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姓名:吳漢忠

職稱:研究員

電話: 02-2789-9528

專長:Molecular Biology,
Cell Biology

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研究人員 / 簡介

2010- Research Fellow, Institute of Cellular and Organismic Biology, Academia Sinica
2010- Professor, Institute of Pathology and Graduate Institute of Oral Biology, National Taiwan University
2010- Joint Appointment Research Fellow, Genomics Research Center, Academia Sinica
201905- Acting-CEO, National Biotechnology Research Park/BioHub Taiwan
2016-2018, Director, Department of Intellectual Property and Technology Transfer, Academia Sinica
2017-2018, Acting Director, Institute of Cellular and Organismic Biology, Academia Sinica
2010-2016, Vice Director in Institute of Cellular and Organismic Biology, Academia Sinica
1993, Ph.D. Institute of Pathology, National Taiwan University, Taiwan
   

吳漢忠 老師 實驗室

  • 癌症之標靶蛋白及標靶治療研究與影像研究

           癌症是人類最常見的死因之一,全世界每年的死亡人數已經超過八百萬人。而化學療法易產生抗藥性,是治療癌症失敗的主因。化學療法為了避免抗癌藥物造成正常組織毒性而產生的副作用,常常只能給予次適當濃度的抗癌藥物,因此伴隨著抗藥性以及癌細胞轉移的發生,終究造成治療的失敗。因此,標靶藥物傳輸系統能夠減低藥物的副作用,增加抗癌療效,有希望發展成為新的癌症療法。近年來,本實驗室為了解決此問題,發展出一套噬菌體顯現法(Phage display)來尋找癌細胞、腫瘤幹細胞或腫瘤血管上的特殊表現受體。2018諾貝爾化學獎得獎者為史密斯(George P. Smith )和溫特(Gregory P. Winter),史密斯發展噬菌體顯現法顯現胜肽庫,應用於開發新蛋白質,溫特則是利用噬菌體顯現法顯現抗體庫,開發專一性抗體。利用此方法首次開發出治療性抗體藥物adalimumab (Humira),對抗TNF-a,被批准用於治療自體免疫疾病。我們已經利用噬菌體顯現法技術,成功地研發出高品質之人類抗體庫(Library size: 6 × 1010),搭配親和力成熟技術,針對數種癌症和感染性疾病,成功研發出超過15個具有潛力運用於治療與診斷之人類抗體。
           利用噬菌體顯現法胜肽庫與抗體庫的方法,我們已經尋獲許多能導向癌細胞、腫瘤血管、醣抗原與特殊受體之標靶胜肽與人類抗體。為了進一步發展標靶治療,我們將標靶配體接合微脂體抗癌藥物,用以治療移殖人類腫瘤的免疫不全鼠。具有標靶配體功能的帶藥微脂體能更有效的抑制腫瘤生長,顯示較佳的治療效果,以及無明顯副作用等優點,未來具有臨床潛力運用在癌症的標靶治療、以及設計標靶基因轉換載體等(Sci Transl Med 2015)。 並且,我們將標靶胜肽或抗體接合至量子點或超順磁氧化鐵奈米粒子,進行活體腫瘤造影分析。運用螢光或MRI系統分析,我們發現標靶胜肽可更為精準、有效率的將顯影試劑運送至腫瘤組織而加強成像,在未來可幫助癌症的診斷與早期偵測。
            針對男性極為好發的前列腺癌,我們也篩選出專一性的胜肽,並已確認此胜肽能辨認前列腺癌細胞株及前列腺癌之臨床檢體。將胜肽接合在螢光物質量子粒(quantum dots)或超順磁氧化鐵微粒(superparamagnetic iron oxide nanoparticles, SPIONs)上,發展成MRI活體造影,可精準測出腫瘤的位置。在小鼠的腫瘤異體移植(xenograft)及原位癌(orthotopic)模式中,以帶有專一性胜肽之艾黴素(doxorubicin)或溫諾平(vinorelbine)的微脂體進行治療,能夠加強對癌症的治療效果,並且延長小鼠的存活時間。研究成果證明此專一性胜肽,對於前列腺癌治療及分子影像有極大的應用潛力。此成果已申請全球專利,且論文已發表於著名的生物材料期刊(Biomaterials 2016)。
           肺癌位居全世界癌症死亡率之首。我們篩選出數條能與肺癌細胞專一性結合之標靶胜肽。其中,三條標靶胜肽 (HSP1、HSP2和HSP4)對於肺癌細胞有高度的專一性與親和力,且不會與正常細胞結合。在非小細胞肺癌的動物模式中,發現HSP1、HSP2和HSP4接合的標靶微脂體具有顯著療效。在細胞株及肺癌病人組織切片的免疫染色發現這三條胜肽可以辨識非小細胞肺癌(包括:肺腺癌、鱗狀細胞癌和大細胞癌) 及小細胞肺癌。因此,這三條胜肽可用於不同亞型 (subtype) 的肺癌病人做出最佳的治療策略,亦可發展成活體造影或組織病理學上的偵檢試劑,極具臨床潛力。此部分成果已申請全球專利,且論文已被重要的癌症治療及診斷期刊接受(Theranostics 2017)。

    登革病毒研究

           登革病毒的感染會引起登革熱,全球有40%的人口生活在可能被感染的危險區域,每年約有三億九千萬個登革熱病例產生,其中約有五十萬人會引起嚴重的出血性登革熱或是登革休克症候群。目前尚無可以專一性分辨四型登革病毒之抗原(蛋白或胜肽),也無有效且安全的疫苗及專一性的治療性抗體。而登革出血熱之致病機轉,是經由不同型登革病毒間交叉感染;或是病毒與宿主間一次感染的交互作用;或是病毒感染後所產生的免疫病理反應,至今仍尚未定論。為了解決這些問題,本實驗室建立多株對抗四型登革病毒之單株抗體,藉由研究這些抗體的B細胞抗原決定位(epitopes),來了解登革病毒:(1)專一性及中和性的抗原決定位(JGV 2003; CVI 2007; PLoS NTD 2012; Adv Health Mat 2014);(2)致病性與自體抗體抗原決定位之位置(JV 2008; JBC 2011; PLoS NTD 2015; PLoS One 2015),運用冷凍電子顯微鏡(Cryo-EM) 技術,研究抗體依賴性增強作用(antibody-dependent enhancement, ADE)之分子機轉,進一步釐清登革出血熱之致病機轉;(3)研發登革熱之治療性抗體(PLoS NTD 2012)及安全有效之登革熱疫苗(PLoS NTD, 2015);(4)研發不分型及分型之快篩試劑,已成功開發可專一辨別四種登革血清型之抗體,用以研發高靈敏度和高專一性之偵檢套組。我們所研發之偵檢套組,不僅檢測靈敏度優於市售之試劑外(Int J Mol Sci 2015; Am J Trop Med Hyg 2017),也能解決目前市售快篩試劑無法分型之問題。另外,我們也成功發展出可以治療登革病毒第二型及第四型感染的單株抗體。未來,將進一步運用Cryo-EM及X-ray crystallography研究登革抗原-抗體結構及其致病機轉。

     

  • 姓名職稱電話Email備註
    吳漢忠研究員02-2789-9558
    hcw0928@gate.sinica.edu.tw
  • 著作目錄

    1. Kuan, I. I., Chen, C. H., Lu, J. and Wu, H. C.* (2019). The extracellular domain of epithelial cell adhesion molecule (EpCAM) enhances multipotency of mesenchymal stem cells through EGFR-LIN28-LET7 signaling. Journal of Biological Chemistry 294, 7769-7786.
    2. Huang, J. R., Lee, M. H., Li, W. S. and Wu, H. C.* (2019). Liposomal irinotecan for treatment of colorectal cancer in a preclinical model. Cancers 11, 281.
    3. Liang, K. H., Tso, H. C., Hung, S. H., Kuan, I. I., Lai, J. K., Ke, F. Y., Chuang, Y. T., Liu, I. J., Wang, Y. P., Chen, R. H. and Wu, H. C.* (2018). Extracellular domain of EpCAM enhances tumor progression through EGFR signaling in colon cancer cells. Cancer Letters 433, 165-175.
    4. Huang, S. T., Wang, Y. P., Chen, Y. H., Lin, C. T., Li, W. S. and Wu, H. C.* (2018). Liposomal paclitaxel produces fewer hematopoietic and cardiovascular complications than bioequivalent doses of Taxol. International Journal of Oncology 53, 1105-1117.
    5. Wu, C. H., Lan, C. H., Wu, K. L., Wu, Y. M., Jane, W. N., Hsiao, M., and Wu, H. C.* (2018). Hepatocellular carcinoma-targeted nanoparticles for cancer therapy. International Journal of Oncology 52, 389-401.
    6. Chi, Y. H., Hsiao, J. K., Lin, M. H., Chang, C, Lan, C. H. and Wu, H. C.* (2017). Lung cancer-targeting peptides with multi-subtype indication for combinatorial drug delivery and molecular imaging. Theranostics 7, 1612-1632.
    7. Kuan, I. I., Liang, K. H., Wang, Y. P., Kuo, T. W., Meir, Y. J. J., Wu, S. C. Y., Lu, J., and Wu, H. C.* (2017). EpEX/EpCAM and Oct4 or KLF4 alone are sufficient to generate induced pluripotent stem cells through STAT3 and HIF2Scientific Reports 7: 41852.
    8. Tang, Y. L., Liu, I. J., Li, P. C., Chiu, C. Y., Lin, C. Y., Huang, C. H., Chen, Y. H., Fu, C. Y., Chao, D. Y., King, C. C., and Wu, H. C.* (2017). Generation and characterization of anti-NS1 monoclonal antibodies and development of diagnostics for dengue virus type 2. The American Journal of Tropical Medicine and Hygiene 97, 1049-1061.
    9. Yeh, C. Y., Hsiao, J. K., Wang, Y. P., Lan, C. H. and Wu, H. C.* (2016). Peptide-conjugated nanoparticles for targeted imaging and therapy of prostate cancer. Biomaterials 99, 1-15.
    10. Wu, C. H., Liu, I. J., Lu, R. M. and Wu, H. C.* (2016). Advancement and applications of peptide phage display technology in biomedical science. Journal of Biomedical Science 23, 8.
    11. Abdu-Allah, H. M., Huang, S. T., Chang, T. T., Chen, C. L., Wu, H. C.* and Li, W. S.* (2016). Nature-inspired design of tetraindoles: optimization of the core structure and evaluation of structure-activity relationship. Bioorganic & Medicinal Chemistry Letters 26, 4497 - 4503.
    12. Wu, C. H., Kuo, Y. H., Hong, R. L., Wu, H. C.* (2015). α-Enolase-binding peptide enhances drug delivery efficiency and therapeutic efficacy against colorectal cancer. Science Translational Medicine 7, 290ra91, 1-14.
    13.  Liao, M. Y., Lai, J. K., Kuo, M. Y. P., Lu, R., Lin, C. W., Cheng, P. C., Liang, K. H., Wu, H. C.* (2015). An anti-EpCAM antibody EpAb2-6 for the treatment of colon cancer. Oncotarget 6, 24947-24968.
    14. Tang, C.T., Li, P. C., Liu, I. J., Liao, M. Y., Chiu, C. Y., Chao, D. Y., Wu, H. C.* (2015). An epitope-substituted DNA vaccine improves safety and immunogenicity against dengue virus type 2. PLoS Neglected Tropical Diseases 9, e0003903.
    15. Tang, Y. L., Chiu, C. Y., Lin, C. Y., Huang, C. H., Chen, Y. H., Destura, R. V., Chao, D. Y., Wu, H. C.* (2015). Establishment and comparison of two different diagnostic platforms for detection of DENV1 NS1 protein. International Journal of Molecular Sciences 16, 27850–27864.
    16. Liao, M. Y., Kuo, M. Y. P., Lu, T. Y., Wang, Y. P., Wu, H. C.* (2015). Generation of an anti-EpCAM antibody and epigenetic regulation of EpCAM in colorectal cancer. International Journal of Oncology 46, 1788-1800.
    17. Tang, C. T., Liao, M. Y., Chiu, C. Y., Shen, W. F., Chiu, C. Y., Cheng, P. C., Chang, G. J. J., Wu, H. C.* (2015). Generation of monoclonal antibodies against dengue virus type 4 and identification of enhancing epitopes on envelope protein. PLoS ONE 10, e0136328.
    18. Hsiao, J. K., Liau, H. W., A. Yu, Wu, H. C.*, Lin, C.T.* (2015). A multifunctional peptide for targeted imaging and chemotherapy for nasopharyngeal and breast cancers. Nanomedicine: NBM 11, 1425-1434.
    19. Shen, Y. A., Liu, C. S., Chang, Y. H., Chen, P. H., He, C. L., Wu, H. C.* and Chuang, C. M.* (2015). Subtype-specific binding peptides enhance therapeutic efficacy of nanomedicine in the treatment of ovarian cancer. Cancer Letters 360, 39-47.
    20.  Lin, C. W., Sun, M. S., Liao, M. Y., Chung, C. H., Chi, Y. H., Chiou, L. T., Yu, J., Lou, K. L., and Wu, H. C.* (2014) Podocalyxin-like 1 promotes invadopodia formation and metastasis through activation of Rac1/Cdc42/Cortactin signaling in breast cancer cells. Carcinogenesis 35, 2425-2435.
    21. Lin, C. W., Sun, M. S. and Wu, H. C.* (2014) Podocalyxin-like 1 is associated with tumor aggressiveness and metastatic gene expressions in human oral squamous cell carcinoma. International Journal of Oncology 45, 710-718.
    22. Wang, H. K., Tsai, C. H., Chen, K. H., Tang, C. T., Leou, J. S., Li, P. C., Tang, Y. L., Hsieh, H. J., Wu, H. C.* and Cheng, C. M.* (2014) Cellulose-based diagnostic devices for diagnosing serotype-2 dengue fever in human serum. Advanced Healthcare Materials 3, 187-196.
    23. Wu, J. C., Tseng, P. Y., Tsai, W. S., Liao, M. Y., Lu, S. H., Frank, C. W., Chen, J. S., Wu, H. C.* and Chang, Y. C.* (2013) Antibody conjugated supported lipid bilayer for capturing and purification of viable tumor cells in blood for subsequent cell culture. Biomaterials 34, 5191-5199.
    24. Wang, Y. P., Liu, I. J., Chiang, C. P. and Wu, H. C.* (2013) Astrocyte elevated gene-1 is associated with metastasis in head and neck squamous cell carcinoma through p65 phosphorylation and upregulation of MMP1. Molecular Cancer 12, 109.
    25. Tung, K. H., Lin, C.W., Kuo, C.C., Li, L.T., Kuo, Y.H., Lin, C.W., and Wu, H. C.* (2013) CHC promotes tumor growth and angiogenesis through regulation of HIF-1 and VEGF signaling. Cancer Letters 331, 58-67. 5.992.
    26. Chang, D. K., Li, P.C., Jane, W. N. and Wu, H. C.* (2013) Peptide-mediated Liposomal Doxorubicin Enhances Drug Delivery Efficiency and Therapeutic Efficacy in Animal Models. PLoS ONE 8, e83239.
    27. Lu, R. M., Chen, M. S., Chang, D. K., Chiu C. Y., Lin, W. C., Yan, S. L., Wang, Y. P., Kuo, Y. S., Lo, A. and Wu, H. C.* (2013) Targeted drug delivery systems mediated by a novel peptide in breast cancer therapy and imaging. PLoS ONE 8, e66128.
    28. Lin, C. W., Liao, M. Y., Lin, W. W., Wang, Y. P., Lu, T.Y. and Wu, H. C.* (2012) Epithelial cell adhesion molecule regulates tumor initiation and tumorigenesis via activating reprogramming factors and epithelial-mesenchymal transition genes expression in colon cancer. Journal of Biological Chemistry 287, 39449-39459.
    29. Li, P. C., Liao, M. Y., Cheng, P. C., Liang, J. J., Liu, I. J., Chiu, C. Y., Lin, Y. L., Chang, G. J. J. and Wu, H. C.* (2012) Development of a humanized antibody with high therapeutic potential against dengue virus type 2. PLoS Neglected Tropical Diseases 6, e1636.

     

    *Corresponding author

     

     

     

     
  • 2008 Academia Sinica Young Investigator Award (2008年中央研究院年輕學者研究著作獎)
    2010 Yung-Shing Young Investigator Award (2010年第五屆永信李天德醫藥科技獎)
    2011 8th National Innovation Award (2011 第八屆國家新創獎)
    2012 9th National Innovation Award (2012 第九屆國家新創獎)
    2013 10th National Innovation Award (2013 第十屆國家新創獎)
    2011-14 NSC Outstanding Research Award, National Science Council, Taiwan (2011 國科會傑出研究獎)
    2015-18 MOST Outstanding Research Award, Ministry of Science and Technology, Taiwan (2015 科技部傑出研究獎)
    2015-25 Chair, Taiwan Bio-development Foundation Award (2015 台灣生技醫藥發展基金會TBF生技講座)
    2015 Ho Jen-Dui Distinguished Honor Award (侯金堆傑出榮譽獎)
    2018-21 Special Research Fellow Award, Ministry of Science and Technology, Taiwan (2018 科技部特約研究員獎)
    2018 International Inventor Prize and Lifetime Achievement Academic Award (2018第十四屆IIP國際傑出發明家終身成就獎)
    2018 The Executive Yuan Award for Outstanding Science and Honors Technology Contribution (2018行政院傑出科技貢獻
       

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    115台北市南港區研究院路二段128號
    Tel: 02-27899515
    Fax: 02-27858059
    icob@gate.sinica.edu.tw
    Copyright © ICOB 2013. All rights reserved. 最佳瀏覽網頁方式請用最新版IE11或其他瀏覽器 /瀏覽人數:1531887--
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