Study the Origin and Mechanisms of Castration Resistance Characterized by Outgrowth of Prostate Cancer Cells with Low/Negative Androgen Receptor
Abstract
Prostate cancer is the most common form of cancer in men. Given the key role of androgen receptor (AR) signaling in disease progression, the current approach to treat prostate cancer is AR-targeted therapy. While this initially results in tumor regression, aggressive disease typically recurs, making the treatment of what is now called castration-resistant prostate cancer (CRPC) the major challenge in the field. Charles Sawyers laboratory developed a second-generation AR inhibitor, enzalutamide, that has increased both patient survival and quality of life, but resistance remains as a major problem with complex molecular mechanisms. One of the resistance mechanisms we have found is that a small subset of resistant tumors shows low or absent AR expression, which can explain the nonresponsiveness of tumors to AR-targeted therapy. This finding is significant, because this subtype of CRPC with low/absent AR has been previously reported in patients with poor prognosis. However, treatment options for this form of disease are currently not available due to the lack of study. Thus, the main objective of this proposed research is to study the molecular mechanisms of this subtype of resistant cancer with a hope to develop effective therapeutic strategies. Our previous data have indicated that AR signaling in prostate cancer is not homogeneous, with a wide spectrum of cells with low to high AR activities. Our hypothesis is that (1) the prostate cancer cells with low AR activity might be less sensitive to the AR inhibitor, enzalutamide, and progress to resistant tumors with low/absent AR or (2) enzalutamide treatment might induce reprogramming of cells with high AR activity to become low/absent AR cells, causing them to acquire resistance to the treatment. The results of this study will provide valuable information on developing therapeutic strategies to treat patients with this deadly subtype of prostate cancer. The results will suggest if we need to eliminate the pre-existing cells with low AR (hypothesis #1) or inhibit the treatment-induced reprogramming of cells to become low AR cells (hypothesis #2). Completion of this fellowship will provide us potential drug targets for each possible mechanism, which can be used to establish a platform for further drug development. The speed at which we translate this information into useful strategies will be dictated by the nature of the drug targets. If there are already drugs targeting the candidate factors/pathways, appropriate trials could start in the next 3-5 years. However, it will take longer if appropriate drugs do not already exist. Overall, increased knowledge of this deadly subtype of prostate cancer holds great potential to decrease suffering and improve survival of prostate cancer patients. My career goal is to become a head of a laboratory studying the mechanisms of acquired resistance in prostate cancer. During my graduate research, I have developed passion for studying mechanisms of treatment resistance in prostate cancer in a hope to identify more effective therapies. Therefore, this proposed research is a logical extension of my PhD studies and also aligns with my career goal, where I can further explore my background and interest in studying the mechanisms of acquired resistance in prostate cancer. My postdoctoral mentor, Charles Sawyers has been investigating the molecular mechanisms of treatment resistance in prostate cancer with fundamental breakthroughs such as development of a next-generation AR inhibitor, enzalutamide. I believe that completion of this fellowship in the Sawyers laboratory will help me to achieve my long-term career goal of understanding mechanisms of treatment resistance in prostate cancer and making significant improvement on patient survival.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510540
Entities
People
- Eugine Lee
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army