Persistent androgen receptor-mediated transcription in castration-resistant prostate cancer under androgen-deprived conditions, "Beyond the Abstract," by Li Jia, PhD

BERKELEY, CA (UroToday.com) - Prostate cancer is fueled by the male sex hormone, or androgen, which interacts with a cellular receptor called androgen receptor (AR). Upon androgen binding, the AR, a master transcription factor in the prostate, binds to thousands of genomic loci and activates a cell-type specific gene-expression program. Elimination of circulating androgen through surgical or medical castration is initially a very effective treatment for advanced prostate cancer. Unfortunately, almost all patients eventually progress to so-called castration-resistant prostate cancer (CRPC). In the early stages of CRPC, the presence of residual androgen due to incomplete suppression and intratumoral androgen synthesis is thought to drive tumor growth. Next-generation CRPC drugs have therefore focused on further suppression of androgen signaling through inhibition of androgen synthesis (abiraterone) and blockage of androgen binding to AR (MDV3100).[1, 2] While these newly FDA-approved anti-androgen therapies have been a major breakthrough in CRPC treatment, many patients are not responsive, and those who initially respond typically develop resistance within a year. The major challenges in CRPC treatment are:

  1. how to predict which patients will respond to anti-androgen drugs, and
  2. how to develop novel therapeutic strategies for CRPC patients when anti-androgen therapies fail.

The fact that all anti-androgen approaches eventually fail strongly demonstrates the need to identify and target alternative androgen-independent AR-signaling pathways. While there is a growing body of evidence that AR can become transactivated in the absence of androgen, the genome-wide transcriptional activity of AR under androgen-independent conditions remains poorly characterized. More importantly, the key androgen-independent AR target genes responsible for CRPC growth are largely unknown. For this reason, we have recently sought to determine whether and how AR functions under androgen-deprived conditions. We have discovered a novel androgen-independent AR-signaling pathway that plays a critical role in the late stages of CRPC when androgen is severely depleted. More importantly, we discovered a distinct set of genes that are responsible for CRPC cell survival and growth in an environment where androgen levels are reduced to below castrate levels. We believe that the androgen-independent AR pathway identified in our studies is an important mechanism of anti-androgen drug (abiraterone and MDV3100) resistance. The identified genes are potential biomarkers and therapeutic targets in anti-androgen resistant CRPC.

References:

  1. Scher, H. I., Fizazi, K., Saad, F., Taplin, M. E., Sternberg, C. N., Miller, K., de Wit, R., Mulders, P., Chi, K. N., Shore, N. D., Armstrong, A. J., Flaig, T. W., Flechon, A., Mainwaring, P., Fleming, M., Hainsworth, J. D., Hirmand, M., Selby, B., Seely, L., and de Bono, J. S. (2012) N Engl J Med 367, 1187-1197
  2. de Bono, J. S., Logothetis, C. J., Molina, A., Fizazi, K., North, S., Chu, L., Chi, K. N., Jones, R. J., Goodman, O. B., Jr., Saad, F., Staffurth, J. N., Mainwaring, P., Harland, S., Flaig, T. W., Hutson, T. E., Cheng, T., Patterson, H., Hainsworth, J. D., Ryan, C. J., Sternberg, C. N., Ellard, S. L., Flechon, A., Saleh, M., Scholz, M., Efstathiou, E., Zivi, A., Bianchini, D., Loriot, Y., Chieffo, N., Kheoh, T., Haqq, C. M., and Scher, H. I. (2011) N Engl J Med 364, 1995-2005

Written by:
Li Jia, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Assistant Professor
Center for Pharmacogenomics
Department of Internal Medicine
Washington University School of Medicine
660 So. Euclid Avenue, Campus Box 8220
St. Louis, MO 63110 USA

 

Persistent androgen receptor-mediated transcription in castration-resistant prostate cancer under androgen-deprived conditions - Abstract

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