Michigan Cancer Research Fund                                                                                            American Cancer Society
   
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Research Project Description and Objectives from Aaron Van Dyke, PhD, MCRF 2011 Fellow

Project Name: Modulating Androgen Receptor with Bifunctional Recruiters
Aaron Van Dyke, Phd

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:                                                                                                           

  1. Synthesize a collection of bifunctional recruiters that vary in the type of molecules that bind AR/HDACs as well as the distance between these molecules. This will help identify the optimal features of these molecular bridges.
  2. Assess the ability of bifunctional recruiters to cause recruitment of HDACs to AR. Chromatin immunoprecipiation (ChIP) is one technique that will be employed, providing a picture of which proteins associate with one another on DNA.
  3. Assess the impact of HDAC recruitment on AR-regulated transcription. A hallmark of activated AR is its ability to promote transcription. By monitoring the levels of both natural and artificial reporters, we will assess the effectiveness of our drugs at blocking AR function.

Summer 2011 Update
We have successfully completed goal #1 of our proposed research, synthesizing a collection of 9 different bifunctional recruiters. The prediction is that these drugs will be able to bring together AR and HDACs. With these 9 drugs in hand, we have begun testing their ability to bring AR and HDACs together on DNA.

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
Over the past year we have devoted significant time towards achieving goal #2 — demonstrating that we can bring together both AR and HDACs on DNA. So far, our "molecular snapshots" have shown that our drugs cause AR to bind to DNA. This is an important result as it demonstrates that the drugs we have prepared are able to enter living cells. To date, however, we have been unable to observe HDACs on the same region of DNA — the overarching goal of this work. One reason for this negative result is that HDACs generally make only indirect contacts with DNA. The technique we're using, chromatin immunoprecipiation (ChIP), was developed for observing proteins — like AR — that directly bind to DNA. We're currently optimizing this protocol to be able to observe proteins that bind indirectly in our "molecular snapshots."

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
Transcription, the biological process wherein our genetic code (DNA) is converted into a set of instructions (RNA), requires the assembly of different proteins. The overarching goal of our research has been to develop drugs that will act like chemical bridges to promote these protein assemblies - especially in cancers where assemblies become imbalanced and result in too much (activated) or too little (repressed) transcription. Our initial molecular bridges targeted proteins known as HDACs because of their ability to repress transcription. However, despite showing our bridges could interact with these proteins, we were unable to observe the desired functional outcome.

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.