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 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.

 

Summer 2019 Update from Dr. Jennifer Cash: Dr. Cash is currently a Research Investigator at the University of Michigan Life Sciences Institute and is applying for faculty positions at research intensive universities where she plans to oversee research focusing on cancer-implicated proteins and understanding regulation of their functions in the body. Over the past year, she has made significant progress toward understanding how the metastatic proteins P-Rex1 and P-Rex2 are regulated in the body. Her team has determined how a key regulator called PIP3 binds to P-Rex2 to turn on P-Rex2 activity, work that is complementary to our previous studies on P-Rex1. They have also gone on to determine the three-dimensional configuration of P-Rex1 bound to another important regulator protein called G beta gamma, leading to insights into how this binding activates P-Rex1. This work is currently under consideration for publication. These studies have been presented at several local and regional conferences over the past year, including at the large Experimental Biology meeting this spring in Orlando. At this conference, Dr. Cash’s poster presentation received a Blue Ribbon Pick from the American Society for Pharmacology and Experimental Therapeutics. The work of Dr. Cash’s team is now funded through an NIH R01 grant. Data generated during her time funded by the ACS/MCRF was critical in receiving this grant.

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