Joint Fellowship Training Program
Wen Jin Wu, M.D., Ph.D.
Organizational Affiliation and Position:
Senior Investigator, Division of Monoclonal Antibodies (DMA)
Office of Biotechnology Products (OBP), Office of Pharmaceutical Science (OPS), Center for Drug Evaluation and Research (CDER), FDA
Running Title of Program:
Investigating the mechanisms of trastuzumab resistance and cardiotoxicity
Research Project Summary (if applicable):
Human Epidermal Growth Factor Receptor 2 (HER2) is overexpressed in approximately 20-25% of breast cancers, and overexpression of HER2 is associated with an aggressive tumor phenotype. Treatment with trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of HER2, significantly improves outcomes for women with HER2-positive breast cancer. However, tumor resistance to trastuzumab poses a significant hurdle in breast cancer therapy. Clinical data showed that approximately two thirds of HER2-positive metastatic breast cancer patients demonstrated primary resistance to single-agent trastuzumab and that the majority of patients with HER2-positive breast cancer who achieve an initial response to trastuzumab acquired resistance within one year. The research project in our laboratory involves studies of the molecular mechanisms contributing to trastuzumab resistance. Trastuzumab treatment was also linked to serious cardiotoxicity, and the mechanisms of which remain elusive. The second area of our research interest focuses on understanding the mechanisms of trastuzumab-induced cardiotoxicity and identifying safety biomarkers for trastuzumab-induced cardiotoxicity.
Proposed Project for IOTF Fellow:
The fellow will carry out research programs concerning important current issues related to the therapeutic resistance of monoclonal antibodies and trastuzumab-induced cardiotoxicity. The research projects will be focused on understanding the mechanisms of trastuzumab resistance. The IOTF fellow may have the opportunity to work on a different research project that is currently conducted in our laboratory depending on fellow’s background and interest.
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 therapeutic monoclonal antibodies.
- Wu WJ and Dokmanovic M: Trastuzumab. In: Schwab M. (Ed.) Encyclopedia of Cancer: SpringerReference. Springer-Verlag Berlin Heidelberg, 2009. DOI: 10.1007/Springer Reference_177618 2012-06-10 09:14:21 UTC
- Dokmanovic M, Hirsch DS, Shen Y, Bonacci TM, Wu WJ. Trastuzumab regulates IGFBP-2 and IGFBP-3 to mediate growth inhibition: implications for the development of predictive biomarkers for trastuzumab-resistance. Mol Cancer Ther 2011;10:917-928.
- Hirsch DS, Shen Y, Dokmanovic M, Wu WJ. pp60c-Src phosphorylates and activates vaculolar protein sorting 34 to mediate cellular transformation. Cancer Res 2010;70:5974-5983.