Identifying Androgen Receptor-Independent Mechanisms of Prostate Cancer Resistance to Second-Generation Antiandrogen Therapy
Abstract
Enzalutamide, one of the newest prostate cancer treatments, represents a significant improvement over earlier generation drugs, but still falls significantly short of the goal of curing metastatic prostate cancer. Nearly 50% of patients do not respond to enzalutamide, and the responses that are seen are typically temporary. This proposal seeks to identify novel strategies for circumventing this resistance to provide more durable treatments for our patients. Our preliminary data indicate that a gene known as serum/glucocorticoid-regulated-kinase 1 (SGK1), when expressed at high levels, can transform prostate cancers into a type that is highly resistant to enzalutamide. Our laboratory has the necessary tools and expertise to further characterize the effects of SGK1 and to determine whether approaches that can silence the effects of SGK1 would be effective as therapeutics for prostate cancers resistant to enzalutamide. This research will be a critical component of my training, which is geared towards helping me to establish a career as an independent physician-scientist focused on laboratory-based advancement of prostate cancer research. This proposal, carried out under the mentorship of Dr. Charles Sawyers, a leading prostate cancer researcher, forms the centerpiece of the integrated physician-scientist training program at Memorial Sloan Kettering Cancer Center (MSKCC) in which I am currently enrolled. I am supplementing this research with clinical training in prostate cancer medical oncology with Dr. Howard Scher, a leading clinical oncologist and prostate cancer researcher. This training regimen -- 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 me with a strong foundation to enable me to achieve my career goals. If successful, the results of my research project will address the large fraction of patients with metastatic prostate cancer who have been treated with and have developed resistance to enzalutamide. The potential impact of this project is to establish the scientific proof-of-concept that therapies that negate the effects of SGK1 would be powerful tools for the treatment of prostate cancer resistant to enzalutamide. SGK1 inhibitors have not been tested in humans and the risk of drug-related toxicity is present, but this risk is mitigated by the observation of minimal side effects in mice treated with these agents. If our project succeeds, it is estimated that approximately 1 to 2 years of additional work will be needed before these agents can be tested in patients. 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 resistant prostate cancers seem to be able to grow in the presence of enzalutamide despite enzalutamide maintaining the switch in the "off" position. Our research proposes to identify a novel mechanism through which prostate cancers can thrive in this "off" state. This will shed further light on the biology driving prostate cancer and, if successful, provide a powerful new strategy for treating these highly resistant cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510276
Entities
People
- David Wise
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army