Development of molecular targeted therapy for lung cancer metastasis considering characteristics of organ microenvironment

2009 Fiscal Year Final Research Report

• Project/Area Number: 17016051
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokushima
• Principal Investigator: SONE Saburo The University of Tokushima, 大学院・ヘルスバイオサイエンス研究部, 教授 (40145024)
• Co-Investigator(Kenkyū-buntansha): YANO Seiji 金沢大学, がん研究所, 教授 (30294672) ; NISHIOKA Yasuhiko 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 准教授 (70274199) ; KAKIUCHI Soji 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 准教授 (50380100) ; GOTO Hisatsugu 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 講師 (00437641) ; HANIBUCHI Masaki 徳島大学, 医学部・歯学部附属病院, 講師 (80335794)
• Project Period (FY): 2005 – 2009
• Keywords: 骨転移 / 破骨細胞 / 血管新生 / 樹状細胞 / 可溶性VEGF受容体 / EGFR阻害薬 / 薬剤耐性 / 肝細胞増殖因子

Research Abstract

We focused on cancer microenvironment and found that drugs which suppressed osteoclast-function inhibited lung cancer bone metastasis. The factor selectively expressed in bone metastatic lesions acted as an inhibitor of multiple organ metastasis. Dendritic cells produced soluble VEGF receptor 1, suppressed angiogenesis, and thereby inhibited lung cancer progression. Humanized anti-HM1.24 antibody inhibited growth of HM1.24 expressing lung cancer cells. Hepatocyte growth factor (HGF) induced resistance to EGFR tyrosine kinase inhibitors, indicating that HGF may be important target for overcoming the resistance in lung cancer.

Research Products

• [Journal Article] Hepatocyte growth factor reduces susceptibility to an irreversible epidermal growth factor receptor inhibitor in EGFR-T790M mutant lung cancer. (2010)
  • Author(s): Yamada T, Matsumoto K, Wang W, Li Q, Nishioka Y, Sekido Y, Sone S, Yano S.
  • Journal Title: Clin Cancer Res 16 Pages: 174-183
  • Peer Reviewed
• [Journal Article] Crosstalk to stromal fibroblasts induces resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors (2009)
  • Author(s): Wang W, Li Q, Yamada T, Matsumoto K, Matsumoto I, Oda M, Watanabe G, Kayano Y, Nishioka Y, Sone S, Yano S.
  • Journal Title: Clin Cancer Res 15 Pages: 6630-6638
  • Peer Reviewed
• [Journal Article] Intensification therapy with anti-parathyroid hormonerelated protein antibody plus zoledronic acid for bone metastases of small cell lung cancer cells in severe combined immunodeficient mice. (2009)
  • Author(s): Yamada T, Muguruma H, Yano S, Ikuta K, Ogino H, Kakiuchi S, Hanibuchi M, Uehara H, Nishioka Y, Sone S.
  • Journal Title: Mol Cancer Ther 8 Pages: 119-126
  • Peer Reviewed
• [Journal Article] E7080, a multi-tyrosine kinase inhibitor, suppresses the progression of malignant pleural mesothelioma with different proangiogenic cytokine production profiles. (2009)
  • Author(s): Ikuta K, Yano S, Trung VT, Hanibuchi M, Goto H, Li Q, Wang W, Yamada T, Ogino H, Kakiuchi S, Uehara H, Sekido Y, Uenaka T, Nishioka Y, Sone S.
  • Journal Title: Clin Cancer Res 15 Pages: 7229-7237
  • Peer Reviewed
• [Journal Article] Expression of soluble vascular endothelial growth factor receptor-1 in human monocyte-derived mature dendritic cells contributes to their antiangiogenic property. (2009)
  • Author(s): Kishuku M, Nishioka Y, Abe S, Kishi J, Ogino H, Aono Y, Azuma M, Kinoshita K, Rentsenh, B, Makino H, Ranjan P, Minakuchi K, Sone S.
  • Journal Title: J Immunol 183 Pages: 8176-8185
  • Peer Reviewed
• [Journal Article] A Bone metastasis model with osteolytic and osteoblastic properties of human lung cancer ACC-LC-319/bone2 in natural killer cell-depleted severe combined immunodeficient mice. (2009)
  • Author(s): Otsuka S, Hanibuchi M, Ikuta K, Yano S, Goto H, Ogino H, Yamada T, Kakiuchi S, Nishioka Y, Takahashi T, Sone S.
  • Journal Title: Oncol Res 17 Pages: 581-591
  • Peer Reviewed
• [Journal Article] Chimeric and humanized anti-HM1. 24 antibodies mediate antibody-dependent cellular cytotoxicity against lung cancer cells. (2009)
  • Author(s): Wang W, Nishioka Y, Ozaki S, Jalili A, Verma VK, Hanibushi M, Abe S, Minakuchi K, Matsumoto T, Sone S.
  • Journal Title: Lung Cancer 63 Pages: 23-31
  • Peer Reviewed
• [Journal Article] HM1. 24 (CD317) is a novel target against lung cancer for immunotherapy using anti-HM1. 24 antibody. (2009)
  • Author(s): Wang W, Nishioka Y, Ozaki S, Jalili A, Abe S, Kakiuchi S, Kishuku M, Minakuchi K, Matsumoto T, Sone S.
  • Journal Title: Cancer Immunol Immunother 58 Pages: 967-976
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. (2008)
  • Author(s): Yano S, Wang W, Li Q, Matsumoto K, Sakurama H, Nakmura T, Ogino H, Kakiuchi S, Hanibuchi M, Nishioka Y, Uehara H, Mitsudomi T, Yatabe Y, Nakamura T, Sone S.
  • Journal Title: Cancer Res 68 Pages: 9479-9487
  • Peer Reviewed
• [Journal Article] Novel dual targeting strategy with vandetanib induces tumor cell apoptosis and inhibits angiogenesis in malignant pleural mesothelioma cells expressing RET oncogenic rearrangement. (2008)
  • Author(s): Ogino H, Yano S, Kakiuchi S, Yamada T, Ikuta K, Nakataki E, Goto H, Hanibuchi M, Nishioka Y, Ryan A, Sone S.
  • Journal Title: Cancer Letters 265 Pages: 55-66
  • Peer Reviewed
• [Journal Article] Lysophosphatidic acid stimulates the proliferation and motility of malignant pleural mesothelioma cells through lysophosphatidic acid receptors, LPA1 and LPA2. (2008)
  • Author(s): Yamada T, Yano S, Ogino H, Ikuta K, Kakiuchi S, Hanibuchi M, Kanematsu T, Taniguchi T, Sekido Y, Sone S.
  • Journal Title: Cancer Sci 99 Pages: 1603-1610
  • Peer Reviewed
• [Journal Article] Follistatin suppresses the production of experimental multiple-organ metastasis by small cell lung cancer cells in natural killer cell-depleted SCID mice. (2008)
  • Author(s): Ogino H, Yano S, Kakiuchi S, Muguruma H, Ikuta K, Hanibuchi M, Uehara H, Tsuchida K, Sugino H, Sone S.
  • Journal Title: Clin Cancer Res 14 Pages: 660-667
  • Peer Reviewed
• [Journal Article] Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity. (2008)
  • Author(s): Maekawa Y, Minato Y, Ishifune C, Kurihara T, Kitamura A, Kojima H, Yagita H, Sakata-Yanagimoto M, Saito T, Taniuchi I, Chiba S, Sone S, Yasutomo K.
  • Journal Title: Nat Immunol 9 Pages: 1140-1147
  • Peer Reviewed
• [Journal Article] Molecular pathogenesis and its therapeutic modalities of lung cancer metastasis to bone. (2007)
  • Author(s): Sone S, Yano S.
  • Journal Title: Cancer Metastasis Rev 26 Pages: 685-289
  • Peer Reviewed
• [Journal Article] CXCL9 and 11 in patients with pulmonary sarcoidosis: a role of alveolar macrophages. (2007)
  • Author(s): Nishioka Y, Manabe K, Kishi J, Wang W, Inayama M, Azuma M, Sone S.
  • Journal Title: Clin Exp Immunol 49 Pages: 317-326
  • Peer Reviewed
• [Journal Article] The therapeutic efficacy of anti-vascular endothelial growth factor antibody, bevacizumab, and pemetrexed against orthotopically implanted human pleural mesothelioma cells in SCID mice. (2007)
  • Author(s): Li Q, Yano S, Ogino H, Wang W, Uehara H, Nishioka Y, Sone S.
  • Journal Title: Clin Cancer Res 13 Pages: 5918-5925
  • Peer Reviewed
• [Journal Article] Novel orthotopic implantation model of human malignant pleural mesothelioma (EHMES-10 cells) highly expressing vascular endothelial growth factor and its receptor. (2006)
  • Author(s): Nakataki E, Yano S, Matsumori Y, Goto H, Kakiuchi S, Muguruma H, Bando Y, Uehara H, Hamada H, Kito E, Yokoyama A, Sone S.
  • Journal Title: Cancer Sci 97 Pages: 183-191
  • Peer Reviewed
• [Journal Article] The neuromedin U-growth hormone secretagogue receptor 1b/neurotensin receptor 1 oncogenic signaling pathway as a therapeutic target for lung cancer. (2006)
  • Author(s): Takahashi K, Furukawa C, Takano A, Ishikawa N, Kato T, Hayama S, Suzuki C, Yasui W, Inai K, Sone S, Ito T, Nishimura H, Tsuchiya E, Nakamura Y, Daigo Y.
  • Journal Title: Cancer Res 66 Pages: 9408-9419
  • Peer Reviewed
• [Journal Article] ZD6474, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, inhibits growth of experimental lung metastasis and production of malignant pleural effusions in a non-small cell lung cancer model. (2006)
  • Author(s): Matsumori Y, Yano S, Goto H, Nakataki E, Wedge SR, Ryan AJ, Sone S.
  • Journal Title: Oncol Res 16 Pages: 15-26
  • Peer Reviewed
• [Journal Article] Antitumor vascular strategy for controlling experimental metastatic spread of human small-cell lung cancer cells with ZD6474 in natural killer cell-depleted severe combined immunodeficient mice. (2005)
  • Author(s): Yano S, Muguruma H, Matsumori Y, Goto H, Nakataki E, Edakuni N, Tomimoto H, Kakiuchi S, Yamamoto A, Uehara H, Ryan A, Sone S.
  • Journal Title: Clin Cancer Res 11 Pages: 8789-8798
  • Peer Reviewed
• [Journal Article] Reveromycin A inhibits osteolytic bone metastasis of small-cell lung cancer cells, SBC-5, through an antiosteoclastic activity. (2005)
  • Author(s): Muguruma H, Yano S, Kakiuchi S, Uehara H, Kawatani M, Osada H, Sone S.
  • Journal Title: Clin Cancer Res 11 Pages: 8822-8828
  • Peer Reviewed
• [Journal Article] Colon cancer cell-derived high mobility group 1/amphoterin induces growth inhibition and apoptosis in macrophages. (2005)
  • Author(s): Kuniyasu H, Yano S, Sasaki T, Sasahira T, Sone S, Ohmori H.
  • Journal Title: Am J Pathol 166 Pages: 751-759
  • Peer Reviewed
• [Journal Article] Plakophilin 3 oncogene as prognostic marker and therapeutic target for lung cancer. (2005)
  • Author(s): Furukawa C, Daigo Y, Ishikawa N, Kato T, Ito T, Tsuchiya E, Sone S, Nakamura Y.
  • Journal Title: Cancer Res 65 Pages: 7102-7110
  • Peer Reviewed
• [Presentation] HGF induces resistance to EGFR tyrosine kinase inhibitors in lung cancer with EGFR activating mutations. (2009)
  • Author(s): Yano S.
  • Organizer: The 14th Congress of the Asian Pacific Society of Respirology
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2009-11-17
• [Presentation] Role of tumor and host-derived HGF in drug resistance to EGFR inhibitors in EGFR activating mutation-positive lung cancer. (2009)
  • Author(s): Kakiuchi S, et al.
  • Organizer: AACR -NCI-EORTC Molecular Targets and Cancer Therapeutics Coference.
  • Place of Presentation: Boston, USA
  • Year and Date: 2009-11-16
• [Presentation] HGF-MET経路によるEGFR -TKI耐性誘導の分子機構とその克服に向けた戦略. (2009)
  • Author(s): 矢野聖二
  • Organizer: 第50回日本肺癌学会総会(特別セッション)
  • Place of Presentation: 東京
  • Year and Date: 2009-11-13
• [Presentation] Hepatocyte growth factor as an inducer of EGFR-TKI resistance in lung cancer harboring EGFR activating mutations. (2009)
  • Author(s): 矢野聖二
  • Organizer: 第68回日本癌学会学術総会(International Sessions)
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-01
• [Presentation] らヒト肺癌多臓器転移モデルにおけるマルチキナーゼ阻害薬E7080の転移抑制効果. (2009)
  • Author(s): 西岡安彦
  • Organizer: 第18回日本がん転移学会学術集会・総会(シンポジム)
  • Place of Presentation: 旭川
  • Year and Date: 2009-07-24
• [Presentation] ら肺がんの骨転移メカニズムと分子標的治療の探索. (2009)
  • Author(s): 後東久嗣
  • Organizer: 第13回日本がん分子標的治療学会学術集会(シンポジウム)
  • Place of Presentation: 徳島
  • Year and Date: 2009-06-26
• [Presentation] Lung cancer: Update from early diagnosis to molecular -targeted and individualized therapy. (2009)
  • Author(s): Sone S, et al.
  • Organizer: 2009 Asian-Pacific Forum on Respiratory Diseases and West China Conference on Respiratory Diseases (招待講演)
  • Place of Presentation: 成都市, 中国
  • Year and Date: 2009-06-06
• [Presentation] Validation of Molecular -targeted Therapy in Bone Metastasis Models of Lung Cancer. (2009)
  • Author(s): Sone S, et al.
  • Organizer: VIII International Meeting on Cancer Induced Bone Disease (招待講演)
  • Place of Presentation: Sydney, Australia
  • Year and Date: 2009-03-26
• [Presentation] Induction of antibody -dependent cellular cytotoxicity by chimeric and humanized anti-HM1. 24 (CD317) antibody against human lung cancer cells. (2007)
  • Author(s): Nishioka Y.
  • Organizer: ATS 2007 International Conference
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2007-05-21
• [Presentation] Disease models to identify and validate molecular targets in lung cancer progression. (2007)
  • Author(s): Sone S.
  • Organizer: ATS 2007 International Conference (Meet the Professor Seminer)
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2007-05-21
• [Presentation] Critical determinants of organ specific lung cancer metastasis. (2006)
  • Author(s): Sone S.
  • Organizer: The 11th International Congress of the Metastasis Research Society iointed with the 15th Annual Meeting of Japanese Association for Metastasis Research(Presidential Lecture)
  • Place of Presentation: 徳島
  • Year and Date: 2006-09-03
• [Presentation] HM1. 24 (CD317) is a novel immunological target against lung cancer: implication for immunotherapy using anti-HM1. 24 antibody. (2006)
  • Author(s): Nishioka Y, et al.
  • Organizer: ATS 2006 International Conference
  • Place of Presentation: San Diego, USA
  • Year and Date: 2006-05-21
• [Presentation] 肺がん転移の悪性化要因に対する分子標的治療の展開 (2005)
  • Author(s): 曽根三郎
  • Organizer: 第59回日本口腔科学会(招請講演)
  • Place of Presentation: 徳島
  • Year and Date: 2005-04-22
• [Book] がん分子標的治療研究実践マニュアル (2009)
  • Author(s): 曽根三郎, ら
  • Total Pages: 329
  • Publisher: (株)金芳堂
• [Patent(Industrial Property Rights)] 分子標的薬に対する感受性が低下している癌の治療薬および分子標的薬に対する感受性を増強する医薬組成物 (2009)
  • Inventor(s): 矢野聖二、松本邦夫
  • Industrial Property Rights Holder: 金沢大学
  • Industrial Property Number: 特許 特願2009-078621
  • Filing Date: 2009-03-27
  • Acquisition Date: 2009-03-27