Mechanism of acquired drug resistance to VEGFR2 tyrosine kinase inhibitor in vascular endothelial cells

2009 Fiscal Year Final Research Report

• Project/Area Number: 19209018
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Kinki University
• Principal Investigator: NISHIO Kazuto Kinki University, 医学部, 教授 (10208134)
• Co-Investigator(Kenkyū-buntansha): ARAO Tokuzo 近畿大学, 医学部, 講師 (20441074)
• Project Period (FY): 2007 – 2009
• Keywords: ファーマコゲノミックス / 血管新生

Research Abstract

(1) HUVEC clones resistant to VEGFR2-TKI Ki8751 exhibited the downregulation of VEGFR2, a decreased signal response to VEGF stimulation, and the loss of vascular endothelial markers. These results strongly suggest that an escape from VEGFR2 signaling-dependency is one of the mechanisms of resistance to VEGFR2-TKI in vascular endothelial cells.
(2) We identified VEGFR2+pTyr+ peripheral blood Leukocytes as a feasible and non-invasive pharmacodynamic biomarker in vivo. Our findings suggest the clinical utility of VEGFR2+pTyr+ PBLs as a VEGF signal-specific biomarker of VEGFR2 tyrosine kinase inhibitors for use in early clinical trials.
(3) Phase I clinical and biomarker study demonstrated that BIBF 1120-treatment significantly increased percentage of CD133+CD117-cells (p<0.001) on Day 29 compared with pre-treatment, and conversely decreased that of CD133-CD117+ cells (p<0.01). Our biomarker data provide a novel insight into CD133 and CD117 positive cells as a potential pharmacodynamic biomarker for an anti-angiogenic inhibitor.

Research Products

• [Journal Article] FOXQ1 is overexpressed in colorectal cancer and enhances tumorigenicity and tumor growth. Cancer Res (2010)
  • Author(s): Kaneda H, Arao T, Tanaka K, Tamura D, Aomatsu K, Kudo K, Sakai K, Velasuco MA, Matsumoto K, Fujita Y, Yamada Y, Tsurutani J, Okamoto I, Nakagawa K, Nishio K
  • Journal Title: E-pub ahead or print
• [Journal Article] mTOR signal and hypoxia-inducible factor-1 alpha regulate CD133 expression in cancer cells. (2009)
  • Author(s): Matsumosto K, Arao T, Tanaka K, Kaneda H, Kudo K, Fujita Y, Tamura D, Aomatsu K, Tamura T, Yamada Y, Saijo N, Nishio K
  • Journal Title: Cancer Res 69(18) Pages: 7160-4
• [Journal Article] N-myc downstream regulated gene 1/Cap43 suppresses tumor growth and angiogenesis of pancreatic cancer through attenuation of inhibitor of kB kinase s expression. (2009)
  • Author(s): Hosoi F, Izumi H, Kawahara A, Murakami Y, Kinoshita H, Kage M, Nishio K, Kohno K, Kuwano M, Ono M
  • Journal Title: Cancer Res 69(129) Pages: 4983-91
• [Journal Article] Identification of predictive biomarkers for response to Trastuzumab using plasma FUCA activity and N-Glycan identified by MALDI-TOF-MS. (2009)
  • Author(s): Matsumoto K, Shimizu C, Arao T, Andoh M, Katsumata N, Kohno T, Yonemori K, Koizumi F, Yokote H, Aogi K, Tamura K, Nishio K, Fujiwara Y
  • Journal Title: J Proteome Res 8(2) Pages: 457-62
• [Journal Article] SRPX2 is overexpressed in gastric cancer and promotes cellular migration and adhesion. (2009)
  • Author(s): Tanaka K, Arao T, Maegawa M, Matsumoto K, Kaneda H, Kudo K, Fujita Y, Yokote H, Yanagihara K, Yamada Y, Okamoto I, Nakagawa K, Nishio K
  • Journal Title: Int J Cancer 124(5) Pages: 1072-80
• [Journal Article] RPN2 gene congers docetaxel resistance in breast cancer. (2008)
  • Author(s): Honma K, Iwao-Koizumi K, Takeshita F, Yamamoto Y, Yoshida T, Nishio K, Nakagawa S, Kato K, Ochiya T
  • Journal Title: Nature Med 14(9) Pages: 939-48
• [Journal Article] Identification of prognostic biomarkers in gastric cancer using endoscopic biopsy samples. (2008)
  • Author(s): Yamada Y, Arao T, Gotoba T, Taniguchi H, Oda I, Shirao K, Shimada Y, Hamaguchi T, Kato K, Hamano T, Koizumi F, Tamura T, Saito D, Shimoda T, Saka M, Fukagawa T, Katai H, Sasako M, Nishio K
  • Journal Title: Cancer Sci 99(11) Pages: 2193-9
• [Journal Article] EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line. (2008)
  • Author(s): Fuakai J, Yokote H, Yamanaka R, Arao T, Nishio K, Itakura T
  • Journal Title: Mol Cancer Ther 7(9) Pages: 2768-78
• [Journal Article] Expression of HER2 and estrogen receptor alpha depends upon nuclear localization of Y-box binding protein-1 in human breast cancers. (2008)
  • Author(s): Fujii T, Kawahara A, Basaki Y, Hattori S, Nakashima K, Nakano K, Shirouzu K, Kohno K, Yanagawa T, Yamada H, Nishio K, Ono M, Kuwano M, Kage M
  • Journal Title: Cancer Res 68(5) Pages: 1504-12
• [Journal Article] Abberant expression of Fra-2 promotes CCR4 expression and cell proliferation in adult T-cell leukemia. (2008)
  • Author(s): Nakayama T, Hieshima K, Arao T, Jin Z, Nagakubo D, Shirakawa A-K, Yamada Y, Fujii M, Oiso N, Kawada A, Nishio K, Yoshie O
  • Journal Title: Oncogene 27(33) Pages: 3221-32
• [Journal Article] Antibody-dependent cellular cytotoxicity of cetuximab against tumor cells with wild-type of mutant epidermal growth factor receptor. (2007)
  • Author(s): Kimura H, Sakai K, Arao T, Shimoyama T, Tamura T, Nishio K
  • Journal Title: Cancer Sci 98(8) Pages: 1275-80
• [Journal Article] AZD2171 shows potent antitumor activity against gastric cancer over-expressing FGFR2/KGFR. (2007)
  • Author(s): Takeda M, Arao T, Yokote H, Komatsu T, Yanagihara K, Sasaki H, Yamada Y, Tamra T, Fukuoka K, Kimura H, Saijo N, Nishio K
  • Journal Title: Clin Cancer Res 13(10) Pages: 3051-7
• [Presentation] Use of amplification of the 8q24 and 20q11-13 loci to predict progression-free survival of advanced epithelial ovarian cancer patients receiving standard therapy. (2009)
  • Author(s): Nishio K
  • Organizer: American Society of Clinical Oncology 45th Annual Meeting 2009
  • Place of Presentation: Orlando
  • Year and Date: 20090529-20090602
• [Presentation] Correlation of FcR IIa-H131R and IIIa-V158F polymorphisms and clinical outcome of trastuzumab in both neoadjuvant and metastatic setting in patients with HER-2 positive breast cancer. (2009)
  • Author(s): Nishio K
  • Organizer: American Society of Clinical Oncology 45th Annual Meeting 2009
  • Place of Presentation: Orlando
  • Year and Date: 20090529-20090602
• [Presentation] Phase I dose escalation study and biomarker analysis of E7080 in patients with advanced solid tumors. (2009)
  • Author(s): Nishio K
  • Organizer: American Society of Clinical Oncology 45th Annual Meeting 2009
  • Place of Presentation: Orlando
  • Year and Date: 20090529-20090602
• [Presentation] Identification of prognostic biomarkers for gastric cancer by gene expression analysis. (2009)
  • Author(s): Nishio K
  • Organizer: American Society of Clinical Oncology 45th Annual Meeting 2009
  • Place of Presentation: Orlando
  • Year and Date: 20090529-20090602
• [Presentation] A phase I and pharmacokinetic/pharmacodynamic study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in Japanese patients with solid tumor. (2009)
  • Author(s): Nishio K
  • Organizer: American Society of Clinical Oncology 45th Annual Meeting 2009
  • Place of Presentation: Orlando
  • Year and Date: 20090529-20090602
• [Presentation] Phase I dose escalation study of E7080, a novel anti-angiogenic multikinase inhibitor, in Japanese patients with advanced solid tumors. (2009)
  • Author(s): Nishio K
  • Organizer: American Society of Clinical Oncology 45th Annual Meeting 2009
  • Place of Presentation: Orlando
  • Year and Date: 20090529-20090602
• [Book] 入門腫瘍内科学新しい分子マーカー(遺伝子発現プロファイル・CTC) (2009)
  • Author(s): 西尾和人
  • Publisher: 篠原出版新社
• [Patent(Industrial Property Rights)] ロタキサン化合物及び抗ガン剤 (2009)
  • Inventor(s): 西尾和人, 他
  • Industrial Property Rights Holder: 近畿大学, 他
  • Industrial Property Number: 特許権・PCT/JP2009/005503
  • Filing Date: 2009-10-21
• [Patent(Industrial Property Rights)] 治療効果観察のためのバイオマーカー使用方法又はシステム (2009)
  • Inventor(s): 西尾和人, 他
  • Industrial Property Rights Holder: 近畿大学, 他
  • Industrial Property Number: 特許権・EP 09154964.2
  • Filing Date: 2009-04-05
• [Patent(Industrial Property Rights)] 胃癌の判定方法 (2009)
  • Inventor(s): 西尾和人, 荒尾徳三, 他
  • Industrial Property Rights Holder: 近畿大学, 他
  • Industrial Property Number: 特許権・特許公開2009-276153
  • Acquisition Date: 2009-11-26
• [Patent(Industrial Property Rights)] N結合型糖鎖を利用した膵臓癌の診断方法 (2009)
  • Inventor(s): 西尾和人, 荒尾徳三, 他
  • Industrial Property Rights Holder: 近畿大学, 他
  • Industrial Property Number: 特許権・特許公開2009-270996
  • Acquisition Date: 2009-11-19
• [Patent(Industrial Property Rights)] 5員複素環化合物を有効成分とする抗ガン剤および新規5員複素環化合物 (2009)
  • Inventor(s): 西尾和人, 他
  • Industrial Property Rights Holder: 近畿大学, 他
  • Industrial Property Number: 特許権・特許公開2009-256274
  • Acquisition Date: 2009-11-05
• [Patent(Industrial Property Rights)] ErB受容体薬に対する患者の応答を予測またはモニタリングする方法 (2009)
  • Inventor(s): 西尾和人, 他
  • Industrial Property Rights Holder: アストラゼネカ, 他
  • Industrial Property Number: 特許権・特許公表2009-511008
  • Acquisition Date: 2009-03-19
• [Patent(Industrial Property Rights)] 抗癌剤の有効性予測方法 (2009)
  • Inventor(s): 西尾和人, 他
  • Industrial Property Rights Holder: 近畿大学, 他
  • Patent Publication Number: 特許権・特開2009-244147
  • Acquisition Date: 2009-10-22
• [Patent(Industrial Property Rights)] 抗癌剤の有効性予測方法 (2009)
  • Inventor(s): 西尾和人, 荒尾徳三, 他
  • Industrial Property Rights Holder: 住友ベークライト, 他
  • Patent Publication Number: 特許権・特開2009-050189
  • Acquisition Date: 2009-03-12
• [Patent(Industrial Property Rights)] 胃癌高発現遺伝子特定による胃癌診断および創薬への利用 (2008)
  • Inventor(s): 西尾和人, 荒尾徳三, 他
  • Industrial Property Rights Holder: 西尾和人, 荒尾徳三, 他
  • Patent Publication Number: 特許権・特開2008-118915
  • Acquisition Date: 2008-05-29