Mechanisms and Therapeutic Targeting of Nuclear Shape Instability in Lethal Prostate Cancer
Abstract
Most prostate cancers are highly treatable with standard therapies. However, aggressive prostate cancer is one of the most frequent causes of cancer-related death worldwide, and about 30,000 men in North America die from prostate cancer every year. Our understanding of aggressive prostate cancer at the molecular level is still poor. Important unresolved questions are: What are the molecular characteristics of aggressive prostate cancer and can these be identified early so that treatment can begin as soon as possible in the course of the disease? Can we identify features of aggressive cancers that would suggest specific lines of therapy? Because treatment for aggressive disease takes place over the course of years and repeated biopsy is most often not feasible, are there ways to follow cancer evolution using blood draws? This last idea is known as “liquid biopsy.” We have identified a novel molecular marker that signifies disrupted tumor cell nuclei. Paradoxically, destabilization of the structure of the cancer cell nucleus can make the tumor cells more aggressive and metastatic. We have shown that microscopic visualization of a nuclear membrane protein called “emerin” can report destabilized cancer cell nuclei in preclinical models of prostate cancer and in human prostate cancer specimens. Disrupted localization of emerin is a poor prognostic indicator in human prostate cancer. Visualizing emerin in prostate cancer cells identifies a condition called “nuclear shape instability,” abbreviated NSI. We have been studying NSI using genetic and molecular methods and have found that these cells shed membrane-enclosed particles, termed extracellular vesicles (EVs), into their environment. Analysis of these particles indicates they contain material from cell nuclei, including chromosomal DNA, suggesting they arise from cells with NSI. Tumor cells exhibiting NSI can be more sensitive to therapeutic agents, such as taxanes. Collectively, these findings suggest it is possible to identify NSI in the circulation of patients using a blood test and that such a test might indicate an effective therapeutic path. This project will attempt to determine the molecular mechanisms that promote NSI and that produce EVs containing chromosomal DNA. We will determine whether EVs from cells with NSI contain genomic DNA. We will test the hypothesis that a novel protein driver of metastasis in drug-resistant prostate cancer, ONECUT2, will produce NSI, and we will test whether inhibiting this protein using a drug-like small molecule we developed can reverse this process. We will attempt to determine whether preclinical PC models of NSI produce EVs that contain genomic DNA and determine whether EVs with nuclear content are associated with aggressive prostate cancer in patients. Finally, we will test a novel strategy for identifying patients with active ONECUT2 by using our technology for isolating and characterizing EVs in the blood. NSI is a poorly characterized and understood feature of prostate cancer cells. We believe this cancer cell property can be targeted with rational therapies. Prostate cancer is a disease where “biopsy is hard but blood is easy.” This project represents a first-in-field strategy to evaluate NSI in prostate cancer patients using methods that could be adapted to a clinical blood test.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010695
Entities
People
- Michael R Freeman
Organizations
- Cedars-Sinai Medical Center
- United States Army