Combination effects of kinase inhibitors with anti-cancer drugs on scirrhous gastric carcinoma.

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591573
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Osaka City University
• Principal Investigator: YASHIRO Masakazu Osaka City University, 大学院・医学研究科, 准教授 (60305638)
• Project Period (FY): 2008 – 2010
• Keywords: スキルス胃癌 / 分子標的治療 / キナーゼ阻害剤 / 抗癌剤 / トランスレーショナルリサーチ

Research Abstract

Scirrhous carcinomas carry an extreme poor prognosis. FGFR-2/K-samII, a tyrosine kinase growth factor receptor, is overexpressed on scirrhous gastric cancer cells. Transforming growth factor-β (TGFβ) signals are closely associated with the distant metastases of gastric cancer. The aim of this study is to clarify the effect of a FGFR-2/K-samII inhibitor, Ki23057, or a TGFβ receptor (TβR) inhibitor, Ki26894, in combination with anticancer drugs TS1 (a 5-fluorouracil analog), on the development of scirrhous gastric cancer. The combined administration of TS1and Ki23057 decreases orthotopic tumors as well as LN metastasis more effectively than TS1 alone. The Ki26894 plus TS1 administration group also significantly suppressed tumor growth and decreased LN metastasis more effectively than either alone. These findings suggested that the combined treatment with 5-FU and FGFR-2 phosphorylation inhibitor or TβR inhibitor produced synergistic anti-tumor effects, and appears therapeutically promising in scirrhous gastric carcinoma treatment.

Research Products

• [Journal Article] Cancer-stromal interactions in scirrhous gastric carcinoma. Review. (2010)
  • Author(s): Yashiro M, Hirakawa K
  • Journal Title: Cancer Microenvironment. 3 Pages: 127-135
• [Journal Article] Synergistic antitumor effects of FGFR2 inhibitor with 5-fluorouracil on scirrhous gastric carcinoma. (2010)
  • Author(s): Yashiro M, Shinto O, Nakamura K, Tendo M, Matsuoka T, Matsuzaki T, Kaizaki R, Miwa A, Hirakawa K
  • Journal Title: Int J Cancer. 126 Pages: 1004-1016
• [Journal Article] Monoclonal Antibodies to Fibroblast Growth Factor Receptor 2 Effectively Inhibit Growth of Gastric Tumor Xenografts. (2010)
  • Author(s): Zhao WM, Wang L, Park H, Chhim S, Tanphanich M, Yashiro M, Kim KJ.
  • Journal Title: Clin Cancer Res. 16(23) Pages: 5750-5758
• [Journal Article] Establishment and characterization of a new hypoxia-resistant cancer cell line, OCUM-12/Hypo, derived from a scirrhous gastric carcinoma. (2010)
  • Author(s): Kato Y, Yashiro M, Noda S, Tendo M, Kashiwagi S, Doi Y, Nishii T, Matsuoka J, Fuyuhiro Y, Shinto O, Sawada T, Ohira M, Hirakawa K
  • Journal Title: Br J Cancer. 102 Pages: 898-907
• [Journal Article] Inhibitory effect of a TGFbeta receptor type-I inhibitor, Ki26894, on invasiveness of scirrhous gastric cancer cells. (2010)
  • Author(s): Shinto O, Yashiro M, Shimizu K, Shimizu K, Shimizu T, Miwa A, Hirakawa K
  • Journal Title: Br J Cancer. 102 Pages: 844-851
• [Journal Article] Hypoxia upregulates adhesion ability to peritoneum through a transforming growth factor-beta-dependent mechanism in diffuse-type gastric cancer cells. (2010)
  • Author(s): Noda S, Yashiro M, Nshii T, Hirakawa K
  • Journal Title: Eur J Cancer. 46 Pages: 995-1005
• [Journal Article] Elevated dietary linoleic acid increases gastric carcinoma cell invasion and metastasis in mice. (2010)
  • Author(s): Matsuoka T, Adair JE, Lih FB, Hsi LC, Rubino M, Eling TE, Tomer KB, Yashiro M, Hirakawa K, Olden K, Roberts JD.
  • Journal Title: Br J Cancer. 103 Pages: 1182-1191
• [Journal Article] Transforming growth factor-beta decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells. (2010)
  • Author(s): Ehata S, Johansson E, Katayama R, Koike S, Watanabe A, Hoshino Y, Katsuno Y, Komuro A, Koinuma D, Kano RM, Yashiro M, Hirakawa K, Aburatani H, Fujita N, Miyazono K.
  • Journal Title: Oncogene in press
• [Journal Article] Role of the Stemness Factors Sox2, Oct3/4, and Nanog in Gastric Carcinoma. (2010)
  • Author(s): Matsuoka J, Yashiro M, Sakurai K, Kubo N, Tanaka H, Muguruma K, Sawada T, Ohira M, Hirakawa K
  • Journal Title: Journal of Surgical Research in press
• [Journal Article] Significance of a phosphorylated Smad2 in gastric carcinoma at advanced stage. (2010)
  • Author(s): Shinto O, Yashiro M, Toyokawa T, Nishii T, Kaizaki R, Matsuzaki T, Noda S, Kubo N, Tanaka H, Doi Y, Ohira M, Muguruma K, Sawada T, Hirakawa K
  • Journal Title: BMC Cancer 10 Pages: 652
• [Journal Article] Biodistribution of humanized anti-VEGF monoclonal antibody/bevacizumab on peritoneal metastatic models with subcutaneous xenograft of gastric cancer in mice. (2010)
  • Author(s): Yagi Y, Fushida S, Harada S, Tsukada T, Kinoshita J, Oyama K, Fujita H, Ninomiya I, Fujimura T, Kayahara M, Kinuya S, Yashiro M, Hirakawa K, Ohta T.
  • Journal Title: Cancer chemotherapy and pharmacology. 66 Pages: 745-753
• [Journal Article] Combination effect of a TGF-beta receptor kinase inhibitor with 5-FU analog S1 on lymph node metastasis of scirrhous gastric cancer in mice. (2010)
  • Author(s): Shinto O, Yashiro M, Kawajiri H, Shimizu K, Shimizu T, Miwa A, Hirakawa K
  • Journal Title: Cancer Science 101 Pages: 1846-1852
• [Journal Article] Expression of a hypoxia-associated protein, carbonic anhydrase-9, correlates with malignant phenotypes of gastric carcinoma. (2010)
  • Author(s): Kato Y, Yashiro M. Noda S, Kashiwagi S, Matsuoka J, Fuyuhiro Y, Doi Y, Hirakawa K
  • Journal Title: Digestion 82 Pages: 246-251
• [Journal Article] Establishment and characterization of multidrug-resistant gastric cancer cell lines. (2010)
  • Author(s): Zhang X, Yashiro M., Qiu H, Nishii T, Matsuzaki T, Hirakawa K
  • Journal Title: Anticancer research. 30 Pages: 915-921
• [Journal Article] Clinical Significance of Vimentin-positive Gastric Cancer Cells. (2010)
  • Author(s): Fuyuhiro Y, Yashiro M, Noda S, Kashiwagi S, Matsuoka J, Doi Y, Kato Y, Kubo N, Ohira M, Hirakawa K
  • Journal Title: Anticancer Res. 30(12) Pages: 5239-5243
• [Journal Article] Myofibroblasts are associated with the progression of scirrhous gastric carcinoma. (2010)
  • Author(s): Fuyuhiro Y, Yashiro M, Noda S, Kashiwagi S, Matsuoka J, Doi Y, Kato Y, Muguruma K, Sawada T, Hirakawa K
  • Journal Title: Experimental and Therapeutic Medicine 1 Pages: 547-551
• [Journal Article] Proteomic differential display analysis shows up-regulation of 14-3-3 sigma protein in human scirrhous-type gastric carcinoma cells. (2010)
  • Author(s): Kuramitsu Y, Baron B, Yoshino S, Zhang X, Tanaka T, Yashiro M, Hirakawa K, Oka M, Nakamura K
  • Journal Title: Anticancer Res. 30(11) Pages: 4459-4465
• [Journal Article] Effects of valproic acid on the cell cycle and apoptosis through acetylation of histone and tubulin in a scirrhous gastric cancer cell line. (2010)
  • Author(s): Yagi Y, Fushida S, Harada S, Kinoshita J, Makino I, Oyama K, Tajima H, Fujita H, Takamura H, Ninomiya I, Fujimura T, Ohta T, Yashiro M, Hirakawa K
  • Journal Title: J Exp Clin Cancer Res. 17:29 Pages: 149
• [Journal Article] Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity. (2010)
  • Author(s): Tanaka H, Shinto O, Yashiro M, Yamazoe S, Iwauchi T, Muguruma K, Kubo N, Ohira M, Hirakawa K
  • Journal Title: Oncol Rep. 24(6) Pages: 1637-1643
• [Journal Article] 胃癌:転移の臨床病理学的特徴 (2010)
  • Author(s): 八代正和、平川弘聖
  • Journal Title: 細胞工学 別冊 Pages: 32-38
• [Journal Article] 未分化胃癌(sig、 por)の特性と自然史 (2010)
  • Author(s): 八代正和, 平川弘聖
  • Journal Title: 外科治療 103(4) Pages: 325-332
  • Peer Reviewed
• [Journal Article] スキルス胃癌 (2010)
  • Author(s): 八代正和
  • Journal Title: 消化器の臨床 13(3) Pages: 233-239
  • Peer Reviewed
• [Journal Article] Effects of VEGFR-3 phosphorylation inhibitor on lymph node metastasis in an orthotopic diffuse-type gastric carcinoma model. (2009)
  • Author(s): Yashiro M, Shinto O, Nakamura K, Tendo M, Matsuoka T, Matsuzaki T, Kaizaki R, Ohira M, Miwa A, Hirakawa K
  • Journal Title: Br J Cancer 101 Pages: 1100-1106
  • Peer Reviewed
• [Journal Article] Diffuse-type gastric carcinoma : progression, angiogenesis, and transforming growth factor beta signaling. (2009)
  • Author(s): Komuro A, Yashiro M, Iwata C, Morishita Y, Johansson E, Matsumoto Y, Watanabe A, Aburatani H, Miyoshi H, Kiyono K, Shirai YT, Suzuki HI, Hirakawa K, Kano MR, Miyazono K.
  • Journal Title: J Natl Cancer Inst 101 Pages: 592-604
  • Peer Reviewed
• [Journal Article] Epigenetic regulation of the embryonic oncogene ERas in gastric cancer cells. (2009)
  • Author(s): Yashiro M, Yasuda, K, Nishii, T, Kaizaki, R, Sawada, T, Ohira, M, Hirakawa, K.
  • Journal Title: Int J Oncol 35 Pages: 997-1003
  • Peer Reviewed
• [Journal Article] Allelic imbalance at p53 and microsatellite instability are predictive markers for resistance to chemotherapy in gastric carcinoma. (2009)
  • Author(s): Yashiro M, Inoue, T, Nishioka, N, Matsuoka, T, Boland, C R, Hirakawa, K.
  • Journal Title: Ann Surg Oncol 16 Pages: 2926-2935
  • Peer Reviewed
• [Journal Article] Co-expression of keratinocyte growth factor and K-sam is an independent prognostic factor in gastric carcinoma. (2009)
  • Author(s): Toyokawa T, Yashiro M, Hirakawa K
  • Journal Title: Oncol Rep 21 Pages: 875-880
  • Peer Reviewed
• [Journal Article] HER2 overexpression correlates with survival after curative resection of pancreatic cancer. (2009)
  • Author(s): Komoto M, Nakata B, Amano R, Yamada N, Yashiro M, Ohira M, Wakasa K, Hirakawa K
  • Journal Title: Cancer Sci 100 Pages: 1243-1247
  • Peer Reviewed
• [Journal Article] In vitro and in vivo evidence that a combination of lapatinib plus S-1 is a promising treatment for pancreatic cancer. (2009)
  • Author(s): Komoto M, Nakata B, Nishii T, Kawajiri H, Shinto O, Amano R, Yamada N, Yashiro M, Hirakawa K
  • Journal Title: Cancer science.
• [Journal Article] receptor expression is associated with colon cancer in ulcerative colitis. (2009)
  • Author(s): Wada K, Tanaka H, Maeda K, Inoue T, Noda E, Amano R, Kubo N, Muguruma K, Yamada N, Yashiro M, Sawada T, Nakata B, Ohira M, Hirakawa K Vitamin D
  • Journal Title: Oncol Rep 22 Pages: 1021-1025
  • Peer Reviewed
• [Journal Article] Direct cancer-stromal interaction increases fibroblast proliferation and enhances invasive properties of scirrhous-type gastric carcinoma cells. (2009)
  • Author(s): Semba S, Kodama Y, Ohnuma K, Mizuuchi E, Masuda R, Yashiro M, Hirakawa K, Yokozaki H.
  • Journal Title: Br J Cancer
  • Peer Reviewed
• [Journal Article] DNA methyltransferase inhibitor 5-aza-CdR enhances the radiosensitivity of gastric cancer cells. (2009)
  • Author(s): Qiu H, Yashiro M, Shinto O, Hirakawa K
  • Journal Title: Cancer Sci 100 Pages: 181-188
  • Peer Reviewed
• [Journal Article] Cancer stem cell-like SP cells have a high adhesion ability to the peritoneum in gastric carcinoma. (2009)
  • Author(s): Nishii T, Yashiro M, Shinto O, Sawada T, Ohira M, Hirakawa K
  • Journal Title: Cancer Sci 100 Pages: 1397-1402
  • Peer Reviewed
• [Journal Article] Synergistic antiproliferative effect of mTOR inhibitors in combination with 5-fluorouracil in scirrhous gastric cancer. (2009)
  • Author(s): Matsuzaki T, Yashiro M, Kaizaki R, Yasuda K, Doi Y, Sawada T, Ohira M, Hirakawa K
  • Journal Title: Cancer Sci
  • Peer Reviewed
• [Journal Article] c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-beta signaling in diffuse-type gastric carcinoma. (2009)
  • Author(s): Kiyono K, Suzuki HI, Morishita Y, Komuro A, Iwata C, Yashiro M, Hirakawa K, Kano MR, Miyazono K.
  • Journal Title: Cancer Sci
  • Peer Reviewed
• [Journal Article] Local angiotensin II-generation in human gastric cancer : correlation with tumor progression through the activation of ERK1/2, NF-kappaB and survivin. (2009)
  • Author(s): Kinoshita J, Fushida S, Harada S, Yagi Y, Fujita H, Kinami S, Fujimura T, Kayahara M, Yashiro M, Hirakawa K, Ohta T.
  • Journal Title: Int J Oncol 34 Pages: 1573-1582
• [Journal Article] Expression of ERas oncogene in gastric carcinoma. (2009)
  • Author(s): Kaizaki R, Yashiro M, Shinto O, Yasuda K, Hirakawa K
  • Journal Title: Anticancer Res 29 Pages: 2189-2193
  • Peer Reviewed
• [Journal Article] スキルス胃癌の病態に基づいた分子標的治療TGFβレセプター阻害剤による腹膜転移抑制 消化器疾患と分子標的薬 (2009)
  • Author(s): 八代正和、川尻成美、神藤理、濱島好男、梶本哲也、野出学、平川弘聖
  • Journal Title: 癌の臨床 55(1) Pages: 81-90
• [Journal Article] 臨牀消化器内科 (2009)
  • Author(s): 八代正和、神藤理、豊川貴弘、川尻成美、中村和憲、平川弘聖
  • Journal Title: 24(2) Pages: 193-200
• [Journal Article] FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival. (2008)
  • Author(s): Kunii K, Davis L, Gorenstein J, Hatch H, Yashiro M, Di Bacco A, Elbi C, Lutterbach B.
  • Journal Title: Cancer Res 68(7) Pages: 2340-2348
  • Peer Reviewed
• [Journal Article] A novel transforming growth factor beta receptor kinase inhibitor, A-77, prevents the peritoneal dissemination of scirrhous gastric carcinoma. (2008)
  • Author(s): Kawajiri H, Yashiro M, Shinto O, Nakamura K, Tendo M, Takemura S, Node M, Hamashima Y, Kajimoto T, Sawada T, Ohira M, Hirakawa K
  • Journal Title: Clin Cancer Res 14 Pages: 2850-2860
  • Peer Reviewed
• [Journal Article] Ulcerative colitis-associated colorectal cancer is frequently associated with the microsatellite instability pathway. (2008)
  • Author(s): Fujiwara I, Yashiro M, Kubo N, Maeda K, Hirakawa K
  • Journal Title: Dis Colon Rectum 51 Pages: 1387-1394
  • Peer Reviewed
• [Journal Article] Laparoscopic resection of periadrenal paraganglioma : a report of 2 cases. (2008)
  • Author(s): Noda E, Ishikawa T, Maeda K, Inoue T, Amano R, Kubo N, Tanaka H, Muguruma K, Yamashita Y, Yashiro M, Yamada N, Onoda N, Sawada T, Nishiguchi Y, Ohira M, Hirakawa K
  • Journal Title: Surgical laparoscopy, endoscopy & percutaneous techniques. 18 Pages: 310-314
• [Journal Article] Efficacy of S-1 for gastric cancer patients with positive peritoneal lavage cytology. (2008)
  • Author(s): Ako E, Ohira M, Yamashita Y, Kubo N, Yashiro M, Sawada T, Nakata B, Kato Y, Hirakawa K
  • Journal Title: Hepatogastroenterology 55 Pages: 1939-1942
  • Peer Reviewed
• [Journal Article] スキルス胃癌 (2008)
  • Author(s): 八代正和、石川哲郎、平川弘聖
  • Journal Title: 消化器外科 31(5) Pages: 866-872
  • Peer Reviewed
• [Journal Article] スキルス胃癌の進展機序と線維芽細胞の増殖 (2008)
  • Author(s): 八代正和、石川哲郎、平川弘聖
  • Journal Title: 日本臨床 66(5) Pages: 119-126
  • Peer Reviewed
• [Journal Article] TGFβ受容体阻害剤を用いた胃癌分子標的治療 (2008)
  • Author(s): 八代正和、川尻成美、神藤 理、濱島好男、梶本哲也、野出 学、平川弘聖
  • Journal Title: 日本臨床 66(5) Pages: 475-479
  • Peer Reviewed
• [Journal Article] Identification of HLA-A^*2402-restricted epitope peptide derived from ERas oncogene expressed in human scirrhous gastric cancer.
  • Author(s): Iwauchi T Tanaka H; Yamazoe S; Yashiro M, Yoshii M; Kubo, N; Muguruma, K; Sawada, T; Ohira, M; Hirakawa, K.
  • Journal Title: Cancer Science in press
• [Presentation] Effects of VEGFR-3 phosphorylation inhibitor on lymph node metastasis in diffuse-type gastric carcinoma. (2010)
  • Author(s): 八代正和, et al.
  • Organizer: 101st Annual Meeting of American Association for Cancer Research
  • Place of Presentation: Washington DC
  • Year and Date: 20100417-20100421
• [Presentation] Significance of carbonic anhydrase-9 in gastric carcinoma. (2010)
  • Author(s): Kato Y, Yashiro M, et al.
  • Organizer: 101st Annual Meeting of American Association for Cancer Research
  • Place of Presentation: Washington DC
  • Year and Date: 20100417-20100421
• [Presentation] Cancer-associated myofibroblast may stimulate vimentin expression of gastric cancer cells. (2010)
  • Author(s): Fuyuhiro Y, Yashiro M, et al.
  • Organizer: 101st Annual Meeting of American Association for Cancer Research
  • Place of Presentation: Washington DC
  • Year and Date: 20100417-20100421
• [Presentation] Significance of stemness factor, Sox2, in gastric cancer. (2010)
  • Author(s): Matsuoka J, Yashiro M,, et al.
  • Organizer: 101st Annual Meeting of American Association for Cancer Research
  • Place of Presentation: Washington DC
  • Year and Date: 20100417-20100421
• [Presentation] 胃癌と大腸癌の病態比較:胃・大腸重複癌の発癌経路の検討 (2009)
  • Author(s): 八代正和、ほか
  • Organizer: 第95回日本消化器病学会総会
  • Place of Presentation: 札幌
  • Year and Date: 20090507-20090509
• [Presentation] A novel transforming growth factorβ receptor kinase inhibitor, A-77, prevents the peritoneal dissemination of scirrhous gastric carcinoma. (2009)
  • Author(s): 八代正和, et al.
  • Organizer: 100th Annual Meeting of American Association for Cancer Research
  • Place of Presentation: Colorado
  • Year and Date: 20090418-20090422
• [Presentation] Hypoxic condition promotes the adhesion ability of gastric cancer cells to peritoneum. (2009)
  • Author(s): Noda.S, Yashiro M, et al.
  • Organizer: 100th Annual Meeting of American Association for Cancer Research
  • Place of Presentation: Colorado
  • Year and Date: 20090418-20090422
• [Presentation] c-Met inhibitor might be a promising molecular-targeted molecule against for CPT11-resistant cancer stem cells. (2009)
  • Author(s): Nishii. T, Yashiro M, et al.
  • Organizer: 100th Annual Meeting of American Association for Cancer Research
  • Place of Presentation: Colorado
  • Year and Date: 20090418-20090422
• [Presentation] スキルス胃癌の分子生物学的特徴と標的分子 (2009)
  • Author(s): 八代正和、ほか
  • Organizer: 第81回日本胃癌学会
  • Place of Presentation: 東京
  • Year and Date: 20090304-20090306
• [Presentation] FGF受容体およびTGFβ受容体を標的としたスキルス胃癌の分子標的治療 (2008)
  • Author(s): 八代正和、ほか
  • Organizer: 第46回日本癌治療学会総会
  • Place of Presentation: 愛知
  • Year and Date: 20081030-20081101
• [Presentation] スキルス胃癌の病態に基づいた分子標的治療薬の検討 (2008)
  • Author(s): 八代正和、ほか
  • Organizer: 第108回日本外科学会定期学術集会
  • Place of Presentation: 長崎
  • Year and Date: 20080515-20080517
• [Presentation] A novel molecular targeting compound as FGF-R2 phosphorylation inhibitor, Ki23057, for scirrhous gastric cancer. (2008)
  • Author(s): 八代正和, et al.
  • Organizer: 99th Annual Meeting of American Association for Cancer Research
  • Place of Presentation: San Diego
  • Year and Date: 20080412-20080416
• [Presentation] Synergistic effects of mTOR inhibitor on the growth of gastric cancer in combination with 5-Fluorouracil. (2008)
  • Author(s): Matsuzaki T, Yashiro M
  • Organizer: 99th Annual Meeting of American Association for Cancer Research
  • Place of Presentation: San Diego
  • Year and Date: 20080412-20080416
• [Presentation] Inhibitory effect of TGFβ receptor inhibitor, SB-431542, on the lymph node metastasis of gastric cancer. (2008)
  • Author(s): Shinto O, Yashiro M
  • Organizer: 99th Annual Meeting of American Association for Cancer Research
  • Place of Presentation: San Diego
  • Year and Date: 20080412-20080416
• [Book] スキルス胃癌-基礎と臨床-(新編)(曽和融生、井藤久雄編) (2010)
  • Author(s): 八代正和
  • Publisher: 医薬ジャーナル社
• [Remarks] ホームページ等
  • URL: http://www.med.osaka-cu.ac.jp/surgical-oncology