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Androgen receptor (AR) is a protein that, when activated, stimulates the growth and survival of prostate cancer cells. Many drugs developed to treat prostate cancer aim to prevent this activation, keeping AR in a repressed state. Unfortunately, AR evolves over time and becomes resistant to these therapies, highlighting the need for new approaches to modulate AR.
Cells have enzymes called histone deacetylases (HDACs) that suppress the function of many proteins. If one were able to recruit these HDAC machines to AR, they may repress its function. My research will test this hypothesis by developing molecules to achieve this recruitment, drugs we term bifunctional recruiters. In cells, bifunctional recruiters will act like molecular bridges; contacting AR on one end and HDACs on the other, bringing the two in close proximity.
The goals of my research are to:
Summer 2011 Update
Pursuant to goal #2, we are employing a technique called ChIP that allows us to take a "molecular snapshot" of what proteins are associated with DNA.
We have not begun work on goal #3 as of this time. We are awaiting the results of our ChIP studies.
Summer 2012 Update
While we have yet to observe the ability of our drugs to bring together AR and HDACs on DNA, this maybe a limitation of the ChIP technique and not necessarily an indication that the drugs are failing to perform as desired. Thus, we've begun work on goal #3, testing the drugs with an alternative technique: an artificial reporter. Fellow MCRF postdoctoral researcher David DeGraff at Vanderbilt University is an expert in the field of AR-regulated transcription. Dr. DeGraff has generously provided us with the materials needed to begin work on goal #3. This exchange exemplifies one of the greatest benefits of being an MCRF researcher, collaborations that put cancer research on a fast track.
Summer 2013 Update
Therefore, we sought a complementary approach, targeting proteins known as bromodomains that can activate transcription. The overall goals of our research remain the same:
1) Design and synthezise a collection of chemical bridges to target bromodomains.
2) Confirm the binding of chemical bridges to their protein targets.
3) Demonstrate the ability of chemical bridges to affect transcription.
In collaboration with leading cancer researcher James Bradner at the Dana Farber Cancer Institute, we synthesized our chemical bridges and showed they bind to their intended targets (goals 1 and 2). We then tested the ability of our compounds to activate transcription. Gratifyingly, they are very strong activators, even more so than existing drugs for these proteins (goal 3). We are curently undertaking studies in collaboration with Dr. Bradner to investigate our drugs in various cellular models of leukemia.
Summer 2014 Update
In Fall 2013, I joined the Department of Chemistry at Fairfield University in Connecticut in a tenure-track position as an Assistant Professor. My responsibilities include teaching Organic and Biochemistry, and developing new courses in the cross-disciplinary field of Chemical Biology. I have also establised an undergraduate-driven research group, with dedicated research space and state-of-the-art instrumentation. I'm excited to work with the undergraduate population as many of them have never been exposed to cancer research. The American Cancer Society and the Michigan Cancer Research Fund have provided indispensable support and training that I know will ensure a long and productive career at Fairfield University. I am deeply thankful for the MCRF donors who have sponsored my research at the University of Michigan and who continue to support high-quality research across the nation.
Summer 2015 Update
We recently received an update from 2011 MCRF Fellow Aaron Van Dyke, PhD, who will begin his third year of a tenure-track appointment at Fairfield University this fall. Fairfield University is a primarily undergraduate institution with a vibrant research culture. Professor Van Dyke’s group has built off work from his ACS-MCRF Postdoctoral Fellowship and published an article in Molecular Endocrinology. The 11-page article describes how small organic molecules can be used to control protein partnerships inside of cells. Controlling these partnerships, in turn, affects the function of glucocorticoid receptor, a critical therapeutic target in a range of hematological cancers. We are pleased to note that the grant Aaron received from ACS/MCRF is cited in the “Acknowledgments” section near the end of the article!
Aaron is also thriving in the classroom; he was selected by students to receive the Alpha Sigma Nu 2015 Undergraduate Teacher of the Year award. As an added honor, he served as Grand Marshall at Fairfield's 2015 undergraduate commencement exercises. Heartfelt congratulations to Aaron as he furthers his scientific and teaching accomplishments at Fairfield!
Summer 2016 Update
Aaron reports that a labeling strategy developed by his group is a first step towards developing a tool for illuminating and studying enzymes in their native environment. Enzymes are a class of proteins that regulate cellular growth and development, and it is known that malfunctions in enzyme function lead to a number of human cancers. Existing tools target genetically modified enzymes (enzymes that are not native to the cell, but are synthetic and used to model native proteins). By studying native enzymes, his group will gain a better understanding of what drives cancer development and discover targets for developing new therapeutics.
Summer 2018 Update from Dr. Van Dyke: I’m completing my fifth year as an Assistant Professor of Chemistry at Fairfield University, a Jesuit University in southeast Connecticut. Our department supports a vibrant undergraduate research culture. I mentor six students, ranging from sophomores to seniors. As a chemical biology group, my lab is interested in applying the tools of chemistry to better understand biological systems. To date, we have developed a method for selectively tagging native enzymes without altering their intrinsic function. This is useful because it will allow us to observe the behavior of disease-causing proteins in their original state. Additionally, our lab has received a two-year grant from the United States Department of Agriculture, in collaboration with the Department of Biology at Fairfield University, to investigate the immunomodulatory properties of eggs. While much is known about the cholesterol and lipid effects of eggs, much remains to be explored about how these bioactive foods affect our body’s immune system. This grant and these research projects would not have been possible without the career-boosting postdoctoral fellowship provided by the ACS–MCRF.
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