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Research Project Description from Jennifer Cash, PhD, 2014 MCRF Fellow
Project Name: Understanding Regulation of P-Rex1, an Enhancer of Metastatic Potential
One trademark of cancer is the ability of tumor cells to move to a remote site in the body and form another tumor in a process called metastasis. Cancer metastasis is a critical problem in cancer patients, as it causes the majority of cancer deaths. Currently, most anti-cancer drugs only work to inhibit cancer growth. Therefore, there is an important unmet need for therapeutics that inhibit the ability of cancer to metastasize. One molecule strongly linked to cancer progression and metastasis is the enzyme P-Rex1. Increased levels of P-Rex1 are associated with poor patient outcome in breast cancer and have been shown to facilitate metastasis of melanoma and prostate cancer cells. Therefore, P-Rex1 is an attractive target for the development of anti-metastasis drugs. However, the structure and the molecular basis for regulation of this enzyme by signaling lipids and cell surface receptors are not understood. Knowledge of these features will enable our long-term goal of developing selective chemical probes that could ultimately serve as therapeutic leads targeting P-Rex1.
Towards this goal, we have been using a technique called X-ray crystallography to determine atomic structures of fragments of P-Rex1 that reveal how certain molecules interact with it and increase its activity. In this proposal, we will fully describe the molecular details of how key regulators bind to the enzyme. These sites of interaction are "hotspots" that can be targeted by small molecule inhibitors with the goal of thwarting the ability of P-Rex1 to promote cell migration and thus suppressing cancer metastasis.
Summer 2016 Update
Over the last year, we have made significant progress toward understanding how P-Rex1 is regulated in the body. We have determined how a key regulator called PIP3 binds to P-Rex1 and that this binding is essential for turning on P-Rex1 activity. We have also identified other characteristics of P-Rex1 that may be important for its regulation in the body. This work is described in our recent publication in the journal Structure (doi:10.1016/j.str.2016.02.022).
Our work has also been presented at both local and regional meetings, including the Experimental Biology meeting this spring in San Diego. At this meeting, I received a Postdoctoral Best Presentation Award from the Division for Molecular Pharmacology of the American Society for Pharmacology and Experimental Therapeutics. Since receiving an ACS/MCRF fellowship, I have enjoyed participating in a variety of ACS events. For example, I was invited to the University of Michigan women’s basketball annual Pink Game where I spoke on court during halftime about my research and my personal experience with breast cancer (http://www.lsi.umich.edu/research-highlights-7). I appreciate being able to join into these ACS events, as they bring together researchers and survivors as well as the people doing the fundraising, which is invaluable in reminding me why I do science on a daily basis.
Summer 2018 Update from Dr. Cash: I am presently working on structural and biochemical studies of the metastatic protein P-Rex1 towards understanding how this protein is regulated in the body, particularly in cancer metastasis, which is the project that I was working on while funded by MCRF. Since our 2016 publication on this work in the journal Structure, we have made substantial breakthroughs on this project and will submit multiple manuscripts for publication within the next year. I am currently a research investigator at the University of Michigan in the labs of John Tesmer and Michael Cianfrocco where I am learning an exciting new technique called cryo-electron microscopy in order to address “bigger picture” questions on this project. Our labs just recently received an NIH R01 to continue this work. Right now, I am on the job market for a faculty position to start up my own lab, where I will be taking this project with me as well as pursuing other related projects focusing on cancer-implicated proteins and understanding regulation of their functions in the body. Having something as prestigious as an ACS-MCRF postdoctoral fellowship on my record has been very helpful in applying for these positions.
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