Effects of Phthalates on Androgen Receptor Regulation Associated with Castration-Resistant Prostate Cancer Development
Abstract
Scientific Objective and Rationale: Androgen deprivation therapy is initially effective for most prostate cancer patients, but it recurs after several years and becomes resistant, defined as castration-resistant prostate cancer (CRPC). The molecular mechanisms of the transition to CRPC are poorly understood. The androgen receptor (AR) is known to play a key role in prostate cancer progression. CRPC grows either through AR signaling or without AR signaling (i.e., AR-negative cells). Numerous mechanisms were introduced to show how CRPC continues to grow through AR signaling. Current CRPC therapies are mostly aimed to either inhibit AR expression or block androgen biosynthesis based on those findings. However, there is a considerable population of CRPC patients that are typically ignored, showing a loss of AR in the tumor. For this group of patients, current treatments are ineffective. However, little research is conducted to investigate the pathways that are associated with the AR-negative CRPC development. Therefore, the overall goal is to elucidate molecular mechanisms involved in the CRPC development specifically in the AR-negative cell population. Nowadays, high attention is given to the effects of environmental toxicants on biological systems because we are all exposed to these environmental factors for decades, and many studies have shown association of environmental toxicant exposure with adverse health outcomes. However, very little is known of their impact on PRCA progression. Phthalates are widely used in plastics and many everyday products. The proposed project will investigate the effects of phthalates on AR regulation at molecular levels and determine its role in the CRPC development. This project will use PRCA models both in vitro and in vivo, which will be exposed to phthalates. PRCA xenografts will be implanted into mice and assessed for PRCA aggressiveness. Additionally, AR levels and their epigenetic alterations will be measured. Career Goals: I am committed to a career as a principal investigator in a major research university to probe fundamental questions that are essential to prostate cancer etiology and treatment. My research training to date has been focusing on chemistry (formal education) and environmental toxicology (doctoral research). My attention is focused on prostate cancer because my father was diagnosed with stage III prostate cancer. My father went through additional tests and recently received a robotics surgery. It was a difficult time for my father and my family and we are aware of possible side effects and recurrence of cancer. As a daughter and a scientist, this family situation highly motivated me to focus on prostate cancer research. The proposed training will provide me an outstanding environment at the world-class resources and training institute to attend various seminars and courses on campus to develop a mature understanding and appreciation of the field of cancer biology, so that I can effectively design my own research to address complex problems in prostate cancer research. I will also develop scientific communication skills through grant writing workshops, peer-reviewed journal publications, and presentations in national/international meetings. The proposed research plan will provide me an opportunity to learn novel techniques for prostate cancer research as well as an opportunity to interact with outstanding scientists including clinicians who focus on patient care as well as the underlying biological mechanisms of prostate cancer progression. These interactions will enable me to frame my research in the context of true medical needs and keep me aware of how to translate my research from the laboratory to the clinic. My background in chemistry and toxicology combined with the proposed research plan will uniquely position me to become an independent investigator in prostate cancer research. Research Applicability and Contributions of the Propose
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610246
Entities
People
- Clara Jeong
Organizations
- United States Army
- University of Wisconsin–Madison