Advanced prostate cancer occurs when the androgen receptor (AR), a protein that controls the decisions related to prostate growth and signaling, is hyperactivated. Its inhibition is the rationale behind hormone therapy, the best treatment currently available for metastatic prostate cancer. Although initially effective, hormone therapy eventually fails, as most men develop resistance. As a result, 26,000 patients die each year in the United States.
Genome sequencing studies have revealed that over half of the ways men develop resistance to hormone therapy are through compensatory boosts in AR signaling, through AR gene amplifications, or through activating mutations. This suggests that the drugs we have now are not effective enough to help the majority of patients who have become resistant to hormone therapy through increases in the levels of AR signaling.
A major limitation in making a more potent AR drug is that there is not a complete picture of how AR looks or works, knowledge that requires understanding of its atomic details. My proposed research focuses on determination of the three-dimensional structure of AR when it is activated and when it is inhibited with the newest hormone therapy, enzalutamide. I will use two complementary methods, x-ray crystallography and cryoelectron microscopy, a technique that has recently advanced to revolutionize protein structure determination.
Once obtained, a structure of inhibited AR would reveal the molecular interactions between AR and the drug enzalutamide, which would accelerate design of a more potent derivative of enzalutamide within a few years. Additionally, a molecular snapshot of activated or enzalutamide-inhibited AR could lead to a fundamental change in how we target AR, as either of these structures could illuminate previously unknown regions of AR that are essential for its activity, always present in patients, and druggable. Though the implications from such a structure may not provide benefits to patients as quickly as resolving the molecular details of the interaction between AR and enzalutamide due to the extra time required for drug discovery efforts, the outcome may result in a treatment that is much more effective at reducing the incidences of AR hyperactivation experienced with hormone therapy.
My career aspiration is to run a multidisciplinary laboratory that focuses on how alterations of proteins related to DNA and RNA biology contribute to prostate cancer. After developing an expertise to trap and characterize protein complexes central to RNA biology during my Ph.D., I wanted to apply my mechanistic thinking to address a long-standing problem in prostate cancer and structural biology that would have the greatest impact on patient care. To achieve this goal, I am performing my post-doctoral training at Memorial Sloan Kettering Cancer Center (MSKCC), in the laboratory of Dr. Charles Sawyers, a world-class prostate cancer biologist known for the development of enzalutamide and understanding the mechanisms of its resistance. I have also established a collaboration with Dr. Sebastian Klinge at Rockefeller University, who is an expert in x-ray crystallography and cryo-electron microscopy. Both Dr. Sawyers and Dr. Klinge are excellent mentors and committed to the success of this project. We meet regularly to discuss research progress, as well as career goals.
Both institutions have tremendous resources and collaborative environments. MSKCC has the added benefit that the boundaries are blurred between basic and clinical research, as physicians and scientists regularly present and work alongside each other. In summary, my post-doctoral training will prepare me to be able to think as both a prostate cancer and a structural biologist, as I have the rare opportunity to rectify the genetics of prostate cancer with what occurs at the protein level and how it relates to patient care. This unique ability will prove advantageous to effectively studying this complicated disease in my future laboratory. |
