A Whole Blood Assay for AR-V7 and AR in Patients with Prostate Cancer

Overview

Journal J Urol

Publisher Wolters Kluwer

Specialty Urology

Date 2016 Jul 25

PMID 27449259

Citations 30

Authors

Xichun Liu

Elisa Ledet

Dongying Li

Ary Dotiwala

Allie Steinberger

Allison Feibus

Jianzhuo Li

Yanfeng Qi

Jonathan Silberstein

Benjamin Lee

Yan Dong

Oliver Sartor

Haitao Zhang

Affiliations

Soon will be listed here.

Abstract

Purpose: Most prostate cancer mortality can be attributed to metastatic castration resistant prostate cancer, an advanced stage that remains incurable despite recent advances. The AR (androgen receptor) signaling axis remains active in castration resistant prostate cancer. Recent studies suggest that expression of the AR-V (AR splice variant) AR-V7 may underlie resistance to abiraterone and enzalutamide. However, controversy exists over the optimal assay. Our objective was to develop a fast and sensitive assay for AR-Vs in patients.

Materials And Methods: Two approaches were assessed in this study. The first approach was based on depletion of leukocytes and the second one used RNA purified directly from whole blood preserved in PAXgene® tubes. Transcript expression was analyzed by quantitative reverse transcription-polymerase chain reaction.

Results: Through a side-by-side comparison we found that the whole blood approach was suitable to detect AR-Vs. The specificity of the assay was corroborated in a cancer-free cohort. Using the PAXgene assay samples from a cohort of 46 patients with castration resistant prostate cancer were analyzed. Overall, AR-V7 and AR were detected in 67.53% and 29.87% of samples, respectively. Statistical analysis revealed a strong association of AR-V positivity with a history of second line hormonal therapies.

Conclusions: To our knowledge this is the first study to demonstrate that PAXgene preserved whole blood can be used to obtain clinically relevant information regarding the expression of 2 AR-Vs. These data on a castration resistant prostate cancer cohort support a role for AR-Vs in resistance to therapies targeting the AR ligand-binding domain.

Citing Articles

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The Prognostic Value of Liquid Biopsies for Benefit of Salvage Radiotherapy in Relapsed Oligometastatic Prostate Cancer.

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Advances in the Current Understanding of the Mechanisms Governing the Acquisition of Castration-Resistant Prostate Cancer.

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Liquid Biopsy Based Circulating Biomarkers in Metastatic Prostate Cancer.

Dathathri E, Isebia K, Abali F, Lolkema M, Martens J, Terstappen L Front Oncol. 2022; 12:863472.

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Androgen receptor variant shows heterogeneous expression in prostate cancer according to differentiation stage.

Gjyrezi A, Galletti G, Zhang J, Worroll D, Sigouros M, Kim S Commun Biol. 2021; 4(1):785.

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References

Hu R, Dunn T, Wei S, Isharwal S, Veltri R, Humphreys E . Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009; 69(1):16-22. PMC: 2614301. DOI: 10.1158/0008-5472.CAN-08-2764. View

Galletti G, Portella L, Tagawa S, Kirby B, Giannakakou P, Nanus D . Circulating tumor cells in prostate cancer diagnosis and monitoring: an appraisal of clinical potential. Mol Diagn Ther. 2014; 18(4):389-402. PMC: 4149177. DOI: 10.1007/s40291-014-0101-8. View

Lara O, Tong X, Zborowski M, Chalmers J . Enrichment of rare cancer cells through depletion of normal cells using density and flow-through, immunomagnetic cell separation. Exp Hematol. 2004; 32(10):891-904. DOI: 10.1016/j.exphem.2004.07.007. View

Cottard F, Asmane I, Erdmann E, Bergerat J, Kurtz J, Ceraline J . Constitutively active androgen receptor variants upregulate expression of mesenchymal markers in prostate cancer cells. PLoS One. 2013; 8(5):e63466. PMC: 3642121. DOI: 10.1371/journal.pone.0063466. View

Yang L, Lang J, Balasubramanian P, Jatana K, Schuller D, Agrawal A . Optimization of an enrichment process for circulating tumor cells from the blood of head and neck cancer patients through depletion of normal cells. Biotechnol Bioeng. 2008; 102(2):521-34. PMC: 3906726. DOI: 10.1002/bit.22066. View

Thomas M . The leukocyte common antigen family. Annu Rev Immunol. 1989; 7:339-69. DOI: 10.1146/annurev.iy.07.040189.002011. View

Liu G, Sprenger C, Sun S, Epilepsia K, Haugk K, Zhang X . AR variant ARv567es induces carcinogenesis in a novel transgenic mouse model of prostate cancer. Neoplasia. 2013; 15(9):1009-17. PMC: 3769880. DOI: 10.1593/neo.13784. View

Todenhofer T, Hennenlotter J, Feyerabend S, Aufderklamm S, Mischinger J, Kuhs U . Preliminary experience on the use of the Adnatest® system for detection of circulating tumor cells in prostate cancer patients. Anticancer Res. 2012; 32(8):3507-13. View

Antonarakis E, Lu C, Wang H, Luber B, Nakazawa M, Roeser J . AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014; 371(11):1028-38. PMC: 4201502. DOI: 10.1056/NEJMoa1315815. View

10.

Sun F, Chen H, Li W, Yang X, Wang X, Jiang R . Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors. J Biol Chem. 2013; 289(3):1529-39. PMC: 3894334. DOI: 10.1074/jbc.M113.492140. View

11.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

12.

Sun S, Sprenger C, Vessella R, Haugk K, Soriano K, Mostaghel E . Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest. 2010; 120(8):2715-30. PMC: 2912187. DOI: 10.1172/JCI41824. View

13.

Li Y, Chan S, Brand L, Hwang T, Silverstein K, Dehm S . Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res. 2012; 73(2):483-9. PMC: 3549016. DOI: 10.1158/0008-5472.CAN-12-3630. View

14.

Cao B, Qi Y, Zhang G, Xu D, Zhan Y, Alvarez X . Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy. Oncotarget. 2014; 5(6):1646-56. PMC: 4039237. DOI: 10.18632/oncotarget.1802. View

15.

Xu D, Zhan Y, Qi Y, Cao B, Bai S, Xu W . Androgen Receptor Splice Variants Dimerize to Transactivate Target Genes. Cancer Res. 2015; 75(17):3663-71. PMC: 4558376. DOI: 10.1158/0008-5472.CAN-15-0381. View

16.

Harouaka R, Kang Z, Zheng S, Cao L . Circulating tumor cells: advances in isolation and analysis, and challenges for clinical applications. Pharmacol Ther. 2013; 141(2):209-21. PMC: 3947247. DOI: 10.1016/j.pharmthera.2013.10.004. View

17.

Danila D, Anand A, Schultz N, Heller G, Wan M, Sung C . Analytic and clinical validation of a prostate cancer-enhanced messenger RNA detection assay in whole blood as a prognostic biomarker for survival. Eur Urol. 2013; 65(6):1191-7. PMC: 4113474. DOI: 10.1016/j.eururo.2013.07.006. View

18.

Helo P, Cronin A, Danila D, Wenske S, Gonzalez-Espinoza R, Anand A . Circulating prostate tumor cells detected by reverse transcription-PCR in men with localized or castration-refractory prostate cancer: concordance with CellSearch assay and association with bone metastases and with survival. Clin Chem. 2009; 55(4):765-73. PMC: 2782624. DOI: 10.1373/clinchem.2008.117952. View

19.

Gandhok N, Looney S, Koochekpour S, Sartor O . Relationships between reverse transcriptase-polymerase chain reaction for prostate specific antigen, survival, and various prognostic laboratory factors in patients with hormone refractory prostate cancer. Urol Oncol. 2005; 23(3):163-7. DOI: 10.1016/j.urolonc.2004.11.009. View

20.

Guo Z, Yang X, Sun F, Jiang R, Linn D, Chen H . A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 2009; 69(6):2305-13. PMC: 2672822. DOI: 10.1158/0008-5472.CAN-08-3795. View