Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Prostate cancer

Exosomal AR-V7 is a marker of hormonal therapy resistance

Androgen receptor splice variant 7 (AR-V7) can be isolated from exosomal RNA in the bloodstream, with the potential to be used as a new prognostic test, according to a recent study published in European Urology.

Credit: sergunt/iStock/Getty

The constitutively active AR-V7 lacks a ligand-binding domain (LBD) and is associated with resistance to hormonal prostate cancer therapies, in particular enzalutamide (which binds to the LBD on the wild-type receptor) and abiraterone. A validated marker for determining resistance to these second-line therapies would be extremely useful for treatment planning and prognostication, as the currently available biomarkers, such as PSA, are poor. “The AR-V7 analysis developed on RNA extracted from plasma-derived exosomes could represent a sensitive, easy-to-perform, and fast laboratory approach to screen patients,” corresponding author Marzia Del Re told Nature Reviews Urology.

Del Re and colleagues developed a new approach to isolating AR-V7 from circulating exosomal RNA in order to confirm its role as a marker of therapeutic resistance.

VCaP cells, which are known carriers of AR-V7, were used to develop the AR-V7 RNA isolation digital droplet PCR (ddPCR) method. Once the ddPCR method was finalized and the sensitivity assessed, 36 patients with metastatic castration-resistant prostate cancer (mCRPC) were enrolled, who donated 3 ml blood before enzalutamide or abiraterone therapy was commenced. A further sample was taken at disease progression. Exosomes were isolated from the blood samples and the RNA was then extracted.

The AR-V7 transcript was detectable, even at low levels (2 copies/ml) using the ddPCR platform. 14 of the 36 patients were AR-V7+ at baseline, before hormonal therapy was started. Of these, seven had a sample also taken at disease progression, which showed a nonsignificant increase in AR-V7 levels. Progression-free survival, measured by either clinical or radiographic progression, was longer in AR-V7 patients than AR-V7+ patients (20 months versus 3 months; P <0.001), in whom overall survival was significantly shorter (8 months versus not reached; P <0.001), suggesting that exosomal AR-V7 is a valuable resistance marker. AR-V7+ patients were more likely to be younger, have a tumour Gleason Score >8, visceral metastases, increased PSA, and have received prior docetaxel, than those who were AR-V7. “The findings suggest that plasma-derived exosomal RNA is a reliable source of AR-V7 and that ddPCR can sensitively detect it,” commented Del Re. “Moreover, our data confirmed that resistance to hormonal therapy can be predicted by AR-V7, making it a clinically relevant biomarker.”

The AR-V7 test is already available in Del Re's laboratory for patients who have progressed under hormonal therapy, with a very short turnaround time. They now plan to analyse additional mechanisms of resistance — that is, other common androgen receptor splice variants — to better understand tumour heterogeneity and progression towards refractoriness to hormonal manipulation.

References

  1. 1

    Del Re, M. et al. The detection of androgen receptor splice variant 7 in plasma-derived exosomal RNA strongly predicts resistance to hormonal therapy in metastatic prostate cancer patients. Eur. Urol. http://dx.doi.org/10.1016/j.eururo.2016.08.012 (2016)

Download references

Authors

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fenner, A. Exosomal AR-V7 is a marker of hormonal therapy resistance. Nat Rev Urol 13, 695 (2016). https://doi.org/10.1038/nrurol.2016.220

Download citation

Search

Quick links