Targeting the Oncogenomic Function of the E2F8 Transcription Factor in Lethal Prostate Cancer
Abstract
Prostate cancer is a sex-related disease that requires male hormones for growth and/or survival. The ability of testosterone and dihydrotestosterone (DHT) to activate oncogenic signaling has made hormone deprivation therapy the main treatment of choice for prostate cancer. Although hormone deprivation initially leads to prostate tumor regression and improves patient survival, it fails to eradicate prostate cancer. Treatment resistance inevitably develops, and prostate cancer eventually progresses to a lethal castration-resistant stage (CRPC). The key goals of prostate cancer research are to better understand the biology of lethal stage prostate cancer and to develop an alternative targeted therapy to improve patient outcomes. Patient diagnosis with CRPC rarely requires a biopsy or surgery. As a result, very few CRPC tumors become available to researchers, creating a technical barrier for the study of CRPC. Fortunately, the Stand Up to Cancer (SU2C) project has begun to find solutions for this research challenge by collecting CRPC tumors, analyzing their molecular composition, and sharing the results with the research community. Our group has analyzed the SU2C data in search of CRPC abnormalities in a key group of molecules called transcription factors (TF). TFs can dramatically influence cellular behavior by binding to DNA sequences and controlling the use of genetic information. We have discovered that the most severe cases of CRPC often contain high levels of a specific TF known as E2F8. We hypothesize that abnormally high levels of E2F8 reprogram cellular behavior, contributing to the rapid growth and treatment resistance observed in lethal CRPC. We also removed E2F8 from CRPC cells and observed significant decreases in growth and invasive spread. In this proposal, we aim to use cutting-edge technologies to discover in detail how E2F8 enables CRPC cell growth and invasion and to develop a new treatment to block its effects. Researchers have long sought to develop therapies to block the activities of TFs involved in cancer or other diseases; however, the repeated failure of these efforts has led to the reputation that TFs may be undruggable. We propose to develop a non-traditional form of gene therapy to block E2F8 in CRPC, based on cutting-edge RNA-based CRISPR/Cas13d technology. This new form of gene therapy is thought to directly block the formation of the TF molecule without the unpredictable side effects associated with traditional therapies. Future clinical use will require the therapeutic ingredients to be delivered directly to the tumor inside a delivery capsule (called a nanoparticle) that we propose to make using FDA-approved materials that are biocompatible and biodegradable within the body. We will rigorously evaluate both the efficacy and safety of the new therapy in multiple laboratory models of lethal prostate cancer. In summary, the proposed study will directly address the overarching challenges of the PCRP to define the biology of lethal prostate cancer to reduce death and to develop treatments that improve outcomes for men with lethal prostate cancer. This project investigating the role of E2F8 in CRPC is an important step towards my career goal to become an independent researcher studying the basis of prostate cancer progression to CRPC and pioneering more-effective therapeutics to combat this lethal disease. The proposed research plan will provide a foundation for my future investigations of TF-targeted gene therapies that integrate nanoparticle and CRISPR/Cas13 RNA editing technologies. The successful completion of the proposed project will be followed by more extensive and robust evaluation of safety and effectiveness of this RNA-editing agent in a preclinical setting, with the ultimate goal of progressing to a clinical trial. This fellowship would provide me with valuable opportunities to interact with mentors and collaborators who are experts in identifying genetic
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210039
Entities
People
- Furong Huang
Organizations
- Duke University
- United States Army