Analysis of molecular mechanism forEML4-ALK/ EGFR-TKI resistance and establishment of less invasive diagnosis.

• Project/Area Number: 25462202
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory surgery
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: URAMOTO Hidetaka 産業医科大学, 医学部, 准教授 (90389445)
• Co-Investigator(Kenkyū-buntansha): SO Tomoko 産業医科大学, 医学部, 講師 (00341529) ; TANAKA Fumihiro 産業医科大学, 医学部, 教授 (10283673)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: EML4-ALK / EGFR-TKI / 耐性 / 診断 / 循環腫瘍細胞

Outline of Final Research Achievements

Lung cancer is the leading cause of cancer deaths, which is mainly caused by its resistance to conventional treatment modalities. In fact, some targeting agents are very active to specific population of patients, but most patients who had once responded to these agents finally experience disease progression. The aim of the current study is to reveal biological mechanism of drug resistance using clinical materials, and to develop and establish clinically useful modalities to detect drug resistance. In the study, we identified MED12 as an important molecule associated with resistance to some targeting agents, and documented positive expression of MED12 in 92% of 89 lung cancer tissues. In addition, we have developed a novel detection system of circulating tumor cell (CTC). The CTC-chip system, an alternative of the CellSearch system, has provided sensitive efficiency of 85% in capturing tumor cells spiked in the blood, and can be potentially useful for clinical use.

Research Products

• [Journal Article] ZEB1 Mediates Acquired Resistance to the Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. (2016)
  • Author(s): Yoshida T, Song L, Bai Y, Kinose F, Li J, Ohaegbulam KC, Munoz-Antonia T, Qu X, Eschrich S, Uramoto H, Tanaka F, Nasarre P, Gemmill RM, Roche J, Drabkin HA, Haura EB.
  • Journal Title: PLoS One Volume: 11(1) Issue: 1 Pages: e0147344-e0147344
  • DOI: 10.1371/journal.pone.0147344
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TMPRSS4 Expression as a Marker of Recurrence in Patients with Lung Cancer. (2016)
  • Author(s): Chikaishi Y, Uramoto H, Koyanagi Y, Yamada S, Yano S, Tanaka F.
  • Journal Title: Anticancer Res. Volume: 36 Pages: 121-127
  • Peer Reviewed
• [Journal Article] Comment on ‘Simultaneous Stapling of Pulmonary Vein and Bronchus in Video-Assisted Thoracic Surgery Lobectomy’ (2016)
  • Author(s): Uramoto H, Yamada S, Nakajima Y, Kinoshita H.
  • Journal Title: Annals of Thoracic and Cardiovascular Surgery Volume: 22 Issue: 3 Pages: 196-197
  • DOI: 10.5761/atcs.lte.15-00224
  • NAID: 130005157592
  • ISSN: 1341-1098, 2186-1005
• [Journal Article] Intraoperative ultrasound elastography has little diagnostic benefit for deeper tumours of the lung. (2016)
  • Author(s): Uramoto H, Nakajima Y, Ohtaki K, Kinoshita H.
  • Journal Title: Eur J Cardiothorac Surg. Volume: 49 Issue: 5 Pages: 1538-1539
  • DOI: 10.1093/ejcts/ezv340
  • Peer Reviewed
• [Journal Article] rognostic impact of clinical variables on surgically resected small-cell lung cancer: Results of a retrospective multicenter analysis (FIGHT002A and HOT1301A) (2015)
  • Author(s): Yokouchi H, Ishida T, Yamazaki S, Kikuchi H, Oizumi S, Uramoto H, Tanaka F, Harada M, Akie K, Sugaya F, Fujita Y, Fukuhara T, Takamura K, Kojima T, Harada T, Higuchi M, Matsuura Y, Honjo O, Minami Y, Watanabe N, Nishihara H, Suzuki H, Dosaka-Akita H, Isobe H, Nishimura M, Munakata M
  • Journal Title: Lung Cancer Volume: 90 Issue: 3 Pages: 548-53
  • DOI: 10.1016/j.lungcan.2015.10.010
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Careful diagnosis of aortic invasion in patients with lung cancer using modern diagnostic imaging. (2015)
  • Author(s): Uramoto H, Kinoshita H.
  • Journal Title: Asian Pac J Cancer Prev. Volume: 16 Issue: 5 Pages: 2105-2105
  • DOI: 10.7314/apjcp.2015.16.5.2105
  • Peer Reviewed
• [Journal Article] The 30-day mortality and hospital mortality after chest surgery described in the annual reports published by the Japanese Association for Thoracic and Cardiovascular Surgery. (2015)
  • Author(s): Uramoto H, Okumura M, Endo S, Tanaka F, Yokomise H, Masuda M.
  • Journal Title: Gen Thorac Cardiovasc Surg. Volume: 63(5) Issue: 5 Pages: 279-83
  • DOI: 10.1007/s11748-015-0524-0
  • Peer Reviewed
• [Journal Article] Possibility of determining the degree of adhesion of the lymph node to the pulmonary artery preoperatively. (2015)
  • Author(s): Uramoto H, Nozu S, Nakajima Y, Kinoshita H.
  • Journal Title: J Cardiothorac Surg. Volume: 10 Issue: 1 Pages: 101-101
  • DOI: 10.1186/s13019-015-0310-1
  • Peer Reviewed / Open Access
• [Journal Article] Easy Diagnosis of Aortic Invasion in Patients with Lung Cancer Using Cine Magnetic Resonance Imaging. (2015)
  • Author(s): Uramoto H, Kinoshita H, Nakajima Y, Akiyama H.
  • Journal Title: Case Rep Oncol. Volume: 8 Issue: 2 Pages: 308-311
  • DOI: 10.1159/000438823
  • Peer Reviewed
• [Journal Article] In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line. (2015)
  • Author(s): Nanjo S, Yano S, et al.
  • Journal Title: Cancer Sci Volume: 106 Issue: 3 Pages: 244-52
  • DOI: 10.1111/cas.12600
  • NAID: 120005830611
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Anomalous pulmonary arterial supply to the pulmonary vein of the right lung: An extremely exceptional case of arterial vein fistulae. (2015)
  • Author(s): Kinoshita, Nakajima Y, Uramoto H
  • Journal Title: Ann Thorac Surg. Volume: 100 Issue: 5 Pages: 1913-1913
  • DOI: 10.1016/j.athoracsur.2015.07.021
  • Peer Reviewed
• [Journal Article] Postoperative bleeding after surgery in patients with lung cancer (2013)
  • Author(s): Uramoto H, Shimokawa H, Tanaka F
  • Journal Title: Anticancer Res Volume: 34 Pages: 981-984
  • Peer Reviewed
• [Journal Article] Erlotinib resistance in lung cancer cells mediated by integrinβ1/Src/Akt-driven bypass signaling (2013)
  • Author(s): Kanda R, Kawahara A, Watari K, Murakami Y, Sonoda K, Maeda M, Fujita H, Kage M, Uramoto H, Costa C, Kuwano M, Ono M(12人中9番目）
  • Journal Title: Cancer Res Volume: 73 Pages: 6243-53
  • Peer Reviewed
• [Journal Article] Angiogenesis of Lung Cancer Utilizes Existing Blood Vessels Rather than Developing New Vessels Using Signals from Carcinogenesis (2013)
  • Author(s): Uramoto H, Yamada S, Tanaka F
  • Journal Title: Anticancer Res Volume: 33 Pages: 1913-6
  • Peer Reviewed
• [Journal Article] Clinical Significance of Expression of Cancer/testis Antigen and Down-regulation of HLA Class-I in Patients with Stage I Non-small Cell Lung Cancer (2013)
  • Author(s): Hanagiri T, Shigematsu Y, Shinohara S, Takenaka M, Oka S, Chikaishi Y, Nagata Y, Baba T, Uramoto H, So T, Yamada S（11人中9番目）
  • Journal Title: Anticancer Res Volume: 33 Pages: 2123-8
  • Peer Reviewed
• [Journal Article] Association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never-smoker women with pulmonary adenocarcinoma. (2013)
  • Author(s): Uramoto H, Tanaka F.
  • Journal Title: Cancer Volume: 119 Issue: 14 Pages: 2660-2660
  • DOI: 10.1002/cncr.28095
  • Peer Reviewed
• [Journal Article] Prognostic Factors and the Significance of Treatment After Recurrence in Completely Resected Stage I Non-small Cell Lung Cancer. (2013)
  • Author(s): Shimada Y, Saji H, Yoshida K, Kakihana M, Honda H, Nomura M, Usuda J, Kajiwara N, Ohira T, Ikeda N
  • Journal Title: Chest Volume: 143 Issue: 6 Pages: 1626-1634
  • DOI: 10.1378/chest.12-1717
  • Peer Reviewed
• [Journal Article] Intrapleural chemotherapy improves the survival of non-small cell lung cancer patients with positive pleural lavage cytology. (2013)
  • Author(s): Baba T, Uramoto H, Kuwata T, Takenoyama M, Chikaishi Y, Oka S, Nagata Y, Shigematsu Y, Shimokawa H, Nakagawa M, So T, Hanagiri T, Tanaka F.
  • Journal Title: Surg Today Volume: 43 Issue: 6 Pages: 648-53
  • DOI: 10.1007/s00595-012-0281-y
  • NAID: 10031176087
  • Peer Reviewed
• [Journal Article] Serum Level of Osteopontin as a Prognostic Factor in Patients Who Underwent Surgical Resection for Non-Small-Cell Lung Cancer (2013)
  • Author(s): Takenaka M, Hanagiri T, Shinohara S, Yasuda M, Chikaishi Y, Oka S, Shimokawa H, Nagata Y, Nakagawa M, Uramoto H, So T, Yamada S, Tanaka F（13人中10番目）
  • Journal Title: Clin Lung Cancer Volume: 14 Issue: 3 Pages: 288-94
  • DOI: 10.1016/j.cllc.2012.09.005
  • Peer Reviewed
• [Journal Article] Discriminative features of thin-slice CT for peripheral intrapulmonary lymph nodes. (2013)
  • Author(s): Takenaka M, Uramoto H, Shimokawa H, So T, Hanagiri T, Aoki T, Tanaka F.
  • Journal Title: Asian J Surg Volume: 36 Issue: 2 Pages: 69-73
  • DOI: 10.1016/j.asjsur.2012.11.005
  • Peer Reviewed
• [Journal Article] Prognostic implications of human leukocyte antigen class I expression in patients who underwent surgical resection for non-small-cell lung cancer (2013)
  • Author(s): Hanagiri T, Shigematsu Y, Kuroda K, Baba T, Shiota H, Ichiki Y, Nagata Y, Yasuda M, Uramoto H, So T, Takenoyama M, Tanaka F（12人中9番目）
  • Journal Title: J Surg Res Volume: 181 Pages: 57-63
  • Peer Reviewed
• [Journal Article] Preoperative embolization followed by palliative therapy for patients unable to undergo the complete removal of a chronic expanding hematoma: A report of a case (2013)
  • Author(s): Kuwata T, Uramoto H, Oka S, Hidehiko Shimokawa H, Shigematsu Y, Baba T, Hanagiri T, Tanaka F（8人中2番目）
  • Journal Title: Asian J Surg Volume: 36 Issue: 1 Pages: 40-2
  • DOI: 10.1016/j.asjsur.2012.06.006
  • Peer Reviewed
• [Journal Article] Cancer/testis antigen expression as a predictor for epidermal growth factor receptor mutation and prognosis in lung adenocarcinoma (2012)
  • Author(s): Baba T, Tanaka F(8人中8番目)
  • Journal Title: Eur J Cardiothorac Surg. Volume: 43 Issue: 4 Pages: 759-764
  • DOI: 10.1093/ejcts/ezs426
  • Peer Reviewed
• [Presentation] 症例に学ぶ最新診断・治療テクニック 特別シンポジウム：ハンズオン＋症例提示 (2015)
  • Author(s): 浦本秀隆
  • Organizer: 第55回日本肺癌学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-11-26
• [Presentation] 症例提示：化学放射線療法後 救済手術が実施された肺腺癌の一例 (2015)
  • Author(s): 浦本秀隆
  • Organizer: 第55回日本肺癌学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-11-26
• [Presentation] 症例提示：左上葉管状切除、２連銃型気管支再建術及び肺動脈合併切除、再建を施行した左肺癌の１切除例 (2015)
  • Author(s): 浦本秀隆
  • Organizer: 第55回日本肺癌学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-11-26
• [Presentation] Capture of EpCAM-negative circulating tumor cells (CTCs) with a “Universal CTC-Chip” (2015)
  • Author(s): Yoneda K, Chikaishi Y, Kawashima E, So T, Uramoto H, Ohnaga T, Tanaka F
  • Organizer: AACR Annual Meeting 2015
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-18
  • Int'l Joint Research
• [Presentation] 融合遺伝子がもたらす新しいがん治療 TGFβ経路によるALK阻害剤耐性 (2013)
  • Author(s): 浦本秀隆
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] EML4-ALK、及びEGFR-TKIに対する耐性関連分子MED12に基づく新しい肺癌治療の戦略 (2013)
  • Author(s): 浦本秀隆、平良彰浩、竹中 賢、近石泰弘、岡壮一、下川秀彦、宗知子、花桐武志、田中文啓
  • Organizer: 第52回日本肺癌学会総会
  • Place of Presentation: ホテルニューオータニ東京
• [Presentation] Novel malignant-mesothelioma-associated antigens (Gene-X and THBS-2) in the diagnosis of malignant pleural mesothelioma (MPM) (2013)
  • Author(s): Tanaka F, Shigematsu Y, Hanagiri T， Uramoto H, So T, Yoneda K, Takuwa T, Hashimoto M, Matsumoto S, Okumura Y, Kondo N, Hasegawa S
  • Organizer: 49ｔｈ American Society of clinical oncology
  • Place of Presentation: Chicago,USA
• [Presentation] Development of detecting systems for circulating tumor cells in malignant pleural mesothelioma patients (2013)
  • Author(s): Chikaishi Y, So T, Oka S, Takenaka M, Nakagawa M, Shimokawa H, Iwata T, Nagata Y, Uramoto H, Hanagiri T, Ohnaga T, Uramoto H, Tanaka F
  • Organizer: AACR (The American Association for Cancer Research) Meeting
  • Place of Presentation: Washington,USA