David J. DeGraff
|Institution||College of Medicine|
|Address||500 University Drive Hershey, PA 17033|
|Phone||717-531-0003 Ext 281295||
||NIH Pathway to Independence Award (K99/R00)|
||New Investigator Award|
||John Quale Travel award|
||Trainee, Integrated Biological Systems Training in Oncology |
||Trainee, Multidisciplinary training in Molecular Endocrinology |
||Trainee, Integrative Graduate Education and Research (IGERT)|
||University Graduate Fellowship|
||Reisher Scholarship Recipient|
Assistant Professor of Pathology, Surgery, and Biochemistry & Molecular Biology
Member, Penn State Hershey Cancer Institute
Post-Doctoral training, Department of Urologic Surgery, Vanderbilt University Medical Center
Ph.D., University of Delaware
B.S., Metropolitan State University of Denver
In 2014, it is estimated that approximately 74,690 people will be diagnosed with bladder cancer in the United States. For reasons that we still do not understand completely, men are much more likely to be diagnosed with bladder cancer than women. Over fifteen thousand people will die from this disease in 2014. Bladder cancer tumors that progress to a stage defined by muscle invasion (MI) are especially dangerous, and require extensive surgery. Unfortunately, surgery is not always curative for MI bladder cancer. Yet, treatment advances for bladder cancer patients have been lacking. Therefore, there is a desperate need for novel therapeutic approaches for the treatment of bladder cancer.
One area potentially ripe for the development of novel therapeutic approaches involves the identification of molecular pathways that control tumor differentiation and histological subtype. While ninety percent of bladder cancer is histopathologically classified as urothelial cell carcinoma (UCC), approximately 20-40% of MI UCC exhibits mixed histology with squamous components, and patients with this type of bladder cancer exhibit relatively poor clinical outcomes. As translational biologists, we hypothesize that new discoveries for the treatment of bladder cancer patients will derive, at least in part from our increased understanding of the molecular mechanisms that are related to mixed urothelial/squamous differentiation. Specifically, we focus on the role of transcription factors in this process, which are master regulators of urothelial differentiation and gene expression.
One such family of transcription factors is the forkhead box (FOX) family of transcription factors. This family contains 43 members in mammals implicated in a variety of malignancies. The ability of FOXA1 to act in the modulation of chromatin structure by “pioneering” increased accessibility for transcription factors to access downstream target genes appears to be central to its influence on tumor biology.
We recently reported that loss of FOXA1 expression is significantly associated with advancing human BLCa tumor stage and grade, and that FOXA1 loss occurs in KSM and in 81% of SCC, as well as 40% of UCC. We have also shown that FOXA1 loss is associated with poor survival in bladder cancer patients, and that genetic ablation of FOXA1 causes sex-specific changes in the bladder urothelium, similar to the case in humans. In addition to follow up studies based on these observations, we are now in the process of identifying key regulatory networks which interact with FOXA family members to regulate urothelial biology, and which additionally mediate chemosensitivity.
We use a variety of techniques (various in vitro approaches, several in vivo approaches including transgenic and knockout mouse models, and tissue recombination xenografting) in the laboratory to identify pathways important for disease progression, which may also serve as new targets. In addition, we work closely with our clinical colleagues (urologic surgeons and genitourinary pathologists) to identify targets and work on ways to bring new approaches to the clinic.
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