Joint Fellowship Training Program

Mentor:
Wen Jin Wu, M.D./Ph.D.

Organizational Affiliation and Position:
Principal Investigator, Division of Monoclonal Antibodies (DMA), Office of Biotechnology Products (OBP), Office of Pharmaceutical Science (OPS), Center for Drug Evaluation and Research (CDER), Food and Drug administration (FDA)

Email:
wen.wu@fda.hhs.gov

Telephone:
301-827-0253

Running Title of Program:
Investigating the mechanisms of therapeutic resistance to monoclonal antibodies.

Research project summary:
The ErbB receptor family, which consists of four receptor tyrosine kinases known as ErbB1/EGFR/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4, are involved in the development of numerous human cancers, and have been intensely pursued as therapeutic targets. HER2 is overexpressed in 20–25% of invasive breast cancers and is associated with an aggressive tumor phenotype. Trastuzumab, a therapeutic monoclonal antibody specifically targeting to HER2, have been shown to improve outcomes for women with HER2-positive breast cancer patients. However, many breast cancers that initially respond to trastuzumab begin to progress again within 1 year and become resistant to trastuzumab treatment. The research project in our laboratory involves studies of the molecular mechanisms contributing to trastuzumab-resistance of breast cancer cells. A second area of research interest focuses on understanding the mechanisms by which Cdc42, a Ras-like small GTPase, regulates degradation pathways for EGFR and E-cadherin in breast cancer cells.

Proposed project for IOTF fellow: The fellow will carry out research programs concerning important current issues related to the therapeutic resistance of monoclonal antibodies. The research projects will be focused on understanding the mechanisms of resistance to therapeutic monoclonal antibodies. Additionally, the IOTF fellow may also have the opportunity to work on a different research project that is currently conducted in our laboratory depending on the fellow’s background and interest.

Regulatory activity:
The Division of Monoclonal Antibodies is responsible for the product quality review of monoclonal antibodies and monoclonal antibody-derived products, including antibody conjugates, Ig-linked fusion proteins, and other antibody related proteins. Our laboratory is involved in regulating novel monoclonal antibodies for the treatment of human cancers. The fellow will participate in regulatory review of investigational new drug (IND) applications. This provides the opportunity for the fellow to work as part of regulatory team to assess the product quality of monoclonal antibodies.

Publications:

1. Dokmanovic, M., Hirsch, D.S. Shen, Y. and Wu, W.J. (2009) Rac1 contributes to trastuzumab-resistance of breast cancer cells: Rac1 as a potential therapeutic target for the treatment of trastuzumab-resistant breast cancer. Mol Cancer Ther 8:1557-69.
2. Wu, W.J. and Hirsch, D.S. (2009) Mechanism of E-cadherin lysosomal degradation. Nat Rev Cancer 9:143.
3. Shen, Y., Hirsch D.S., Sasiela, CA and Wu, W.J. (2008) Cdc42 regulates E-cadherin ubiquitination and degradation through an epidermal growth factor receptor to Src-mediated pathway. J. Biol. Chem. 283:5127-37.
4. Hirsch, D.S., Shen, Y., and Wu, W.J. (2006) Growth and motility inhibition of breast cancer cells by EGFR degradation is correlated with inactivation of Cdc42. Cancer Res 66: 3520-30.
5. Wu, W.J., Tu, S.S., and Cerione, R.A. (2003) Activated Cdc42 sequesters c-Cbl and prevents EGF receptor degradation. Cell 114: 715-725.
6. Wu, W.J., Erickson, J.W., Lin, L., and Cerione, R.A. (2000) The ?-subunit of the coatomer complex binds Cdc42 to mediate transformation. Nature 405: 800-804.