Joint Fellowship Training Program

Mentor:
Wendy C. Weinberg, Ph.D.

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

Email:
wendy.weinberg@fda.hhs.gov

Telephone:
(301)-827-0709

Title of Research Program:
Molecular Mechanisms Involved in Regulating Epithelial Differentiation, Neoplasia, and Therapeutic Efficacy

Research Project Summary:
Despite major advances in identifying rational targets and early promising pre-clinical findings, the majority of cancer treatments proceeding through clinical trials fail. To maximize the predictive value of pre-clinical data supporting clinical trials, the models utilized must reflect as much as possible the disease etiology. Our laboratory applies a variety of in vitro and in vivo approaches to correlate in vitro assay endpoints with pre-clinical in vivo models. Our research focuses on the functional relationships between members of the p53 tumor suppressor gene family in epithelial growth regulation and cancer pathogenesis, as well as their impact on therapeutic efficacy. The wildtype p53 gene product is known to mediate numerous biological processes critical to maintaining normal tissue homeostasis including apoptosis, cell cycle regulation, and DNA repair. p53 homologues p63 and p73 each encode multiple variants capable of overlapping or opposing specific functions of p53, and independent activities of these proteins remain to be elucidated. Our efforts are focused on defining the biological impact and mechanism of action of p63 dysregulation, as has been described in human squamous cell cancers of the head and neck, lung, breast, cervix, and ovaries. The overall goal of our research is to identify biomarkers of tumor progression and responsiveness for monitoring therapeutic efficacy.

Proposed Project for IOTF Fellow:
Research position to evaluate the normal function and effects of dysregulation of specific p53 homologues on normal keratinocyte growth regulation, differentiation and neoplasia, and their interactions with p53 and oncogenic pathways in multistep carcinogenesis. The project will utilize a variety of cellular and molecular biology methodologies, in vivo and in vitro approaches, human cancer cell lines, and novel knockout mice and transgenic mice developed in our lab to clarify the molecular pathways contributing to epithelial cell transformation, and the role of p63 in the response to cancer therapeutics. The particular project to be undertaken will reflect the specific interests of the fellow. Candidates must have a Ph.D. and/or M.D. and experience in cell/molecular biology. Position is located on the main NIH campus in Bethesda, MD. Fellow is invited to participate in journal clubs and data clubs held regularly in conjunction with the NCI and other NIH laboratories.

Regulatory Activity:
The development of antibody-based therapies comprises one of the most active areas of clinical research in oncology today. Many targeted therapies based on our current molecular understanding of cancer pathogenesis are under development to optimize the treatment outcome of tumors with specific genetic alterations. The Division of Monoclonal Antibodies is responsible for product review of antibodies, antibody conjugates, Ig-linked fusion proteins, ScFv, Fab's, and other antibody related proteins, including those currently under development for detection and treatment of solid cancers. Fellow will be mentored to participate in regulatory responsibilities which may range from pre-IND guidance through review of licensing applications and post-marketing manufacturing changes.

Reference(s):

1. King, KE et al: DeltaN-p63-alpha functions as a positive and negative transcriptional regulator and blocks in vitro differentiation of murine keratinocytes. Oncogene 22:3635-3644, 2003.
2. Weinberg, WC et al.: Development and regulation of monoclonal antibody products: Challenges and opportunities. Cancer Met. Rev. 24:569-584, 2005.
3. King, KE et al: Unique domain functions of p63 isotypes differentially regulate distinct aspects of epidermal homeostasis. Carcinogenesis, 27:53-63, 2006.
4. King, KE, and Weinberg, WC: p63: defining roles in morphogenesis, homeostasis and neoplasia of the epidermis. Mol. Carcinog., 46:716-724, 2007.