Determining the Impact of FOXA1 Alterations on the Prostate Epithelium and the Prostate Microenvironment
Abstract
Objective and Rationale: Prostate cancer is the second most common malignancy and the second leading cause of cancer death affecting men in the U.S., accounting for 33,000 death each year. Same as other cancer types, prostate cancer is featured by and driven by genomic alterations. A better understanding of the oncogenic mechanisms behind these genetic alterations will help design better therapeutic strategies for treating cancer patients. In addition, cancer should be studied as an ecosystem because cancer cells are surrounded by a lot of non-cancerous cells and non-cell components, which are called the tumor microenvironment. Activation of an oncogene will not only impact tumor cells themselves, but also impact the surrounding microenvironment, then the transformed microenvironment will promote the growth of tumor cells in return. FOXA1 is a gene found recurrently altered in 10% of primary prostate cancer and 15% of metastatic castration-resistant prostate cancer in Western cohorts. In Asian, the frequency is much higher based on results from a Chinese cohort shows that FOXA1 is mutated in 41% of localized prostate tumors. Using cell culture system, it was demonstrated that FOXA1 mutations drive prostate cancer by altering chromatin landscape and perturbing normal prostate differentiation programs. However, the impact of FOXA1 alterations on prostate gland is not fully uncovered because of the following limitations of the cell culture system: (1) the cultured prostate cells cannot recapitulate the complexity of the prostate epithelium, and (2) the prostate microenvironment, including the mesenchymal cells, immune cells, is missing in the cell culture system. Transgenic mouse models are valuable tools to study oncogenic transformation in native tissue with the microenvironment. In this project, we will study the role of FOXA1 alterations using our innovative transgenic mouse models to address the following key questions: (1) What is the impact of FOXA1 alterations on the native prostate epithelium? (2) What is the impact of FOXA1 alterations on the prostate microenvironment? Applicability and Contributions: At its conclusion, the project will get us a comprehensive mechanistic understanding of the cell transformation driven by FOXA1 alterations in the physiological context, which aligns well with the PCRP Overarching Challenge of defining the biology of lethal prostate cancer to reduce death. The mechanistic insights gained from this project will provide rationale for designing novel therapeutics to target FOXA1-altered prostate cancers. Furthermore, the mouse models used and developed in this project will become valuable preclinical tools for testing and optimizing treatment options for this subset of prostate cancer. Depending on the discoveries made in this project, it may take as short as a few years to develop a tailored strategy that benefits this subset of patients. Career Goals: My career goal is to establish a laboratory that focuses on understanding the mechanism of prostate oncogenesis and providing translational insights to benefit prostate cancer patients. The project proposed here integrates basic biological concepts, cutting-edge technologies, and translational potential, which I am seeking to build upon when running my independent laboratory. Dr. Sawyers is a world-renowned prostate cancer researcher with revolutionary accomplishments in both disease mechanism discovery and targeted therapy development and has an impressive track record of training independent scientists who continue to contribute to the field. I will take advantage of the prostate cancer insight, the powerful research platforms and supportive training environment of the laboratory, the resources of MSKCC, and the internal and external meetings/conferences to improve my multidisciplinary thinking, acquire the experimental techniques, and build collaborations that are critical to complete the project,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210116
Entities
People
- Teng Han
Organizations
- Sloan-Kettering Institute
- United States Army