Michigan Cancer Research Fund                                                                                            American Cancer Society
   
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Research Project Description and Objectives from David DeGraff, PhD
Dr. David DeGraff


Project Name:  Role of Foxa1 Binding Partners in Androgen Regulated Prostate Cancer

Transcription factors act as the molecular "engines" that drive cell behavior. In our laboratory, we study how these molecular engines drive prostate and bladder cancer to a lethal stage.

  1. In prostate cancer, we are exploring ways of shutting these engines down to kill tumors and prevent cancer progression and spreading, or metastasis.
    • We will identify exactly how these engines promote cancer growth and spreading.
    • We will test the influence of eliminating these engines on cancer growth and spreading.
    • These aims will be explored through tissue recombination assays and other experiments involving systems which mimic the biology of the prostate organ. Tissue recombination assays involve mixing tissue samples with components whose transcription factors have been altered, growing the tissues in mice, and then analyzing them to see the impact of variously altered tissues on cancer growth and spreading.
  2. In bladder cancer, we are working to find molecular engines which indicate the presence of the deadliest cancers. This is because it is currently difficult for physicians to determine which patients will face the most deadly form of bladder cancer. Identification of these molecular engines may provide us with a new diagnostic test that will help physicians’ better treat, and potentially cure patients.
    • We will explore the correlation between these molecular engines and clinical outcome by staining 300 bladder cancer tissue samples to screen the samples for specific proteins. Because these particular tissue samples are all linked to patient outcome information, we will be able to see the correlation between the presence of these proteins and overall survival and overall disease-free survival. This may lead to the ability to predict which patients are or are not likely to survive longer, and which cancers are or are not likely to recur faster. This information will contribute to the ability to make decisions about the best way to treat future patients whose tumors resemble the ones represented among our 300 samples.
    • We will also work to identify how these molecular engines promote the malignant behavior of bladder cancer through tissue recombination assays (described above).

Click here to review a video update from Dr. DeGraff in June 2010.

Summer 2011 Update
In the coming year, I will work to identify how loss of FOXA1 cooperates with signal transduction pathways previously implicated in bladder cancer. This will allow me to determine how FOXA1 loss fits into what we already know about bladder cancer. I will also be working to prepare a grant application for the National Institutes of Health for submission in February 2012 which will seek support for my continued studies of FOXA1 and bladder cancer.

Summer 2012 Update
Bladder Cancer: We have recently published a manuscript identifying FOXA1 loss in the majority of patients with the most advanced and aggressive forms of bladder cancer. We are in the process of identifying how FOXA1 loss cooperates with signal transduction pathways that are implicated in bladder tumor progression. I have submitted a grant application for the National Institutes of Health for submission which will seek support for my continued studies of FOXA1 and bladder cancer.

Prostate Cancer: Work focused on increasing our understanding of how NFI transcription factors cooperate with FOXA1 to regulate androgen receptor (AR) signaling is nearing completion. This work is revealing important insights into how increased functionality of the AR during prostate cancer progression is promoted by NFI transcription factors.

Summer 2013 Update
Bladder Cancer: Capitalizing on our previously published manuscript identifying FOXA1 loss in patients with the most aggressive forms of bladder cancer, we are in the process of submitting a manuscript which proves that loss of FOXA1 is a predictor of negative clinical outcome. Additionally, we have identified novel FOXA1 regulated genes implicated in bladder tumor progression. I have capitalized on this discovery by competing for and receiving a two-year research grant from the Bladder Cancer Advocacy Network (BCAN), which focuses on the role of these proteins in chemoresistance.

Prostate Cancer: Work focused on increasing our understanding of how NFI transcription factors cooperate with FOXA1 to regulat androgen receptor (AR) signaling is now completed and has been submitted for publication.

Summer 2014 Update

In March 2014, I became an Assistant Professor in the Department of Pathology at Pennsylvania State University College of Medicine.  I have my own laboratory now, and we are continuing on a path of research that was initiated by our MCRF/ACS grant. I am honored to have received an NIH grant which helps support this ongoing research.

Summer 2016 Update

Since my arrival at Penn State University (PSU) College of Medicine in 2014, I feel like we have been exceedingly productive, and (most importantly), that we are doing the best science we have ever done. This is in large part to the collaborations we have developed between the Departments of Urology and Pathology here at PSU. Specifically, we are making major strides in furthering our understanding of how specific transcription factors contribute to disease progression in bladder cancer.  For example, we recently reported that expression of EZH2 is increased in carcinoma in situ (CIS), which is widely believed to be the precursor of invasive bladder cancer.  In addition, we are using transgenic systems to determine how transcription factors cooperate with other common genetic alterations in bladder cancer to drive disease progression.  Finally, we have several next generation human tumor sequencing projects focused on identifying genetic predictors of disease progression and recurrence.  These projects are conducted in collaboration with members of the Institute for Personalized Medicine at PSU, as well as Memorial Sloan Kettering in New York City. 

While one paragraph is not enough to detail all of the exciting work ongoing at PSU, I can tell you that your initial support of my research was a great investment, as indicated by our novel discoveries.  It is my sincere hope that these projects will yield information that we can use to improve clinical outcomes in patients diagnosed with this dangerous disease. Please stay tuned for more updates.

Since June 2014, Dave has been co-author on 10 published papers!