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Novel Roles of the Androgen Receptor in Bladder Cancer - Beyond the Abstract

A cornerstone of treatment for advanced prostate cancer is androgen deprivation therapy (ADT). In contrast to this androgen antagonism treatment in prostate cancer, androgen agonism treatment is promising in some types of cancer. The most clinically advanced iteration of this idea is found in estrogen-positive breast cancer. It has been found that the androgen receptor (AR) functions as a tumor suppressor in estrogen receptor-positive (ER+) breast cancer.1



In this setting, estrogen and androgen counter each other with the latter antagonizing the pro-growth effects of the former. Earlier findings have led to trials in both ER+ and ER- (triple-negative)/AR+ breast cancer using Enobosarm (GTx-024) such as NCT02463032 and NCT02368691 respectively. Enobosarm is a nonsteroidal selective androgen receptor modulator (SARM) that has tissue-selective anabolic effects in muscle and bone while sparing other androgenic tissue related to virilization in women and prostate effects in men.2

An international Phase 3 registration clinical trial (sponsored by VERU, Inc) evaluating Enobosarm in patients with AR+ and ER+ metastatic breast cancer who failed endocrine therapy and a CDK 4/6 inhibitor, is planned to commence in the second quarter of 2021 (www.adelaide.edu.au/newsroom). Could this same treatment approach apply to other cancer types such as bladder cancer? In bladder cancer, androgen signaling is believed to play an important role in both carcinogenesis and tumor growth.3 The prevailing theory is that inhibiting the androgen receptor in bladder cancer patients may inhibit carcinogenesis and progression.4,5 However, due to the heterogeneity of tumor biology in patients, treating cancer is never that simple. Indeed, there is a growing body of evidence in bladder cancer that loss of AR expression and loss of AR signaling is associated with more advanced cancers and worse prognosis. In this event, increasing AR activity may suppress pro-growth signaling in tumors as it has been shown to do in some breast cancers.

A recently published study illustrates an example of a mechanism that may underlie this observation. This study shows that signaling via AR suppresses CD44,6 a known promoter of bladder cancer tumorigenesis7 and well-known cancer stem cell marker.8 Interestingly, other recent data has shown that the less aggressive luminal subtype of bladder cancers has increased AR expression,9 which is consistent with AR suppressing drivers such as CD44, in some tumors. While much more work is needed to be done to determine which patients benefit from this therapy, androgen agonism with SARMs may represent a novel therapeutic approach for selected patients with bladder cancer, as it has emerged most notably in breast cancer.

Jason E. Duex1 and Dan Theodorescu1,2

  1. Department of Surgery (Urology), Cedars-Sinai Medical Center, Los Angeles, CA, USA
  2. Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA

References:

  1. Hickey, T. E. et al. The androgen receptor is a tumor suppressor in estrogen receptor–positive breast cancer. Nature Medicine 27, 310–320 (2021).
  2. Narayanan, R., Coss, C. C. & Dalton, J. T. Development of selective androgen receptor modulators (SARMs). Molecular and Cellular Endocrinology 465, 134–142 (2018).
  3. Li, P., Chen, J. & Miyamoto, H. Androgen Receptor Signaling in Bladder Cancer. Cancers 9, (2017).
  4. Overdevest, J. B. et al. CD24 expression is important in male urothelial tumorigenesis and metastasis in mice and is androgen regulated. Proc Natl Acad Sci U S A 109, E3588-96 (2012).
  5. Agarwal, N. et al. GON4L Drives Cancer Growth through a YY1-Androgen Receptor-CD24 Axis. Cancer Res 76, 5175–85 (2016).
  6. Sottnik, J. L. et al. Androgen Receptor Regulates CD44 Expression in Bladder Cancer. Cancer Res (2021) doi:10.1158/0008-5472.CAN-20-3095.
  7. Ahmed, M. et al. An Osteopontin/CD44 Axis in RhoGDI2-Mediated Metastasis Suppression. Cancer Cell 30, 432–443 (2016).
  8. Sottnik, J. L. & Theodorescu, D. CD44: A metastasis driver and therapeutic target. Oncoscience 3, 320–321 (2016).
  9. Zhao, S. G. et al. Clinical and Genomic Implications of Luminal and Basal Subtypes Across Carcinomas. Clin Cancer Res 25, 2450–2457 (2019).

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