New approaches to targeting the androgen receptor pathway in prostate cancer

Pedro Isaacsson Velho, Diogo Assed Bastos, Emmanuel S. Antonarakis

Research output: Contribution to journalArticlepeer-review

Abstract

The androgen signaling axis has been the main therapeutic target in the management of advanced prostate cancer for several decades. Over the past years, significant advances have been made in terms of a better understanding the androgen receptor (AR) pathway and mechanisms of castration resistance, along with the development of more potent AR-targeted therapies. New drugs, such as abiraterone, enzalutamide, apalutamide, and darolutamide, have been approved for castration-resistant prostate cancer and also have demonstrated an overall survival benefit in the castration-sensitive state. Despite these major advances, the majority of patients eventually present with disease progression and a rise in prostate-specific antigen, reflecting a continuous dependence of disease on the AR pathway. In this setting, a number of AR-related mechanisms of resistance have been described, and novel strategies to overcome them are an important unmet need. In this manuscript, we review the most promising strategies to target the AR pathway in prostate cancer, including bromodomain and extraterminal (BET)/bromodomain inhibitors, CREB-binding protein/p300 inhibitors, N-terminal domain inhibitors, proteolysis- targeting chimeras, and AR-targeting vaccines. Another interesting and disruptive approach to targeting the AR and potentially reversing resistance to second-generation AR antagonists is the cyclic administration of high-dose testosterone, known as bipolar androgen therapy, which is currently being explored in multiple ongoing trials.

Original languageEnglish (US)
Pages (from-to)228-239
Number of pages12
JournalClinical Advances in Hematology and Oncology
Volume19
Issue number4
StatePublished - Apr 2021
Externally publishedYes

Bibliographical note

Funding Information:
Dr Antonarakis is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Pfizer, Amgen, Lilly, Bayer, AstraZeneca, Bristol Myers Squibb, Clovis, and Merck; has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers Squibb, AstraZeneca, Clovis, and Merck; and is the co-inventor of an AR-V7 biomarker technology that has been licensed to Qiagen. This work by Dr Antonarakis was partially supported by National Institutes of Health Cancer Center Support Grant P30 CA006973 and by Department of Defense grants W81XWH-16-PCRPCCRSA and W81XWH2010079. Drs Velho and Bastos report no conflicts of interest.

Funding Information:
Dr Antonarakis is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Pfizer, Amgen, Lilly, Bayer, AstraZeneca, Bristol Myers Squibb, Clovis, and Merck; has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novar-tis, Tokai, Bristol Myers Squibb, AstraZeneca, Clovis, and Merck; and is the co-inventor of an AR-V7 biomarker technology that has been licensed to Qiagen. This work by Dr Antonarakis was partially supported by National Institutes of Health Cancer Center Support Grant P30 CA006973 and by Department of Defense grants W81XWH-16-PCRP-CCRSA and W81XWH2010079. Drs Velho and Bastos report no conflicts of interest.

Publisher Copyright:
© 2021, Millennium Medical Publishing, Inc.. All rights reserved.

Keywords

  • Androgen receptor
  • Prostate cancer

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