Regulation of the Androgen Receptor Splice Variant, AR-V7, in Castration-Resistant Prostate Cancer
Abstract
Objective and Rationale: Prostate cancer is the second most common cause of cancer death among men in the United States. Treatments that block the actions of androgens (male sex hormones that fuel prostate cancer) are effective in early stages of the disease. However, prostate cancer often progresses to a "castration-resistant" state in which it stops responding to androgen-blocking drugs and for which there is no cure. Two recent drugs, enzalutamide and abiraterone, have improved survival in men with castration-resistant prostate cancer. However, 20% to 40% of patients do not respond to these drugs, and most of those who benefit initially eventually stop responding. Understanding how prostate cancer stops responding to androgen-blocking drugs is crucial for developing new therapies that will reduce death from this disease. One common way that prostate cancers become resistant to androgen-blocking drugs is by producing a shortened form of the androgen receptor, called AR-V7. There is a strong clinical association between AR-V7 levels and lack of response to androgen-blocking drugs, but several open questions remain. For example, how is AR-V7 produced in castration-resistant prostate cancer? What changes in the DNA and proteins of the cancer cell lead to the production of AR-V7? And can these mechanisms be targeted to improve treatments for advanced prostate cancer? This proposal seeks to make progress toward answering the above questions. In Aim 1, we will use DNA sequencing to read the sequence of DNA bases in the genomes of castration-resistant prostate cancer specimens with high levels of AR-V7. We will use a novel sequencing technology, called "10X Genomics," that reads hundreds of thousands of DNA bases at a time, as compared with conventional DNA sequencing technologies that read hundreds of DNA bases at a time. This will allow us to precisely describe complex changes, or "alterations," in the DNA of castration-resistant prostate cancer cells, including alterations that may have been previously undetectable. We will then see whether the DNA alterations we identify are predictive of AR-V7 levels and of response to androgen-blocking drugs. In Aim 2, we will create cellular model systems to understand how these DNA alterations (either newly identified by us or previously identified by other researchers) lead to AR-V7 formation. In Aim 3, we will use a novel DNA-editing technology, termed "CRISPR/Cas9," to investigate every single gene in the tumor for its ability to increase AR-V7 levels and thereby contribute to drug resistance. These studies will help devise ways to (a) detect which prostate cancers are likely to produce AR-V7 and (b) design new therapies to keep AR-V7 levels low in tumors, to prevent them from becoming drug resistant. These strategies would offer hope to patients with advanced prostate cancer whose tumors often contain high amounts of AR-V7. Applicability of Research: This project has two potential clinical applications for men with castration-resistant prostate cancer: (1) the development of molecular tests to predict drug response, based on DNA alterations we identify (Aim 1) or genes we find that increase AR-V7 levels (Aim 3), and (2) the identification of novel therapeutic targets to overcome AR-V7-mediated drug resistance uncovered by experiments in Aim 3. Translation of this work to a patient-related outcome could occur rapidly (within months to a year) for a diagnostic test (application 1). Development of novel therapeutic targets into new drugs would likely take 5 to 10 years (application 2). Principal Investigator Career Goals: My goal is to improve the survival of men with prostate cancer through my work as a medical oncologist and as a scientist. The proposed training plan will allow me to hone the scientific and clinical skills necessary to become a successful independent investigator in translational prostate cancer research. I will pursue scientific traini
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710358
Entities
People
- Srinivas R Viswanathan
Organizations
- Dana–Farber Cancer Institute
- United States Army