Exploring the Glucocorticoid Receptor and Its Target Dickkopf-1 in Androgen Receptor-Independent Prostate Cancer
Abstract
Enzalutamide, one of the newest prostate cancer treatments, represents a significant improvement over previous drugs, but still falls significantly short of the goal of curing metastatic prostate cancer. Nearly 50% of patients do not respond to enzalutamide, and any benefits that are seen are typically temporary. Enzalutamide works by blocking the effects of testosterone and its derivatives from stimulating prostate cancers. Prostate cancers have a cellular switch called the androgen receptor that can be "flipped on" by testosterone and its derivatives. Enzalutamide keeps the switch in the "off" position. A major problem in the field of prostate cancer research is that some resistant prostate cancers seem to be able to grow in the presence of enzalutamide despite enzalutamide maintaining the switch in the "off" position. Our preliminary data indicates that a gene known as glucocorticoid receptor can transform prostate cancers into a type that is highly resistant to enzalutamide and enable prostate cancer to thrive with androgen receptor in the "off" state. This proposal seeks to identify a novel way of detecting glucocorticoid receptor in order to predict who will respond to enzalutamide and to validate a next-generation therapeutic approach to treating enzalutamide-resistant prostate cancer. We have discovered that traces of the glucocorticoid receptor can be detected in cancer cells found in the blood of prostate cancer patients, which should enable non-invasive detection of the presence of this resistance mechanism and spare patients the need for a biopsy. We have found that the glucocorticoid receptor can promote resistance to enzalutamide in diverse forms of prostate cancer that we can grow in the laboratory. Finally, we have discovered a novel gene, Dickkopf-1, that the glucocorticoid receptor might activate, which itself might make prostate cancer vulnerable to an entirely new treatment that works by blocking the activity of Dickkopf-1. If successful, the results of my research project will address the sizeable population of patients with metastatic prostate cancer who have been treated with and developed resistance to enzalutamide. This project has the potential to impact prostate cancer management by: (1) leading to development of a non-invasive test that will better personalize the use of enzalutamide to patients more likely to receive benefit; (2) providing strong scientific grounds to support a clinical trial that will test drugs which block the activity of the glucocorticoid receptor in order to reverse resistance to enzalutamide; and (3) developing the foundation for a clinical trial testing whether blocking Dickkopf-1 activity can be an effective treatment for prostate cancers that have developed resistance to enzalutamide. If our project succeeds, it is estimated that approximately 1 to 2 years of work will be needed before these strategies can be translated into patient care. This research will be a critical component of my training, which is geared toward helping me to establish a career as an independent physician-scientist focused on clinical and laboratory-based advancement of prostate cancer research. This proposal, carried out under the laboratory mentorship of Dr. Charles Sawyers and the clinical mentorship of Dr. Howard Scher, both leading prostate cancer researchers, forms the centerpiece of the integrated physician-scientist training program at Memorial Sloan Kettering Cancer Center. This training regimen, which involves researching an area of great clinical and scientific importance through the use of cutting-edge molecular tools and developing clinical expertise in innovative cancer care, will provide a strong foundation to enable me to achieve my career goals.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710383
Entities
People
- David Wise
Organizations
- New York University
- United States Army