The goal of this project is to understand how proteins that control the packaging and transmission of our genetic information, called transcription factors, are deregulated in ovarian cancer and to leverage this understanding to develop new therapies for this devastating disease. To achieve this goal, we have assembled a group of outstanding investigators from University of Pennsyvlania and The Wistar Institute with extensive expertise in ovarian cancer and the regulation of gene expression by transcription factors. Other team members provide complimentary expertise in key methodologies required to accomplish the proposed studies including cell biology, biochemistry, structural biology, and drug development. These investigators have a strong record of funding from the National Cancer Institute in basic and translational ovarian cancer and/or gene expression, and have co-published more than 20 research articles.
The program includes four highly coordinated, hypothesis-driven projects. Project 1, led by Dr. Rugang Zhang, will study the ARID1A transcription factor and test the hypothesis that ARID1A inactivation promotes ovarian cancer by suppressing a cell state called senescence through altering the ability of ARID1A to promote the expression of certain genes. Project 2, co-led by Drs. Ramin Shiekhattar and José Conejo-Garcia, will study the BRCA1 transcription factor and test the hypothesis that BRCA1 functions as a general stimulatory factor for gene expression and that loss of BRCA1 leads to disruption of key gene expression programs resulting in ovarian cancer. Project 3, led by Dr. Frank Rauscher, will study the Snail and Slug transcription factors and test the hypothesis that a switch in the activities of these proteins mediates ovarian cancer. Project 4, co-led by Drs. Ronen Marmorstein and David Speicher, will study the role of the TCEAL7 and HBO1 protein acetyltransferases in the regulation of gene expression and test the hypothesis that altered protein acetylation status mediated by a disruption of these key proteins stimulates ovarian cancer cell growth.
Importantly, the success of these projects depends on the combined scientific and technical expertise of the group. Together, these studies will provide novel detailed insights into the roles of key transcription factors in ovarian cancer and lead to the identification and characterization of new therapeutic strategies and novel drugs to target key proteins that aberrantly regulate gene expression in ovarian cancer.
- Jose Conejo-Garcia, MD, PhD, Wistar Institute
- Frank Rauscher, III, PhD, Wistar Institute
- Ramin Shiekhattar, PhD, Wistar Institute
- David Speicher, PhD, Wistar Institute
- Rugang Zhang, PhD, Wistar Institute
Dr. Marmorstein obtained his Ph.D. in Chemistry from the University of Chicago and, following a postdoctoral fellowship at Harvard University, joined the faculty at The Wistar Institute in 1994. In 2013, Dr. Marmorstein relocated to the Perelman School of Medicine at the University of Pennsylvania where he is currently a Professor in the Department of Biochemistry and Biophysics and Investigator in the Abramson Family Cancer Research Institute (AFCRI). Dr. Marmorstein also holds adjunct appointments at the Wistar Institute and the Department of Chemistry at the University of Pennsylvania.
Dr. Marmorstein’s laboratory studies the molecular mechanisms of protein post- and co-translational modification with a particular focus on protein acetylation and phosphorylation and chromatin regulation. The laboratory uses a broad range of molecular, biochemical and biophysical research tools centered on macromolecular structure determination. The laboratory is particularly interested in gene regulatory proteins and their upstream signaling kinases that are aberrantly regulated in cancer, melanoma and ovarian cancer in particular, and other age-related disorders. The laboratory also uses high-throughput small molecule screening and structure-based design strategies towards the development of protein-specific small-molecule probes to be used to further interrogate protein function and for development into therapeutic agents.