The Role of Alternate Splicing in Androgen Receptor Isoform Specific Actions
Abstract
The evidence that most castration-resistant prostate cancers (CRPC) remain dependent on androgen receptors is compelling. Many men who fail first-line androgen deprivation therapies therapy respond to one the newer therapies such as Enzalutamide, but many show de novo resistance and most develop resistance. These tumors still may be dependent on androgen receptors. Androgen receptors are hormone-activated transcription factors, which regulate expression of many genes. There are multiple methods for reactivation of androgen receptors. One of the most challenging to overcome is expression of constitutively active variants that lack the hormone binding domain of the androgen receptor and therefore are resistant to all conventional anti-androgen therapies. Expression of one of these variants, AR-V7, has been correlated with resistance to therapies such as Enzalutamide or abiraterone, and it has been suggested by some investigators that by not treating AR-V7-positive patients with these treatments, the patients could move on to other therapies that might be more beneficial, avoid morbidity associated with treatment, and save $150 million/year on treatments that are unlikely to succeed. However, another study found that some patients with AR-V7-positive circulating tumor cells (CTC) did respond to some extent to these therapies. Thus, a better means to identify patients whose tumors are AR-V7-dependent versus expressing too little AR-V7 to develop dependence is needed. For those that are AR-V7-dependent, a better understanding of the actions of AR-V7 is needed in order to develop new therapies either to target AR-V7 itself, or its downstream actions. We have found that not only does AR-V7 change overall gene expression in some unique ways, it also can cause alternative splicing of the coding regions of the genes, so that novel protein forms are expressed. These unique activities are potential biomarkers and therapeutic targets. Thus, we will take advantage of our cell models to identify highly regulated and AR-V7-specific changes that we will then test in data sets from clinical samples to seek to develop a ?signature,? which can be used to stratify patients with CRPC who are likely to respond versus those that will not. Second, we seek to understand how the AR-V7 induces these unique activities and the biological consequences of these activities to determine whether there are useful therapeutic targets in AR-V7-expressing tumors. We will be able to test the gene signature using data from Michigan, MD Anderson, and Johns Hopkins during the course of this study and, if the results are promising, further tests could be done immediately to determine whether the signature can be used to determine who should be treated and who will not benefit. The studies of the therapies are likely to taking longer to be translatable to the clinic. Within the grant, we will be able to identify potential targets, but additional studies would have to be done to determine whether they were good therapeutic targets.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710236
Entities
People
- Nancy Weigel
Organizations
- Baylor College of Medicine
- United States Army