Identifying the Molecular Mechanisms of Prostate Tumorigenesis Associated with Multigenic 3p13-14 Locus Loss Using a Novel CRISPR-Organoid Platform
Abstract
Objective and Rationale: Prostate cancer is the most common malignancy and the second leading cause of cancer death affecting men in the United States, accounting for 30,000 deaths each year. The need for better defining prostate cancer biology and designing therapeutics has made disease modeling and mechanistic study with of high importance. In this regard, prostate cancer research and patient care can be advanced if two challenges can be addressed. First, cancer is a disease of genetic material alterations, but it is challenging to study large chromosomal alterations that affect multiple genes at the same time, which happens to be a frequently occurring event in prostate cancer. Second, the limited efficiency in disease modeling poses another challenge for prostate cancer research at the benchside to catch up with the substantial heterogeneity of patient tumor genome at the bedside. In the proposed project, we aim at overcoming both of the above challenges. By doing so, we are creating a paradigm for studying large chromosomal alterations through rapid disease modeling. Specifically, we are interested in a common large chromosomal deletion that affects 15-20% of prostate cancer patients. Although its prevalence has been appreciated for nearly a decade, there is still very little clue about how it promotes prostate cancer formation, leaving us no insight to leverage for a better therapeutics development due to a paucity of effective research tools. To tackle this challenge, we have combined two cutting-edge technologies, the primary prostate epithelial cell culture and genome engineering, and designed a novel strategy that allows tumor formation in animals as a result of the chromosomal alteration of interest. Our preliminary experiments show evidence for the successful establishment of the tool. In the proposed research, we will continue to leverage the versatility of the tool to address the mechanisms of tumor formation caused by this alteration. Applicability and Contributions: At its conclusion, the project will for the first time comprehensively reveal the disease mechanism of prostate cancer that contains the chromosomal alteration of interest. We anticipate that the 15-20% of affected prostate cancer patients will benefit even further from follow-up studies in two complementary ways. One approach is to exploit the mechanistic discoveries revealed by this project to identify novel treatment targets. Another is to leverage the tumor model established from the project to optimize current treatment options as well as screen for novel therapeutic strategies. Depending on the discoveries, it may take as short as a few years to develop a tailored strategy that benefits this subset of patients. Importantly, the impacts from the proposed research even extends beyond the one type of genome alteration that we study. The experimental pipeline is generic, and in theory can be adapted to model many, if not all, other prostate cancer subtypes. We therefore envisage the versatile disease modeling approaches developed by this study will benefit precision medicine by defining novel cancer drivers and providing animal models to test new treatment strategies. Career Goals: My career goal is to run a multidisciplinary laboratory to provide mechanistic insight into prostate cancer biology and translate the findings into clinically meaningful progress. With a training foundation in basic biology and mechanistic thinking, I plan to build upon and complement my graduate training with a multidisciplinary perspective, expertise in prostate cancer biology, and brand-new skillsets to conduct translational research. The proposed project combines 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 driving force in the prostate cancer research field. Not only has he made revolutionary contributi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910323
Entities
People
- Weiran Feng
Organizations
- Sloan-Kettering Institute
- United States Army