吳漢忠副研究員

Han-Chung Wu

Associate Research Fellow E-mail: hcw0928@gate.sinica.edu.tw Tel: 02-2789-9528

2005-, Associate Research Fellow, Institute of Cellular and Organismic Biology, Academia Sinica 2006-, Joint Appointment Associate Research Fellow, Genomics Research Center, Academia Sinica 2005-, Adjunct Associate Professor, Institute of Pathology, National Taiwan University 2005-, Adjunct Associate Professor, Graduate Institute of Oral Biology, National Taiwan University 2001-2005, Assistant & Associate Professor, Graduate Institute of Oral Biology, National Taiwan University 1996-2001, Assistant & Associate Research Fellow, Institute of Preventive Medicine, National Defense Medical Center 1993, Ph.D. Institute of Pathology, National Taiwan University, Taiwan

1. Identification of cancer-specific peptides and development of ligand-targeted therapy for cancer Cancer is one of the most common causes of death, with 8 million deaths each year worldwide. One major problem in the treatment of cancer is acquired drug resistance to chemotherapy. Ligand-targeted therapy makes possible tumor specificity, has limited toxicity and shows promise for the development of novel therapies for cancer. Recently, we developed methods to identify the receptors expressed specifically on cancer cells and tumor vessels using phage display. Phage display is a powerful method for the rapid identification of peptide ligands for a variety of target molecules (antibodies, enzymes, and cell-surface receptors). We successfully developed these methods to identify serotype-specific and neutralizing B-cell epitopes; specific ligands for receptors; disease-specific antigen mimics from complex serum samples of human patients; cancer cell-specific peptide ligands for the development of ligand-targeted cancer therapy; and tumor homing peptide ligands for the development of anti-angiogenesis therapy. Using these technologies, several peptide ligands have been isolated that home to cancer cell and tumor-specific endothelial cell receptors. In an effort to develop ligand-targeted therapy, we used peptide-linked liposomes that carried doxorubicin to treat SCID mice bearing human cancers. The peptide-functionalised liposomes were found to have an enhanced anti-tumor effect and offer significant clinical potential in a targeted drug delivery system. These novel researches were obtained patents. Academia Sinica has licensing-out these results to a biotechnology company for preclinical try. We plan to identify the ligand-targeted proteins on the plasma membrane of cancer or cancer stem cells, to study the function and cellular signaling pathway of the target proteins and to generate therapeutic antibodies for targeted anti-cancer treatment.

2. Dengue virus research: Dengue virus (DEN) causes serious febrile illnesses in humans, including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The number of annual dengue fever (DF) cases worldwide is estimated to be 50 -100 million, with 250,000 to 500,000 cases of DHF. Two-fifths of the world's population lives in areas with a risk of infection. To date neither effective vaccines nor specific therapy can be used against dengue virus disease, and there is no protein or peptide that can be used for the differentiation of the four serotypes of dengue viral infection. Up to now, it is still not clear whether DHF/DSS is due to primary or secondary infection of DEN or to other immunopathologic mechanisms. To answer these questions, we have generated many monoclonal antibodies against the four serotype-types of DEN. Therefore, we are investigating the following topics: 1. Identification of serotype-specific epitopes and the development of epitope-based diagnosis for dengue viruses. 2. Identification of neutralizing epitopes of dengue viruses. 3. Study the pathogenesis of DHF. 4. Generation of therapeutic antibodies for dengue, and the molecular mechanism of the protective role of these antibodies.

癌症之標的蛋白及標的治療研究

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七百萬人。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劑量,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,標的治療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,已經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。

使用這些技術,許多能導向癌細胞和腫瘤特有的內皮細胞受體之標的胜肽都已被尋獲。為了進一步發展標的治療,我們採取了將標的胜肽與帶有抗癌藥物的微脂體連結,並用來治療移殖人類腫瘤的免疫不全鼠。此具有標的胜肽功能的帶藥微脂體被發現能更有效的抑制腫瘤生長,且於標的藥物傳送系統中展現重要的臨床潛力,已獲得台灣及美國專利。

利用活體內的噬菌體顯現法,我們已經發現了數個標的胜肽能專一性與腫瘤的血管結合,而不與正常血管結合。運用這些胜肽進行標的治療,發現具有極佳的治療效果,以及無明顯副作用等優點。這些腫瘤專一性標的胜肽,未來對於癌症的標的治療、設計標的基因轉換載體以及成像試劑,都深具臨床潛力。目前已授權給生技公司,對這些標的藥物進行臨床前試驗。另一方面我們則研究這些胜肽所結合之標的蛋白,研究這些蛋白的功能及細胞內的訊號傳遞。

登革病毒研究

登革病毒感染,會引起登革熱,嚴重則引起登革出血性熱以及登革休克症候群。每年約有五千萬到一億的登革熱病例產生,其中有二十五至五十萬人會引起出血性登革熱。約有40%地球的人口生活在可能被感染的危險區域。目前尚無有效且安全的疫苗及專一性治療登革病毒引起的疾病,對於四型登革病毒專一性的B細胞抗原決定位(epitopes) 尚不清楚,也沒有抗原(蛋白或胜肽)可以專一性分辨四型登革病毒的感染。對於登革出血熱的致病機轉,是經由不同型登革病毒交叉感染,或是病毒及宿主間一次感染的交互作用,還是病毒感染後所產生的免疫病理反應,至今仍不十分清楚。為了要解決這些問題,本實驗室建立了許多對抗四型登革病毒之單株抗體,希望藉由研究這些抗體的抗原決定位,來了解登革病毒(1)專一性及中和性的抗原決定位,

(2)保護性及致病性抗原決定位之位置,未來將進一步釐清登革出血熱之致病機轉,研發有效且安全之登革疫苗、治療性抗體及偵檢試劑。

  1. Wu, H.C., Lin, Y.J., Lee, J.J., Liu, Y.J., Liang, S.T., Peng, Y., Chiu, Y.W., Wu, C.W., and Lin, C.T. (2003) Functional Analysis of Epstein-Barr Virus in Nasopharyngeal Carcinoma Cells. Laboratory Investigation 83, 797-812.
  2. Wu, H. C.*, Jung, M.Y., Chiu C.Y., Lai, S.C., Jan, J.T., and Shaio, M.F. (2003) Identification of serotype-specific B-cell epitope of dengue virus type 2 and detection of dengue immunized serum samples by epitopebased peptide antigen. Journal of General Virology 84, 2271-2279.
  3. Wu, H.C., Lu, T.Y., Lee, J.J., Hwang, J.K., Lin, Y.J., Wang, C.K., and Lin, C.T. (2004) MDM2 expression in EBV-infected nasopharyngeal carcinoma cells. Laboratory Investigation 84, 1547-1556.
  4. Liu, I.J., Hsueh, P.R. Lin, C.T., Chiu, C.Y., Kao, C.L., Liao, M.Y. and Wu, H. C.* (2004) Disease-specific B cell epitopes for serum antibodies from patients with severe acute respiratory syndrome (SARS) and serologic detection of SARS antibodies by epitope-based peptide antigens. Journal of Infectious Diseases 190, 797-809.
  5. Lee, T.Y., Wu, H. C.* Tseng, Y.L., and Lin, C.T. (2004) A novel peptide specifically binding to nasopharyngeal carcinoma for targeted drug delivery. Cancer Research 64, 8002-8008.
  6. Wu, H. C*., Lin, C. T. and Lee, T. Y. (2006) A novel peptide targeting to nasopharyngeal carcinoma for targeted therapy. Patent # I262192 (Taiwan), Sep 21, 2006 ~ Jun 30, 2023.
  7. Wu, H. C*., Lin, C. T. and Lee, T. Y. (2007) A peptide marker targeting to nasopharyngeal carcinoma cell and application thereof. US Patent # 7,238,665 (USA), Jul 03, 2007 ~ Mar 08, 2024.
  8. Chen, Y. C., Huang H. N., Lin, C. T., Chen, Y. F., King, C. C., and Wu, H. C.* (2007) Generation and characterization of monoclonal antibodies against dengue virus type 1: Epitope mapping and serological detection by epitope-based peptide antigen. Clinical and Vaccine Immunology 14, 404-411.
  9. Lee, T. Y., Lin, C. T., Kuo, S. Y., Chang D. K. and Wu, H. C.* (2007) Tumor-homing peptides with targeting to tumor blood vessels of lung cancer for drug delivery. Cancer Research 67, 10958-10965.
  10. Lo, A., Lin, C. T., Wu, H. C.* (2008) Hepatocellular carcinoma cell-specific peptide ligand for targeted drug delivery. Molecular Cancer Therapeutics 7, 579-589.
    1. Huang, D. Y., Lin, Y. T., Jan, P. S., Huang, Y. C., Liang, S. T., Peng, Y., Huang, C. Y., Wu, H. C.* and Lin,
    2. C. T. (2008) Sox5, a potential marker for nasopharyngeal carcinoma prognosis, down regulates SPARC to enhance tumor progression. Journal of Pathology 214, 445455.
  11. Wu, H. C*., Huang, C. T., and Chang, D. K. (2008) Anti-angiogenic therapeutic drugs for treatment of human cancer. Journal of Cancer Molecules 4, 37-45.
  12. Chang, D. K., Lin, C. T., Wu, C. H. and Wu, H. C.* (2009) A novel peptide enhances therapeutic efficacy of liposomal anti-cancer drugs in moue models of lung cancer. PLoS ONE 4, e4171.
  13. Hwang, Y. C., Lu T. Y., Huang, D. Y., Kuo, Y. S.; Kao, C. F., Yeh, N. H. , Wu, H. C.* and Lin, C. T. (2009). NOLC1, an enhancer for NPC progression, is essential for TP53 to regulate MDM2 expression. American Journal of Pathology (In press).
  14. Chang, D. K., Chiu, C. Y., Kuo, S. Y., Lin, W. C., Lo, A., Wang, Y. P., Li, P. C. and Wu, H. C.* (2009) Peptide-mediated anti-angiogenic drug delivery systems increase therapeutic efficacy of solid tumors. Journal of Biological Chemistry (In press).

*Corresponding author

Link to the complete list of publications