Aberrant activations of cellular kinases and exploration of novel targeted therapy in human solid cancers

2013 Fiscal Year Final Research Report

• Project/Area Number: 23590409
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Jichi Medical University
• Principal Investigator: DOBASHI Yoh 自治医科大学, 医学部, 准教授 (90231456)
• Co-Investigator(Kenkyū-buntansha): ENDO Shunsuke 自治医科大学, 医学部, 教授 (10245037) ; YANAGAWA Takashi 群馬大学, 医学部, 講師 (40400725) ; KITAGAWA Masatoshi 浜松大学, 医学部, 教授 (50294971)
• Co-Investigator(Renkei-kenkyūsha): MATSUBARA Hirochika 山梨大学, 医学部, 講師 (00374166) ; OOI Akishi 金沢大学, 医学系研究科, 教授 (50160411) ; HARUHIKO Sugimura 浜松医科大学, 医学部, 教授 (00196742)
• Project Period (FY): 2011 – 2013
• Keywords: 肺癌 / 骨軟部肉腫 / AKT / mTOR / 遺伝子増幅 / 遺伝子多型 / シグナル伝達

Research Abstract

In lung carcinomas and soft tissue sarcomas, Akt expression/activation, and AKT1-3 gene gains were investigated. In lung carcinomas, immunohistochemistry revealed expression of Akt in 60% and phosphorylated-Akt (p-Akt), Akt1, Akt2 in 40%, but expression of Akt3 was lower as 20% in approximate. A significant correlation between Akt2/p-Akt expression and lymph node metastasis was observed. In sarcomas, the cases showing activated Akt/mTOR pathway revealed worse prognosis in several histological types. FISH analysis indicated "FISH-positive" gene gain (amplification/high level polysomy) of AKT1/2 in 15 to 25% in both tumors. FISH-positive AKTs gene gain accompanied activation of Akt, but not EGFR gains. Microarray analysis revealed that AKT1/2 gene increase induced specific mRNA and microRNA, which are known to be involved in invasion or epithelial-mesenchymal transition. Moreover, a polymorphic site in AKT1 related to cancer predisposition was identified by SNP analysis.

Research Products

• [Journal Article] Significance of Akt activation and AKT gene increases in bone and soft tissue tumors (2014)
  • Author(s): Dobashi, Y., Sato, E., Oda, Y., Inazawa, J., Ooi, A.
  • Journal Title: Hum Pathol Volume: 45(1) Pages: 127-36
  • Peer Reviewed
• [Journal Article] Intratumoral heterogeneous amplification of ERBB2 and subclonal genetic diversity in gastric cancers revealed by multiple ligation-dependent probe amplification and fluorescence in situ hybridization (2014)
  • Author(s): Tajiri. R., Ooi. A., Fujimura, T., Dobashi, Y., Oyama, T., Nakamura, R., Ikeda, H.
  • Journal Title: Hum Pathol Volume: 45(4) Pages: 725-34
  • Peer Reviewed
• [Journal Article] Genetic aberrations as the targets of oncology research : Involvement of paraffin-embedded tissues (2014)
  • Author(s): Dobashi. Y., Goto. A., Endo, T., Ooi, A.
  • Journal Title: Histol. Histopathol Volume: 29(2) Pages: 191-205
  • Peer Reviewed
• [Journal Article] Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors (2013)
  • Author(s): Endo M, Yamamoto H, Setsu N, Kohashi K, Takahashi Y, Ishii T, Iida K, Matsumoto Y, Hakozaki M, Aoki M, Iwasaki H, Dobashi Y, Nishiyama K, Iwamoto Y, Oda Y
  • Journal Title: Clin. Cancer Res. Volume: 19(2) Pages: 450-61
  • Peer Reviewed
• [Journal Article] Effects of Long-Term Treatment with Ranirestat, a Potent Aldose Reductase Inhibitor, on Diabetic Cataract and Neuropathy in Spontaneously Diabetic Torii Rats (2013)
  • Author(s): Ota, A., Kakehashi, A., Toyoda,F., Kinoshita, N., Shinmura, M., Takano, H., Obata, H., Matsumoto, T., Tsuji, J., Dobashi, Y., Fujimoto, W.Y., Kawakami, M., Kanazawa, Y.
  • Journal Title: J Diab Res Volume: 1 Pages: 1-8
  • Peer Reviewed
• [Journal Article] Utility of Fluorescence in situ Hybridization to Detect MDM2 Amplification in Liposarcomas and their Morphological Mimics (2013)
  • Author(s): Kimura, H., Dobashi, Y., Nojima, T., Nakamura, H., Yamamoto, N., Tsuchiya, H., Ikeda, H., Sawada-Kitamura, S., Oyama, T., Ooi, A.
  • Journal Title: Int J Clin Exp Pathol Volume: 6(7) Pages: 1306-16
  • Peer Reviewed
• [Journal Article] Carcinoid tumor of the lung with massive ossification : report of a case showing the evidence of osteomimicry and review of the literature (2013)
  • Author(s): Tsubochi, H., Endo, S., Oda, Y., Dobashi, Y.
  • Journal Title: Int J Clin Exp Pathol Volume: 6(5) Pages: 957-961
  • Peer Reviewed
• [Journal Article] Non-small cell lung carcinoma therapy using mTOR-siRNA (2012)
  • Author(s): Matsubara, H., Sakakibara, K., Kunimitsu, K., Matsuoka, H., Kato, K., Oyachi, N., Dobashi, Y., Matsumoto, M.
  • Journal Title: Int J Clin Exp Pathol Volume: 5(2) Pages: 119-125
  • Peer Reviewed
• [Journal Article] The Akt/Mammalian Target of Rapamycin Pathway Is Activated and Associated With Adverse Prognosis in Soft Tissue Leiomyosarcomas (2012)
  • Author(s): Setsu, N., Yamamoto, H., Kohashi, K., Endo, M., Matsuda, S., Yokoyama, R., Nishiyama, K., Iwamoto, Y., Dobashi, Y., Oda, Y.
  • Journal Title: Cancer Volume: 118(6) Pages: 1637-48
  • Peer Reviewed
• [Journal Article] Gene amplification of ESR1 in breast cancers - Fact or fiction? A fluorescence in situ hybridization and multiplex ligation-dependent probe amplification study (2012)
  • Author(s): Ooi, A., Inokuchi, M., Harada, S., Inazawa, J., Tajiri, J., Sawada-Kitamura, S., Ikeda, H., Kawashima, H., Dobashi, Y.
  • Journal Title: J. Pathol Volume: 227(1) Pages: 8-16
  • Peer Reviewed
• [Journal Article] Molecular alterations in AKT and its protein activation in human lung carcinomas (2012)
  • Author(s): Dobashi, Y., Kimura, M., Matsubara, H., Endo, S., Inazawa, J., Ooi, A.
  • Journal Title: Human Pathol Volume: 43(12) Pages: 2229-40
  • Peer Reviewed
• [Journal Article] Immunohisto- chemical and genetic analyses of the EGFR and HER2 signaling pathways in salivary gland carcinomas (2012)
  • Author(s): Suzuki, S., Dobashi, Y., Minato, H., Tajiri, R., Yoshizaki, T, Ooi, A.
  • Journal Title: Virc hows Archiv Volume: 461(3) Pages: 271-82
  • Peer Reviewed
• [Journal Article] Pulmonary Mucosa-associated Lymphoid Tissue (MALT) lymphoma in Sjögren's syndrome showing only the LIP pattern radiologically (2012)
  • Author(s): Watanabe, Y., Koyama, S., Miwa, C., Okuda, S., Kanai, Y., Tetsuka, K., Nokubi, M., Dobashi, Y., Kawabata, Y., Kanda, Y., Endo, S.
  • Journal Title: Intern Med. Volume: 51(5) Pages: 491-5
  • Peer Reviewed
• [Journal Article] Molecularly Targeted Therapy : Great progress or Evil cycle (2012)
  • Author(s): Dobashi, Y
  • Journal Title: Chemotherapy Volume: 1(3) Pages: 1-2
  • Peer Reviewed
• [Journal Article] Molecularly Targeted Therapy : Past, Present and Future (2012)
  • Author(s): Dobashi, Y., Goto, A., Kimura, M., Nakano, T.
  • Journal Title: Chemotherapy Volume: e1 Pages: 105
  • Peer Reviewed
• [Journal Article] Paradigm of kinase-driven pathway downstream of EGFR/Akt in human lung carcinomas (2011)
  • Author(s): Dobashi, Y., Suzuki, S., Kimura, M., Matsubara, H., Tsubochi, H., Imoto, I.,Ooi, A.
  • Journal Title: Hum. Pathol Volume: 42(2) Pages: 214-26
  • Peer Reviewed
• [Journal Article] Accumulation of AGEs and VEGF in eyes of SDT rats (2011)
  • Author(s): Toyoda, F., Kakehashi, A., Hashimoto, K., Kinoshita, N., Kambara, C., Yamagami, H., Tamemoto, H., Ishikawa, S., Dobashi, Y., Kawakami, M., Kanazawa, Y.
  • Journal Title: Open Diab. J Volume: 4 Pages: 41-44
  • Peer Reviewed
• [Journal Article] Prevention of proliferative diabetic retinopathy and cataract in SDT rats with aminoguanidine, an anti-advanced glycation end product agent (2011)
  • Author(s): Toyoda, F., Kakehashi, A., Ohta, A., Kinoshita, N., Kambara, C., Yamagami, H., Tamemoto, H., Ueba, H., Dobashi, Y., Ishikawa, S., Kawakami, M., Kanazawa, Y.
  • Journal Title: Open Diab. J Volume: 4 Pages: 108-113
  • Peer Reviewed
• [Journal Article] Effects of topical nipradilol on early diabetic retinopathy in SDT rats (2011)
  • Author(s): Kinoshita, N., Kakehashi, A., Dobashi, Y., Ono, R., Toyoda, F., Kambara, C., Yamagami, H., Kitazume, Y., Kobayashi, E., Osakabe, Y., Kudo, M., Kawakami, M., Kanazawa, Y.
  • Journal Title: Open Diab. J Volume: 4 Pages: 114-118
  • Peer Reviewed
• [Journal Article] Regression of multiple duodenal hyperplastic polyps following Helicobacter pylori eradicatio (2011)
  • Author(s): Ugajin T, Miyatani H, Demitsu T, Iwaki T, Ushimaru S, Nakashima Y, Dobashi, Y., Yoshida Y.
  • Journal Title: Digestive Endoscopy Volume: 23(4) Pages: 328
  • Peer Reviewed
• [Journal Article] Kinase-driven pathways downstream of EGFR in human lung carcinomas : perspectives on molecular targeting therapy (2011)
  • Author(s): Dobashi, Y., Koyama, S., Kanai, Y., and Tetsuka, K.
  • Journal Title: Front Biosci. Volume: 16 Pages: 1714-32
  • Peer Reviewed
• [Journal Article] Mammalian target of rapamycin : a central node of complex signaling cascades (2011)
  • Author(s): Dobashi, Y., Watanabe, Y., Miwa, C., Suzuki, S., Koyama, S.
  • Journal Title: Int J Clin Exp Pathol Volume: 4(5) Pages: 476-495
  • Peer Reviewed
• [Journal Article] Clonal profiling of mixed lobular and ductal carcinoma revealed by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization
  • Author(s): Tajiri, R., Inokuchi, M., Sawada-Kitamura, S., Kawashima, H., Nakamura, R., Oyama, T., Dobashi, Y., Ooi, A.
  • Journal Title: Pathol. Int. Volume: (in press)
  • Peer Reviewed
• [Presentation] ヒト肺癌におけるAKT遺伝子, 蛋白質の異常とその意義 (2014)
  • Author(s): 土橋洋, 椙村春彦, 山田茂樹, 大井章史
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島
  • Year and Date: 2014-04-24
• [Presentation] Multiplex ligation-dependent probe amplificationとFISHを用いた胃癌における遺伝子増幅の準網羅的検索 (2014)
  • Author(s): 大井章史, 田尻亮輔, 中村律子, 尾山武, 池田博子, 土橋洋
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島
  • Year and Date: 2014-04-24
• [Presentation] FISHとMLPAを用いた胃癌におけるHER2遺伝子増幅の腫瘍内不均一性の検討 (2013)
  • Author(s): 大井章史, 田尻亮輔, 中村律子, 尾山武, 藤村隆, 土橋洋
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-03
• [Presentation] Significance of Akt activation and AKT gene increases in bone and soft tissue tumors (2013)
  • Author(s): 土橋洋, 小田義直, 稲澤譲治, 大井章史
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-03
• [Presentation] 骨軟部腫瘍におけるAKT遺伝子の異常と蛋白活性化 (2013)
  • Author(s): 土橋洋, 蛭田昌宏, 椙村春彦, 山田茂樹, 大井章史
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2013-06-06
• [Presentation] Utility of FISH to Detect MDM2 Amplification in Liposarcomas and their Morphologic Mimics (2013)
  • Author(s): 大井章史, 土橋洋, 野島孝之, 池田博子, 北村星子, 尾山武
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2013-06-06
• [Presentation] Comparative study of Multiplex ligation-dependent probe amplification and FISH to determine gene amplification in breast cancers (2012)
  • Author(s): 大井章史, 井口雅史, 土橋洋, 田尻亮輔
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-21
• [Presentation] Multiplex ligation-dependent probe amplification法を用いた乳癌の遺伝子増幅の検討 (2012)
  • Author(s): 大井章史, 田尻亮輔, 鈴木潮人, 北村星子, 池田博子, 土橋洋
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-04-27
• [Presentation] ヒト肺癌におけるAKT遺伝子の異常とその意義. (2012)
  • Author(s): 土橋洋, 蛭田昌宏, 椙村春彦, 鈴木潮人, 山田茂樹, 大井章史
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-04-27
• [Presentation] 唾液腺癌におけるEGFR/HER2-Akt-mTORシグナル伝達経路の解析 (2012)
  • Author(s): 鈴木潮人, 土橋洋, 湊宏, 田尻亮輔, 大井章史
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-04-26
• [Presentation] 術中胸水の細胞診標本に病原体と考えられる胞子虫様の原虫を認めた膿胸の一例 (2012)
  • Author(s): 野首光弘, 大木麻衣, 中村啓子, 河野哲也, 土橋洋
  • Organizer: 第51回日本臨床細胞学会総会
  • Place of Presentation: 千葉
  • Year and Date: 2012-03-22
• [Presentation] HSR-like FISH signals of ESR1 in breast carcinomas do not reflect the gene amplification but correlate with the high gene expression status (2011)
  • Author(s): 大井章史, 井口雅史, 原田真市, 鈴木潮人, 土橋洋
  • Organizer: 第70回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-04
• [Presentation] 唾液腺癌におけるEGFR, HER2遺伝子増幅および蛋白過剰発現 (2011)
  • Author(s): 鈴木潮人, 湊宏, 土橋洋, 田尻亮輔, 大井章史
  • Organizer: 唾液腺癌におけるEGFR, HER2遺伝子増幅および蛋白過剰発現
  • Place of Presentation: 東京
  • Year and Date: 2011-04-30
• [Presentation] FISHを用いた大腸癌におけるEGFR遺伝子の増幅の検討 (2011)
  • Author(s): 大井章史, 鈴木潮人, 田尻亮輔, 土橋洋, 源利成
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-04-29
• [Presentation] 肺癌におけるエフェクター分子Aktの活性化と遺伝子変化 (2011)
  • Author(s): 土橋洋, 鈴木潮人, 椙村春彦, 山田茂樹, 大井章史
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-04-28
• [Book] Prophylactic Medical Treatment of Diabetic Retinopathy (2012)
  • Author(s): Kakehashi, A., Ota, A., Toyoda, F., Kinoshita, N., Yamagami, H., Obata, H., Matsumoto, H., Tsuji, J., Dobashi, Y., Fujimoto, W.Y., Kawakami, M. and Kanazawa Y.
  • Total Pages: 291-304
  • Publisher: Diabetic Retinopathy
• [Book] 病理診断に役立つ分子生物学(金井弥栄, 石川俊平, 池田栄二編) (2011)
  • Author(s): 土橋洋
  • Total Pages: 98-106頁
  • Publisher: 文光堂,(東京)