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Antibody Selection Influences the Detection of AR-V7 in Primary Prostate Cancer - Beyond the Abstract

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) is difficult to navigate since predictive markers for routine use are missing. The finding that the androgen receptor (AR) splice variant 7 (AR-V7) can help to identify patients who may not benefit from next-generation anti-androgens was hence met with great enthusiasm.1 However, as always in biology, there is no black and white, and therapeutic responses were subsequently found to have a somewhat less stringent correlation with AR-V7 than initially thought.2 Nevertheless, the detection of AR-V7 in blood, circulating tumor cells or in tumor tissue is an important emerging technique that holds the promise to optimize and personalize the therapy of patients with mCRPC.3



Whether AR-V7 can also be detected in castration-naïve prostate cancer is a matter of debate. While a number of papers suggest that this is the case and that AR-V7 is prognostic when detected in primary prostate cancer,4-7 a recent study could not corroborate these findings.8 Without going into the details of these studies, the paper by our group9 now shows that the antibody selected to detect AR-V7 in primary tumor tissue influences the staining results. While the notion that different antibody clones can produce different stainings is some sort of a truism, the differences in the prognostic potential between the stainings produced by anti-AR-V7 antibodies AG10008 and RM7 are perplexing.

The two antibodies of interest were in fact raised in different species with distinct immunodominance. Rabbits usually recognize more epitopes per antigen than mice. Consequently, the success rate in generating antibodies against small epitopes is higher in rabbits than in mice. The high specificity of rabbit monoclonal antibodies may also have disadvantages since subtle structural variations within a protein of interest may affect epitope recognition to a higher degree than mouse monoclonal antibodies. In consequence, the detection rate and localization of a given cellular protein can vary considerably between mouse monoclonal and rabbit monoclonal antibodies. Differences in epitope recognition may also be influenced by posttranslational modifications or single nucleotide polymorphisms (SNP). An important additional question relates to detection versus function. Expression and activity of AR-V7 may not be linear and is modulated by co-factors as well as dimerization partners.10,11 Varying results between studies may ultimately also reflect differences in patient cohort composition.

The most important conclusion from our study is that complementary methods, in particular the detection of AR-V7 inducible gene products, should be developed and implemented to ensure that AR-V7 is in fact transcriptionally active, in particular when it entails clinical decision-making. In addition, it needs to be emphasized that castration resistance is a highly multifactorial process that involves a plethora of mechanisms, of which the overexpression of AR-V7 is only one.12

Written by: Marcus V. Cronauer, PhD1 and Stefan Duensing, MD2

  1. Department of Pathology, University Hospital Bonn, Bonn, Germany
  2. Department of Urology, Molecular Urooncology, University Hospital Heidelberg, Heidelberg, Germany
References:

  1. Antonarakis, Emmanuel S., Changxue Lu, Hao Wang, Brandon Luber, Mary Nakazawa, Jeffrey C. Roeser, Yan Chen et al. "AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer." New England Journal of Medicine 371, no. 11 (2014): 1028-1038.
  2. Bernemann, Christof, Thomas J. Schnoeller, Manuel Luedeke, Konrad Steinestel, Martin Boegemann, Andres J. Schrader, and Julie Steinestel. "Expression of AR-V7 in circulating tumour cells does not preclude response to next generation androgen deprivation therapy in patients with castration resistant prostate cancer." European urology 71, no. 1 (2017): 1-3.
  3. Scher, Howard I., Ryon P. Graf, Nicole A. Schreiber, Brigit McLaughlin, David Lu, Jessica Louw, Daniel C. Danila et al. "Nuclear-specific AR-V7 protein localization is necessary to guide treatment selection in metastatic castration-resistant prostate cancer." European urology 71, no. 6 (2017): 874-882.
  4. Chen, Xin, Christof Bernemann, Yuri Tolkach, Martina Heller, Cathleen Nientiedt, Michael Falkenstein, Esther Herpel et al. "Overexpression of nuclear AR-V7 protein in primary prostate cancer is an independent negative prognostic marker in men with high-risk disease receiving adjuvant therapy." In Urologic Oncology: Seminars and Original Investigations, vol. 36, no. 4, pp. 161-e19. Elsevier, 2018.
  5. Qu, Y., B. Dai, D. Ye, Y. Kong, K. Chang, Z. Jia, X. Yang, H. Zhang, Y. Zhu, and G. Shi. "Constitutively active AR-V7 plays an essential role in the development and progression of castration-resistant prostate cancer." Sci Rep. 2015; 5: 7654.
  6. Li, Heng, Zhize Wang, Wei Xiao, Libin Yan, Wei Guan, Zhiquan Hu, Lily Wu et al. "Androgen-receptor splice variant-7-positive prostate cancer: a novel molecular subtype with markedly worse androgen-deprivation therapy outcomes in newly diagnosed patients." Modern Pathology 31, no. 1 (2018): 198-208.
  7. Hu, Rong, Thomas A. Dunn, Shuanzeng Wei, Sumit Isharwal, Robert W. Veltri, Elizabeth Humphreys, Misop Han et al. "Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer." Cancer research 69, no. 1 (2009): 16-22.
  8. Sharp, Adam, Ilsa Coleman, Wei Yuan, Cynthia Sprenger, David Dolling, Daniel Nava Rodrigues, Joshua W. Russo et al. "Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer." The Journal of clinical investigation 129, no. 1 (2019): 192-208.
  9. Kaczorowski, Adam, Xin Chen, Esther Herpel, Axel S. Merseburger, Glen Kristiansen, Christof Bernemann, Markus Hohenfellner, Marcus V. Cronauer, and Stefan Duensing. "Antibody selection influences the detection of AR-V7 in primary prostate cancer." Cancer Treatment and Research Communications (2020): 100186
  10. Cato, Laura, Jonas de Tribolet-Hardy, Irene Lee, Jaice T. Rottenberg, Ilsa Coleman, Diana Melchers, René Houtman et al. "ARv7 represses tumor-suppressor genes in castration-resistant prostate cancer." Cancer Cell 35, no. 3 (2019): 401-413.
  11. Cai, Ling, Yi-Hsuan Tsai, Ping Wang, Jun Wang, Dongxu Li, Huitao Fan, Yilin Zhao et al. "ZFX mediates non-canonical oncogenic functions of the androgen receptor splice variant 7 in castrate-resistant prostate cancer." Molecular cell 72, no. 2 (2018): 341-354.
  12. Attard, Parker, Schröder Eeles, and Tannock Tomlins. "De Bono.(2016)." Prostate cancer. The Lancet 387, no. 10013: 70-82.
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