One mechanism used by prostate cancers to escape androgen deprivation and become castrate resistant prostate cancer (CRPC) is generation of splice variant(s) (ARsv) of the androgen receptor (AR) that no longer contain the C-terminal ligand-binding domain and are constitutively active. We have shown that these forms occur not simply because of castration, but also require a decrease in intratumoral androgen levels. Additionally, we have shown in preclinical studies that the newer androgen targeting agents such as abiraterone and MDV3100 are potent agents in generating ARsvs. Moreover, these constitutively active ARsvs generate a mitotic transcriptome that Is significantly altered from the canonical AR-ligand-driven transcriptome. Clinically, the appearance of the ARsvs has been associated with more rapid progression and time to death. However, the ARsv usually is co-expressed with the full-length AR (ARfl), raising the question as to whether ARfl is required for ARsv activity. It has also not been shown how the ARSV transcriptome is generated, i.e. do the ARsvs interact at different sites on chromatin the ARfl? A third issue is whether generation of ARsvs is a transcriptional event due to intragenic rearrangement of the AR gene or whether the variants can also be generated by post-transcriptional splicing mechanisms. Finally, clinical studies have not been performed that identify the clinical spectrum of ARsv presentation. These questions are important to address in order to develop appropriate therapy for the patients that invariably will relapse on even the newest prostate cancer treatments directed at AR inhibition. In this project we will address these questions by addressing the following Hypothesis and performing four specific aims: Hypothesis: Constitutively active androgen receptor splice variants (ARsv) are generated by alternative splicing of AR pre-mRNA in response to decreased intra-tumoral androgen levels as cell stress in induced;these variants maintain AR-driven tumor progression, however, the effect of the AR variant may differ depending on variant structure and whether the variant is acting independently or through dimerization with ARfi. Ultimately, the expression of ARsv will determine development of CRPC and the response to therapy.

Public Health Relevance

Even with the newest therapy for castrate resistant prostate cancer e.g. abiraterone or MDV3100, studies show that recurrence is still driven in most all cases through an AR-mechanism. This proposal will address how this bypass of current therapy occurs and the proposed mechanisms that need to be targeted in this recurrence.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-O)
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Beth Israel Deaconess Medical Center
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