Dissecting Translational Dynamics and Lineage Plasticity in Prostate Cancer
Abstract
Prostate cancer is the most prevalent malignancy and the second leading cause of cancer death in men in the United States. Over the last few decades, advances in our understanding of prostate cancer biology have led to major breakthroughs in the clinic including androgen deprivation therapy (ADT) and androgen receptor (AR) inhibitors. These treatments rely on the finding that prostate cancer cells depend prominently on AR for their survival and accelerated growth. During the initial treatment, prostate cancer is AR-sensitive and responds well to ADT. However, prostate cancer cells progressively evolve and adapt to low androgen conditions and ultimately become castration-resistant. Patients with castration-resistant prostate cancer (CRPC) have limited treatment options as prostate cancer cells become insensitive to AR inhibitors. Even with the tremendous efforts in the prostate cancer research community, treatment-induced CRPC remains the leading cause of death in men with advance staged disease. My research proposal will address the 2022 PCRP Overarching Challenge of defining the biology of prostate cancer progression to lethal prostate cancer to reduce death. To this end, improving our understanding of the biology behind the transition of AR-sensitive prostate cancer to CRPC is critical for the development of new, effective treatments for patients with advanced stage disease. In particular, it will dramatically help patients if we can determine the processes and factors directly responsible for resistance to AR-directed therapies. In this proposal, I will study a new process I recently discovered that drives therapy resistance and will further demonstrate its potential as a therapeutic target. My research focuses on how prostate cancer cells exploit protein synthesis to meet their growth needs, and break their dependence on AR. I found that a molecule called tRNA is critical for driving these processes. It does so by hijacking the protein-making factors of a cell so that cancer cells can make new proteins that help them grow faster and resist ADT or AR inhibitors. My research will explore how prostate cancer selectively induces protein synthesis through tRNA and other elements to create dangerous and lethal forms of the disease. I will use multidisciplinary approaches, including new methods that I have developed, to study the process of protein synthesis in cells. Critical to this work, I will also study tRNA in human tissues from patients with lethal advanced stage disease. It is important to note that my proposed study is exceedingly unique and has never been attempted in the field of prostate cancer before. Therefore, I believe my efforts within the next 3 years will have the great potential of culminating in the discovery of new targets that have not been considered in highly treatment resistant prostate cancer. For example, one of the goals in my proposed research is to define new hidden elements within cancer-causing RNAs that control their ability to make proteins. If I discover such prostate cancer-promoting elements and define how they work, I will be able to collaborate with drug companies to develop a new class of therapeutics that target these regions. The last 2 years of the pandemic have brought a significant investment and research interest in mRNA vaccines and RNA biology. Given the unprecedented advances in RNA-based therapeutics, I foresee that my proposed research will not only tackle important unanswered biological questions underlying therapy resistance in prostate cancer but also bring forth a new paradigm in prostate cancer treatment. My ultimate career goal is to become an independent researcher with a focus on prostate cancer. I joined the Hsieh Lab for my postdoctoral training to expand my expertise in prostate cancer and mRNA biology and to discover new therapeutic approaches for CRPC. Through the co-mentorship of Drs. Hsieh and Pan (tRNA expert), I will learn the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310123
Entities
People
- Yeon Soo Kim
Organizations
- Fred Hutchinson Cancer Center
- United States Army