Analysis of abnormal signaling through KIT and PDGFRA in development of gastrointestinal stromal tumors

2009 Fiscal Year Final Research Report

• Project/Area Number: 17013082
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Hyogo College of Medicine
• Principal Investigator: HIROTA Seiichi Hyogo College of Medicine, 医学部, 教授 (50218856)
• Project Period (FY): 2005 – 2009
• Keywords: GIST / 遺伝子異常 / c-kit / PDGFR

Research Abstract

We made a model mouse of human family with multiple gastrointestinal stromal tumors and germline exon 17-type c-kit gene mutation. The heterozygous and homozygous model mice had a cecal GIST-like tumor and hyperplasia of interstitial cells of Cajal at stomach and colon. The phenotypes were similar with those observed in previously reported model mice with exon 11 or exon 13 c-kit gene mutation. A molecular targeted drug, imatinib, which inhibits constitutively activated mutant KIT was given to the model mice, and we observed inhibition of both tumor growth and KIT activation. We also examined an effect of another molecular targeted drug, nilotinib, which inhibits constitutively activated mutant KIT on tumor growth and KIT activation, and now the manuscript is in preparation.

Research Products

• [Journal Article] Surgical resection of gastrointestinal stromal tumor of esophagus following preoperative imatinib treatment: a case report. (2010)
  • Author(s): S ato H, Kanda T, Hirota S, Bamba T, Sakamoto K, Kosugi S, Matsuki A, Mashima Y, Watanabe G, Hatakeyama K.
  • Journal Title: Esophagus 7 Pages: 65-69
  • Peer Reviewed
• [Journal Article] Urgent surgery for intraperitoneal bleeding from GIST during imatinib therapy. (2010)
  • Author(s): E nomoto T, Kanda T, Yajima K, Hirota S, Matsuki A, Kosugi S-I, Kato T, Ajioka Y, Hatakeyama K.
  • Journal Title: Clin J Gastroenterol 3 Pages: 73-77
  • Peer Reviewed
• [Journal Article] Intracranial metastasis from an esophageal gastrointestinal stromal tumor. (2010)
  • Author(s): H amada S, Itami A, Watanabe G, Nakayama S, Tanaka E, Hojo M, Yoshizawa A, Hirota S, Sakai Y.
  • Journal Title: Intern Med. 49 Pages: 781-785
  • Peer Reviewed
• [Journal Article] Establishment of a lymph node metastasis model from subcutaneous tumors of gastrointestinal stromal tumor model cells. (2009)
  • Author(s): S akurama K, Naomoto Y, Ohara T, Watanabe N, Takaoka M, Nagatsuka H, Tomono Y, Tanida T, Noma K, Tanabe S, Fujiwara Y, Motoki T, Shirakawa Y, Yamatsuji T, Hirota S, Taguchi T, Tanaka N.
  • Journal Title: Oncol Rep. 21 Pages: 407-411
  • Peer Reviewed
• [Journal Article] Inhibition of focal adhesion kinase as a potential therapeutic strategy for Imatinib-resistant gastrointestinal stromal tumor. (2009)
  • Author(s): S akurama K, Noma K, Takaoka M, Tomono Y, Watanabe N, Hatakeyama S, Ohmori O, Hirota S, Motoki T, Shirakawa Y, Yamatsuji T, Haisa M, Matsuoka J, Tanaka N, Naomoto Y.
  • Journal Title: Mol Cancer Ther. 8 Pages: 127-134
  • Peer Reviewed
• [Journal Article] Sunitinib-resistant gastrointestinal stromal tumors harbor cis-mutations in the activation loop of the KIT gene. Japanese Study Group on GIST. (2009)
  • Author(s): N ishida T, Takahashi T, Nishitani A, Doi T, Shirao K, Komatsu Y, Nakajima K, Hirota S.
  • Journal Title: Int J Clin Oncol. 14 Pages: 143-149
  • Peer Reviewed
• [Journal Article] Gastric leiomyosarcoma manifesting peculiar findings: radiological-pathological correlation. (2009)
  • Author(s): M asuzawa N, Kishimoto M, Nishimura A, Ichiba N, Aoki E, Yanagibashi K, Hirota S, Yanagisawa A.
  • Journal Title: Pathol Int. 59 Pages: 306-311
  • Peer Reviewed
• [Journal Article] Involvement of focal adhesion kinase in the progression and prognosis of gastrointestinal stromal tumors. (2009)
  • Author(s): K amo N, Naomoto Y, Shirakawa Y, Yamatsuji T, Hirota S, Fujiwaraa Y, Noma K, Sakurama K, Takaoka M, Nagatsuka H, Gunduz M, Matsuoka J, Tanaka N.
  • Journal Title: Human Pathol 40 Pages: 1643-1649
  • Peer Reviewed
• [Journal Article] In vivo effect of imatinib on progression of cecal GIST-like tumors in exon 17-type c-kit knock-in mice. (2009)
  • Author(s): I shikawa T, Nakai N, Liu N-N, Shiba K, Isozaki K, Matsuda I, Ito K, Fujimoto J, Hatakeyama K, Kanda T, Hirota S.
  • Journal Title: Lab Invest. 89 Pages: 1161-1168
  • Peer Reviewed
• [Journal Article] Efficacy and Safety Profile of Imatinib Mesylate (STI571) in Japanese Patients with Advanced Gastrointestinal Stromal Tumors: a Phase II Study (STI571B1202). (2008)
  • Author(s): N ishida T, Shirao K, Sawaki A, Koseki M, Okamura T, Ohtsu A, Sugiyama T, Miyakawa K, Hirota S.
  • Journal Title: Int J Clin Oncol. 13 Pages: 244-251
  • Peer Reviewed
• [Journal Article] Abberant expression of glycosylation in juvenile gastrointestinal stromal tumors. (2008)
  • Author(s): T akahashi T, Naka T, Fujimoto M, Serada S, Horino J, Terabe F, Hirota S, Miyoshi E, Hirai T, Nakajima K, Nishitani A, Souma Y, Sawa Y, Nishida T.
  • Journal Title: Proteomics Clin Appl. 2 Pages: 1246-1254
  • Peer Reviewed
• [Journal Article] Secondary mutations in the kinase domain of the KIT gene are predominant in imatinib-resistant gastrointestinal stromal tumor. (2008)
  • Author(s): N ishida T, Kanda T, Nishitani A, Takahashi T, Nakajima K, Ishikawa T, Hirota S.
  • Journal Title: Cancer Sci. 99 Pages: 799-804
  • Peer Reviewed
• [Journal Article] Cell adhesion molecule 1 is a novel pancreatic-islet cell adhesion molecule that mediates nerve-islet cell interactions. (2008)
  • Author(s): Koma Y, Furuno T, Hagiyama M, Hamaguchi K, Nakanishi M, Masuda M, Hirota S, Yokozaki H, Ito A.
  • Journal Title: Gastroenterology 134 Pages: 1544-1554
  • Peer Reviewed
• [Journal Article] Juxtamembrane-type c-kit gene mutation found in aggressive systemic mastocytosis induces imatinib-resistant constitutive KIT activation. (2007)
  • Author(s): N akagomi N, Hirota S
  • Journal Title: Lab Invest. 87 Pages: 365-371
  • Peer Reviewed
• [Journal Article] Two cases of gastrointestinal stromal tumor of the stomach with lymph node metastasis. (2007)
  • Author(s): S ato T, Kanda T, Nishikura K, Hirota S, Hashimoto K, Nakagawa S, Ohashi M, Hatakeyama K.
  • Journal Title: Hapato-Gastroenterol 54 Pages: 1057-1060
  • Peer Reviewed
• [Journal Article] Characterization of tyrosine kinase I domain c-kit gene mutation Asn655Lys newly found in primary jejunal gastrointestinal stromal tumor. (2007)
  • Author(s): K inoshita K, Hirota S, Isozaki K, Nishitani A, Tsutsui S, Watabe K, Tamura S, Ishikawa T, Kanda T, Nishida T, Hayashi N.
  • Journal Title: Am J Gastroenterol 102 Pages: 1134-1136
  • Peer Reviewed
• [Journal Article] Familial adenomatous polyposis complicated by chronic myelogenous leukemia: response to imatinib mesylate. (2007)
  • Author(s): I tsukuma T, Ishikawa H, Misawa M, Kai S, Fujimori Y, Nakagawa K, Hirota S, Sugihara A, Terada N, Hara H.
  • Journal Title: J Gastroenterol 42 Pages: 402-405
  • Peer Reviewed
• [Journal Article] Surgical interventions for focal progression of advanced gastrointestinal stromal tumors during imatinib therapy. (2007)
  • Author(s): Hasegawa J, Kanda T, Hirota S, Fukuda M, Nishitani A, Takahashi T, Kurosaki I, Tsutsui S, Hatakeyama K, Nishida T.
  • Journal Title: Int J Clin Oncol 12 Pages: 212-217
  • Peer Reviewed
• [Journal Article] An enhanced risk-group stratification system for more practical prognostication of clinically malignant gastrointestinal stromal tumors. (2007)
  • Author(s): Takahashi T, Nakajima K, Nishitani A, Souma Y, Hirota S, Sawa Y, Nishida T.
  • Journal Title: Int J Clin Oncol. 12 Pages: 369-374
  • Peer Reviewed
• [Journal Article] A mouse model of human multiple GIST family with KIT-Asp820Tyr mutation generated by knock-in strategy. (2007)
  • Author(s): N akai N, Ishikawa T, Nishitani A, Liu N-N, Shincho M, Hao H, Isozaki K, Kanda T, Nishida T, Fujimoto J, Hirota S.
  • Journal Title: J Pathol. 214 Pages: 302-311
  • Peer Reviewed
• [Journal Article] Pleomorphic phenotypes of gastrointestinal stromal tumors at metastatic sites with or without imatinib treatment.
  • Author(s): S akamoto K, Sakurai S, Kanda T, Sakuma Y, Hishima T, Hironaka M, Bamba T, Keira Y, Takano Y, Niki T, Hasegawa T, Hirota S.
  • Journal Title: Cancer Sci. (In press)
  • Peer Reviewed
• [Presentation] GIST治療における病理診断 (2009)
  • Author(s): 廣田誠一
  • Organizer: 第47回日本癌治療学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-23
• [Presentation] GISTの分子標的治療とその基盤 (2009)
  • Author(s): 廣田誠一
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-23
• [Presentation] A mouse model of human GIST (2008)
  • Author(s): Hirota S
  • Organizer: 2008 Korean GIST Multidisciplinary Symposium
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2008-11-29
• [Presentation] A mouse model of human multiple GIST family with KIT-Asp820Tyr mutation generated by knock-in strategy. (2008)
  • Author(s): N akai N, Hirota S, et, al.
  • Organizer: DDW
  • Place of Presentation: San Diego, USA
  • Year and Date: 2008-05-19
• [Presentation] KIT-Asp820Tyr変異を持つ家族性多発性GIST家系のモデルマウスの作成 (2008)
  • Author(s): 伊藤敬, 中井紀博, 新長真由美, 松田育雄, 塚本吉胤, 羽尾裕之, 廣田誠一
  • Organizer: 第97回日本病理学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2008-05-15
• [Book] Gastrointestinal stromal tumors (2006)
  • Author(s): I shikawa T, Kanda T, Shincho M, Hirota S
  • Publisher: Global Research Network, Kerala