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)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
Penning, Trevor M (2017) Aldo-Keto Reductase (AKR) 1C3 inhibitors: a patent review. Expert Opin Ther Pat 27:1329-1340
Sowalsky, Adam G; Kissick, Haydn T; Gerrin, Sean J et al. (2017) Gleason Score 7 Prostate Cancers Emerge through Branched Evolution of Clonal Gleason Pattern 3 and 4. Clin Cancer Res 23:3823-3833
Green, S M; Kaipainen, A; Bullock, K et al. (2017) Role of OATP transporters in steroid uptake by prostate cancer cells in vivo. Prostate Cancer Prostatic Dis 20:20-27
Suominen, Mari I; Fagerlund, Katja M; Rissanen, Jukka P et al. (2017) Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models. Clin Cancer Res 23:4335-4346
Bluemn, Eric G; Coleman, Ilsa M; Lucas, Jared M et al. (2017) Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling. Cancer Cell 32:474-489.e6
Mostaghel, Elahe A; Cho, Eunpi; Zhang, Ailin et al. (2017) Association of Tissue Abiraterone Levels and SLCO Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer. Clin Cancer Res 23:4592-4601
Zou, Min; Toivanen, Roxanne; Mitrofanova, Antonina et al. (2017) Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer. Cancer Discov 7:736-749
Nyquist, Michael D; Prasad, Bhagwat; Mostaghel, Elahe A (2017) Harnessing Solute Carrier Transporters for Precision Oncology. Molecules 22:
Nyquist, Michael D; Corella, Alexandra; Burns, John et al. (2017) Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155. Mol Cancer Res 15:521-531
Zang, Tianzhu; Tamae, Daniel; Mesaros, Clementina et al. (2017) Simultaneous quantitation of nine hydroxy-androgens and their conjugates in human serum by stable isotope dilution liquid chromatography electrospray ionization tandem mass spectrometry. J Steroid Biochem Mol Biol 165:342-355

Showing the most recent 10 out of 74 publications