Deregulation of Protein Synthesis in Prostate Cancer and Drug Resistance
Abstract
Scientific Objective and Rationale: Genetic material in the form of DNA serves as a template at the start of a series of discrete steps that ultimately lead to the generation of proteins, the building blocks of cells, tissues, and whole organisms. Proteins perform critical cellular functions such as growth and division and are the main workhorse for the proper functioning of the cell. Although the role of mutations at the DNA level in prostate cancer has been well described, very little is known about how changes in protein synthesis promote cancer, despite the functional significance of this process. Recent evidence from our lab has shown that this control of protein synthesis is indeed crucial in the formation, progression and behavior of prostate cancer, and can be therapeutically targeted. My work focuses on elucidating the functional role of critical regulatory regions upstream of the start site of protein synthesis in advanced prostate cancer. Currently, it is unknown how these regulatory regions contribute to cancer. Using cutting-edge technologies to precisely measure and monitor the process of protein production, my goal is to provide a global snapshot and functional characterization of these protein synthesis regulatory regions in prostate cancer using patient derived specimens, with a focus on discovering novel therapeutic targets for prostate cancer patients and markers of disease aggressiveness. Additionally, I will also address the pressing issue of drug resistance in current prostate cancer treatment regimens. A new class of promising therapies known as PI3K pathway inhibitors is being tested in clinical trials. Patient responses to these novel inhibitors have varied significantly, and we do not know what makes certain patients more resistant or sensitive to these treatments. We have evidence that protein synthesis control plays a crucial role in mediating drug resistance in prostate cancer, and my goal is to molecularly define this process so we can identify patients who will benefit the most from these new therapies. Career Goals: I am dedicated to the pursuit of an independent research career focused on finding better cures for prostate cancer patients. Through the mentorship of Drs. Andrew Hsieh and Stephen Plymate, as well as institutional support at the Fred Hutchinson Cancer Research Center, I will leverage the funding provided by the Prostate Cancer Research Program to branch into a new field and acquire critical skills in computational biology, protein synthesis control biology, and prostate cancer biology. The completion of the proposed work will enable me to contribute significant insights to the protein synthesis field, define new therapeutic targets and potential markers of disease aggressiveness for the prostate cancer research community, apply for independent funding, and eventually lead my own research enterprise. Applicability of Research: This work will directly benefit men with advanced prostate cancer that has continued to grow and spread to other organs, are non-curative and uniformly fatal, also known as castration-resistant prostate cancer. My work will define a new class of markers, which may predict for future disease behavior thereby impacting patient management. Moreover, some of these may also represent very attractive therapeutic targets. My work in drug resistance will have an immediate impact on patients, as it will help identify those who will have the best response to PI3K pathway inhibitors. Over the next 2 to 3 years, our findings from this study will be immediately put into action through larger clinical trials to validate our predictive markers and will directly impact the lives of many prostate cancer patients. Contributions to Advancing Prostate Cancer Research: The ultimate biological function of a gene is provided by the production of its protein; therefore, direct analysis of protein synthesis is highly important. However, technological limi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610198
Entities
People
- Yiting Lim
Organizations
- Fred Hutchinson Cancer Center
- United States Army