mutation via suppression of constitutive KIT activation (2011)
  • Author(s): Yamada O, Kobayashi M, Sugisaki O, Ishii N, Ito K, Kuroki S, Sasaki Y, Isotani M, Ono K, Washizu T, Bonkobara M.
  • Journal Title: Veterinary Immunology and Immunopathology Volume: 142 Pages: 101-106
• [Journal Article] Canine intestinal mast cell tumor with c-kit exon 8 mutation responsive to imatinib therapy (2011)
  • Author(s): Kobayashi M, Sugisaki O, Ishii N, Yamada O, Ito K, Kuroki S, Sasaki Y, Ono K, Washizu T, Bonkobara M.
  • Journal Title: Veterinary Journal. 2011 in press Volume: (in press) Issue: 1 Pages: 264-267
  • DOI: 10.1016/j.tvjl.2011.10.027
  • Peer Reviewed
• [Journal Article] Imatinib elicited a favorable response in a dog with a mast cell tumor carrying a c-kit c.1523A>T mutation via suppression of constitutive KIT activation (2011)
  • Author(s): Yamada O, Kobayashi M, Sugisaki O, Ishii N, Ito K, Kuroki S, Sasaki Y, Isotani M, Ono K, Washizu T, Bonkobara M
  • Journal Title: Veterinary Immunology and Immunopathology Volume: 142 Pages: 101-106
  • Peer Reviewed
• [Journal Article] Imatinib elicited a favorable response in a dog with a mast cell tumor carrying a c-kitc.1523A>T mutation via suppression of constitutive KIT activation (2011)
  • Author(s): Yamada, ら
  • Journal Title: Veterinary Immunology and Immunopathology Volume: (In press)
  • Peer Reviewed
• [Journal Article] Reconstruction of stratum corneum in organotypically cultured canine keratinocyte-derived CPEK cells (2011)
  • Author(s): Yagihara, ら
  • Journal Title: Veterinary Research Communications Volume: (In press)
  • Peer Reviewed
• [Journal Article] Mutations in the fifth immunoglobulin-like domain of kit are common and potentially sensitive to imatinib mesylate in feline mast cell tumors (2010)
  • Author(s): Isotani M, Yamada O, Lachowicz J. L, Tamura K, Yagihara H, Fujino Y, Ono K, Washizu T, Bonkobara M.
  • Journal Title: British Journal of Haematology Volume: 148(1) Pages: 144-153
• [Journal Article] Mutations in the fifth immunoglobulin-like domain of kit are common and potentially sensitive to imatinib mesylate in feline mast cell tumors. (2010)
  • Author(s): Isotani M, et al.
  • Journal Title: British Journal of Haematology 148 Pages: 144-153
  • Peer Reviewed
• [Journal Article] Expression of canine Kdap in normal, hyperplastic and neoplastic epidermis. (2009)
  • Author(s): Yagihara H, et al.
  • Journal Title: Veterinary Journal 180 Pages: 348-355
  • Peer Reviewed
• [Journal Article] The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-cell responses. (2009)
  • Author(s): Chung JS, et al.
  • Journal Title: European Journal of Immunology 39 Pages: 965-974
  • Peer Reviewed
• [Journal Article] Immunophenotyping and gene rearrangement analysis in dogs with lymphoproliferative disorders characterized by small-cell lymphocytosis. (2009)
  • Author(s): Yagihara H, et al.
  • Journal Title: Journal of Veterinary Diagnostic Investigation 21 Pages: 197-202
  • Peer Reviewed
• [Presentation] 腫瘍の遺伝子検査～犬と猫の肥満細胞腫～ (2012)
  • Author(s): 盆子原誠
  • Organizer: 日本獣医内科学アカデミー/日本獣医臨床病理学会
• [Presentation] 犬の腫瘍の新しい診断・治療戦略～肥満細胞腫～ (2011)
  • Author(s): 盆子原誠
  • Organizer: 予防動物医学研究会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2011-07-11
• [Presentation] 分子生物学から見る肥満細胞腫 (2011)
  • Author(s): 盆子原誠
  • Organizer: West Japan Veterinary Forum
  • Place of Presentation: 大阪
  • Year and Date: 2011-06-19
• [Presentation] イマチニブが奏功したc-kitエクソン8に重複配列挿入変異を有する腸管型肥満細胞腫の犬の1例 (2011)
  • Author(s): 小林, ら
  • Organizer: 日本獣医内科学アカデミー/日本獣医臨床病理学会/日本獣医皮膚科学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-03-13
• [Presentation] 猫の肥満細胞腫の現状と分子標的療法 (2011)
  • Author(s): 盆子原誠
  • Organizer: West Japan Veterinary Forum
• [Presentation] 犬の腫瘍の新しい診断・治療戦略～肥満細胞腫 (2011)
  • Author(s): 盆子原誠
  • Organizer: 予防動物医学研究会シンポジウム
• [Presentation] 犬と猫の肥満細胞腫に対する分子標的療法の展開～c-kit変異とイマチニブの効果～ (2011)
  • Author(s): 盆子原誠
  • Organizer: 日本獣医内科学アカデミー/日本獣医臨床病理学会/日本獣医皮膚科学会
• [Presentation] イマチニブが奏功したc-kitエクソン8に重複配列挿入変異を有する腸管型肥満細胞腫の犬の1例 (2011)
  • Author(s): 小林正人・杉崎修、小堤友香梨・田中優・守谷友加里・石井典子・伊藤慶太・盆子原誠・小野憲一郎・鷲巣月美
  • Organizer: 日本獣医内科学アカデミー/日本獣医臨床病理学会/日本獣医皮膚科学会
• [Presentation] 猫の肥満細胞腫における新規c-kit遺伝子変異の同定とイマチニブによるKITリン酸化抑制の検討 (2010)
  • Author(s): 石井, ら
  • Organizer: 第150回 日本獣医学会学術集会
  • Place of Presentation: 帯広
  • Year and Date: 2010-09-17
• [Presentation] 犬の悪性黒色腫株化細胞に対する分子標的薬の増殖抑制効果に関する研究 (2010)
  • Author(s): 岩田, ら
  • Organizer: 第150回 日本獣医学会学術集会
  • Place of Presentation: 帯広
  • Year and Date: 2010-09-17
• [Presentation] イマチニブが奏功したc-kitエクソン9に点変異を有する肥満細胞腫の犬の1例 (2010)
  • Author(s): 小林, ら
  • Organizer: 第150回 日本獣医学会学術集会
  • Place of Presentation: 帯広
  • Year and Date: 2010-09-17
• [Presentation] イマチニブが奏功したc-kitエクソン9に点変異を有する肥満細胞腫の犬の1例 (2010)
  • Author(s): 小林正人・杉崎修、小堤友香梨・田中優・守谷友加里・石井典子・山田理・礒谷真由・伊藤慶太・盆子原誠、小野憲一郎・鷲巣月美
  • Organizer: 第150回日本獣医学会
• [Presentation] 犬の悪性黒色腫株化細胞に対する分子標的薬の増殖抑制効果に関する研究 (2010)
  • Author(s): 岩田泰介・黒木哲也・森光平・小澤佑太・手塚雅典・中川朋子・廣井輝代・伊藤慶太・盆子原誠・小野憲一郎・鷲巣月美
  • Organizer: 第150回日本獣医学会
• [Presentation] 猫の肥満細胞腫における新規c-kit遺伝子変異の同定とイマチニブによるKITリン酸化抑制の検討 (2010)
  • Author(s): 石井典子・杉崎修・小林正人・山田理・西上達也・吉田俊一・磯谷真弓・伊藤慶太・盆子原誠・小野憲一郎・鷲巣月美
  • Organizer: 第150回日本獣医学会
• [Presentation] イマチニブが奏功したc-kitエクソン9に点変異を有する肥満細胞腫の犬の1例 (2010)
  • Author(s): 杉崎修・小林正人・小堤友香梨・田中優・守谷友加里・石井典子・山田理・礒谷真由・伊藤慶太・盆子原誠・小野憲一郎・鷲巣月美
  • Organizer: 日本獣医臨床病理学会大阪シンポジウム
  • Place of Presentation: 大阪
• [Presentation] 猫の肥満細胞腫におけるc-kit遺伝子変異の解析 (2009)
  • Author(s): 礒谷, ら
  • Organizer: 日本獣医内科学アカデミー/日本獣医臨床病理学会
  • Place of Presentation: 東京
  • Year and Date: 2009-02-14
• [Book] 犬と猫の早期疾病診断学 (2011)
  • Author(s): 盆子原誠, 他
  • Publisher: チクサン出版社
• [Book] 犬と猫の早期疾病診断学(予防動物医学研究会編) (2011)
  • Author(s): 盆子原誠, 他多数
  • Total Pages: 206
  • Publisher: チクサン出版社
• [Remarks]
  • URL: http://www.jspvm.com/department/center/index.html
• [Remarks] 日本獣医生命科学大学「動物疾病制御研究拠点形成プロジェクト」で分子標的薬の薬効評価システムの開発として紹介