肝細胞癌のソラフェニブ著効例における感受性規定遺伝子変異の探索

2011 Fiscal Year Annual Research Report

• Project/Area Number: 23650627
• Research Institution: Kinki University
• Principal Investigator: 西尾 和人 近畿大学, 医学部, 教授 (10208134)
• Co-Investigator(Kenkyū-buntansha): 工藤 正俊 近畿大学, 医学部, 教授 (10298953)
• Project Period (FY): 2011-04-28 – 2012-03-31
• Keywords: 肝細胞癌 / 遺伝子増幅 / FGFRシグナル / ソラフェニブ / バイオマーカー

Research Abstract

本研究の成果として、肝細胞がんに対するソラフェニブ治療著効例の効果予測因子となる11q13の遺伝子増幅を初めて特定した。当該遺伝子増幅領域はFGF3,FGF4,FGF19,cyclinD1等の遺伝子が存在し、ソラフェニブの阻害活性を有するFGFシグナルのリガンドが3遺伝子含まれる。多施設共同臨床試験において全国からソラフェニブ著効例を集積して解析したところ、10例中3例に遺伝子増幅を認めたが、非著効例では1例も認めなかった(p=0.006)。FISH解析でもFGF3の著明な遺伝子増幅を確認した。動物実験において、FGF4強制発現がん細胞はソラフェニブに奏功することを確認した。臨床的因子としては、肺転移症例および低分化型組織例がソラフェニブ著効例の効果予測因子となることを示した。これらの結果は現在投稿中である(Hepatology,in revise)。本研究の成果により、血管新生阻害薬の奏功メカニズムにおいてがん細胞側の効果規定因子があることを初めて示し、臨床的に有効なバイオマーカーを特定した。ソラフェニブに対して著効した肝細胞症例の組織(凍結、パラフィン包埋切片)は、現在も収集を続けている。CGH arrayのコピー数変化の解析については、ソラフェニブ著効例がん組織を試料に解析し、上記の11q13遺伝子増幅領域を同定した。パラフィン包埋切片由来のDNAでも簡便に検出できる新しい方法として、定量的PCRベースの技術であるCopy number assayを臨床応用した。MassArrayシステムを用いた遺伝子変異解析においては、29例の肝細胞がんに対して解析を行い、いくつかの異常を検出して検討を進めている。本研究では肝細胞がんに対するソラフェニブ治療について予定以上の成果が得られたと考えている。

Research Products

• [Journal Article] Slug is upregulated during wound healing and regulates cellular phenotypes in corneal epithelial cells (2012)
  • Author(s): Aomatsu, K., Arao, T., Abe, K., Kodama, A., Sugioka, K., Matsumoto, K., Kudo, K., Kimura, H., Fujita, Y., Hayashi, H., Nagai, T., Shimomura, Y., Nishio, K
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 53(2) Pages: 751-6
• [Journal Article] FGFR2 gene amplification and clinicopathological featuers in gastric cancer (2012)
  • Author(s): Matsumoto, K., Arao, T., Hamaguchi, T., Shimada, Y., Kato, K., Oda, I., Taniguchi, H., Koizumi, F., Yanagihara, K., Sasaki, H., Nishio, K., Yamada, Y
  • Journal Title: Br J Cancer Volume: 106(4) Pages: 727-32
• [Journal Article] Combined effect of ALK and MEK inhibotors in EML4-ALK-positive non-small-cell lung cancer cells (2012)
  • Author(s): Tanizaki, J., Okamoto, I., Takezawa, K., Sakai, K., Azuma, K., Kuwata, K., Yamaguchi, H., Hatashita, E., Nishio, K., Janne, PA., Nakagawa, K
  • Journal Title: Br J Cancer Volume: 106(4) Pages: 763-7
• [Journal Article] Plasuma concentrations of angiogenesis-related molecules in patients with pancreatic cancer (2012)
  • Author(s): Sakamoto, H., Kimura, H., Sekijima, M., Matsumoto, K., Arao, T., Chikugo, T., Yamada, Y., Kitano, M., Ito, A., Takeyama, Y., Kudo, M., Nishio, K
  • Journal Title: Jpn J Clin Oncol Volume: 42(2) Pages: 105-12
• [Journal Article] Successful long-term treatment with pemetrexed of NSCLC associated with EML4-ALK and low thymidylate synthase expression (2012)
  • Author(s): Takeda, M., Okamoto, I., Sakai, K., Tanaka, K., Terashima, M., Nishio, K., Nakagawa, K
  • Journal Title: Clin Lung Cancer Volume: 13(2) Pages: 157-9
• [Journal Article] Integrated analysis of whole genome exon array and array-comparative genomic hybridization in gastric and colorectal cancer cells (2012)
  • Author(s): Furuta, K., Arao, T., Sakai, K., Kimura, H., Nagai, T., Tamura, D., Aomatsu, K., Kudo, K., Kaneda, H., Fujita, Y., Matsumoto, K., Yamada, Y., Yanagihara, K., Sekijima, M., Nishio, K
  • Journal Title: Cancer Sci Volume: 103(2) Pages: 221-7
• [Journal Article] Epidermal growth factor receptor mutation status in circulating free DNA in serum : from IPASS, a phase III study of gefitinib or carboplatin/paclitaxel in non-small cell lung cancer (2012)
  • Author(s): Goto, K., Ichinose, Y., Ohe, Y., Yamamoto, N., Negoro, S., Nishio, K., Itoh, Y., Jiang, H., Duffield, E., McCormack, R., Saijo, N., Mok, T., Fukuoka, M
  • Journal Title: J Thorac Oncol Volume: 7(1) Pages: 115-21
• [Journal Article] Expression changes in arrestin β1 and genetic variation in catechol-0-methyltransferase are biomarkers for the response to morphine treatment in cancer patients (2012)
  • Author(s): Matsuoka, H.
  • Journal Title: Oncol Rep Volume: 27(5) Pages: 1393-9
  • DOI: 10.3892/or.2012.1660
  • Peer Reviewed
• [Journal Article] Marked response to both S-1 and pemetrexed in a patient with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase-positive lung adenocarcinoma (2012)
  • Author(s): Kaneda, H.
  • Journal Title: Acta Oncol Volume: (E-pub ahead of print)
  • DOI: 10.3109/0284186X.2011.653827
  • Peer Reviewed
• [Journal Article] SRFX2 iS a novel chondroitin sulfate proteoglycan that is overexpressed in fastrointestinal cancer (2012)
  • Author(s): Tanaka, K.
  • Journal Title: Plos One Volume: 7(1) Pages: e27922
  • DOI: 10.1371/journal.pone.0027922
  • Peer Reviewed
• [Journal Article] Serum heparan sulfate concertration is correlated with the failure of epidermal growth factor receptor tyrosine kinase inhibitor treatment in patients with lung adenocarcinoma (2011)
  • Author(s): Nishio, M., Yamanaka, T., Matsumoto, K., Kimura, H., Sakai, K., Sakai, A., Sone, T., Horiike, A., Koizumi, F., Kasahara, K., Ohira, T., Ikeda, N., Saijo, N., Arao, T., Nishio, K
  • Journal Title: J Thorac Oncol Volume: 6(11) Pages: 1889-94
• [Journal Article] Activin a inhibits vascular endothelial cell growth and suppresses tumor angiogensis in gastric cancer (2011)
  • Author(s): Kaneda, H., Arao, T., Matsumoto, K., Velasco, MA., Tamura, D., Aomatsu, K., Kudo, K., Sakai, K., Nagai, T., Fujita, Y., Tanaka, K., Yanagihara, K., Yamada, Y., Okamoto, I., Nakagawa, K., Nishio, K
  • Journal Title: Br J Cancer Volume: 5(8) Pages: 1210-7
• [Journal Article] Acquired drug resistanc eto vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor in human vascular enothelial cells (2011)
  • Author(s): Arao, T., Matsumoto, K., Furuta, K., Kudo, K., Kaneda, H., Nagai, T., Sakai, K., Fujita, Y., Tamura, D., Aomatsu, K., Koizumi, F., Nishio, K
  • Journal Title: Anticancer Res Volume: 31(9) Pages: 2787-96
• [Journal Article] Prospective study evaluating the plasma concentrations of twenty-six cytokines and response to morphine treatment in cancer patients (2011)
  • Author(s): Makimura, C.
  • Journal Title: Anticancer Res Volume: 31(12) Pages: 972,125
  • DOI: 10.1007/s00280-011-1738-1
  • Peer Reviewed
• [Journal Article] What can and cannnot be done using a microarray analysis? Treatment stratification and clinical applications in oncology (2011)
  • Author(s): Arao, T.
  • Journal Title: Biol Pharm Bull Volume: 34812 Pages: 1789-93
  • Peer Reviewed
• [Journal Article] Phase I study of continuous afativib (BIBW2992) in patients with advanced non-small cell lung cancer after prior chemotherapy/erlotinib/gefitinib (LUX-Lung 4) (2011)
  • Author(s): Murakami, H.
  • Journal Title: Cancer Chemother Pharmacol Volume: (E-pub ahead of print)
  • DOI: 10.1007/s00280-011-1738-1
  • Peer Reviewed
• [Journal Article] Aza-derivatives of resveratrol are potent macrophage migration inhibitory factor inhibitors (2011)
  • Author(s): Fujita, Y.
  • Journal Title: Invest New Drugs Volume: (E-pub ahead of print)
  • DOI: 10.1007/s10637-011-9749-7
  • Peer Reviewed
• [Journal Article] Activation of ERBB2 signaling causes resistance to the EGFR-derected therapeutic antibody cetuximab (2011)
  • Author(s): Yonesaka, K.
  • Journal Title: Sci Transl Med Volume: 3(99) Pages: 99-86
  • Peer Reviewed
• [Journal Article] Sunitinib inhibits lymphatic endothelial cell functions and lymph node metastasis in a breast cancer model through inhibition of vascular endothelial growth factor receptor 3 (2011)
  • Author(s): Kodera, Y.
  • Journal Title: Breast Cancer Res Volume: 13(3) Pages: r66
  • Peer Reviewed
• [Journal Article] Roles of BIM induction and survivin downregulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification, cancer model through inhibition of vascular endothelial growth factor receptor 3 (2011)
  • Author(s): Tanizaki, J.
  • Journal Title: Oncogene Volume: 30(39) Pages: 4097-106
  • DOI: 10.1038/onc.2011.111
  • Peer Reviewed
• [Presentation] 血清ヘパラン硫酸濃度とEGRチロシンキナーゼ阻害薬耐性 (2011)
  • Author(s): 松本和子
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋市名古屋国際会議場
  • Year and Date: 20111003-20111005
• [Presentation] 大腸がんにおけるHS6ST2発現とその臨床的特徴 (2011)
  • Author(s): 木村英晴
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋市名古屋国際会議場
  • Year and Date: 20111003-20111005
• [Presentation] 肝細胞癌におけるTJP-1とTwist発現の肝癌切除後の予後への影響 (2011)
  • Author(s): 永井知行
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋市名古屋国際会議場
  • Year and Date: 20111003-20111005
• [Presentation] 非小細胞肺がんにおけるEGFR T790の変異の新規検出法 (2011)
  • Author(s): 藤田至彦
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋市名古屋国際会議場
  • Year and Date: 20111003-20111005
• [Presentation] 胃癌のEMT関連遺伝子発現と化学療法治療予後 (2011)
  • Author(s): 荒尾徳三
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋市名古屋国際会議場
  • Year and Date: 20111003-20111005
• [Presentation] A phase II trial of afatinib (BIBW 2992) in patinets (pts) with advanced non-small cell lung cancer previously treated with erkiubub (E) or (2011)
  • Author(s): Yamamoto, N.
  • Organizer: American Society of Clinical Oncology Annual Meeting 2011
  • Place of Presentation: Chicago
  • Year and Date: 20110603-20110607
• [Presentation] An analysis of serum heparan sulfate concentration and EGFR tyrosine kinase inhibitor treatment in patients with non-small cell lung (2011)
  • Author(s): Nishio, M.
  • Organizer: American Society of Clinical Oncology Annual Meeting 2011
  • Place of Presentation: Chicago
  • Year and Date: 20110603-20110607
• [Presentation] Slug is upregulated during wound healing and downregulates TP63 in corneal epithelial cell (2011)
  • Author(s): Aomatsu, K., Nishio, K
  • Organizer: ARVO 2011 Vision Genomics
  • Place of Presentation: Florida
  • Year and Date: 20110501-05
• [Patent(Industrial Property Rights)] ソラフェニブの効果予測方法 (2011)
  • Inventor(s): 西尾和人, 他
  • Industrial Property Rights Holder: 近畿大学, 他
  • Industrial Property Number: 特許権、特願2011-104275
  • Filing Date: 2011-05-09