Androgen Receptor Signaling and the Emergence of Lethal Neuroendocrine Prostate Cancer With the Treatment-Induced Suppression of the Androgen Receptor: A Literature Review.

Meera Dhavale,Linha M Mohammed,Jihan A Mostafa,A B M Nasibul Alam,Mohamed K Abdelaal,Tatjana Blazin,Natalia P Ballestas,Dhruvil Prajapati

doi:10.7759/cureus.13402

Abstract

Androgen receptor signaling primarily influences both the normal growth and proliferation of the prostate gland and the development of prostatic carcinoma. While localized prostate cancers are typically managed with definitive therapies like surgery and radiotherapy, many patients have recurrences in the form of metastatic disease. Androgen deprivation therapy, by way of castration via orchiectomy or with drugs like luteinizing hormone-releasing hormone (commonly called gonadotropin-releasing hormone) agonists and luteinizing hormone-releasing hormone antagonists, is the primary mode of therapy for advanced castration-sensitive prostate cancer. Castration resistance invariably develops in these patients. Further treatment has shifted to newer anti-androgen drugs like enzalutamide or abiraterone and taxane-based chemotherapy. Prolonged inhibition of the androgen receptor signaling pathway causes androgen receptor-independent clonal evolution which leads to the development of treatment-emergent neuroendocrine prostate cancer.All prostate cancers at the initial presentation should undergo evaluation for the markers of neuroendocrine differentiation. Detection of serum biomarkers of neuroendocrine differentiation and circulating tumor cells is a prospective non-invasive method of detecting neuroendocrine transdifferentiation in patients undergoing treatment with androgen receptor pathway inhibitors. It is essential to perform a biopsy in the presence of red flags of neuroendocrine differentiation. Alisertib, an Aurora kinase inhibitor, showed promising clinical benefit in a subgroup of patients with certain molecular alterations. A thorough understanding of the molecular and clinical programming of treatment-emergent neuroendocrine prostate cancer can potentially lead to the development of drugs to prevent the development of this lethal variant of prostate cancer.

Highlights

BackgroundProstate cancer is the most common cancer aside from skin cancers and the second leading cause of cancerrelated death in men in the United States
Their clinical pictures corresponded to the transformation of prostatic adenocarcinoma to treatment-emergent neuroendocrine prostate cancer (t-neuroendocrine prostate cancer (NEPC))
neuroendocrine differentiation (NED) markers were detected in 70.5% of patients who underwent androgen deprivation therapy (ADT) for >13 months compared to 30% in those that hadn’t received any ADT

Summary

Introduction

Ever since Huggins and Hodges first demonstrated the efficacy of the technique to treat metastatic prostate cancers in 1941, androgen deprivation therapy (ADT) in the form of castration via orchiectomy or using luteinizing hormone-releasing hormone agonists (LHRH agonists) and luteinizing hormone-releasing hormone antagonists (LHRH antagonists) has been the first line of management for advanced prostate cancers [4]. Despite primary treatment with ADT, some patients experience recurrences These castration-resistant prostate cancers (CRPC) are usually correlated with rising prostate-specific antigen (PSA) levels, which is indicative of androgen receptor-driven activity [6]. Common mechanisms of castration resistance include alterations in the androgen receptor-signaling pathway, androgen receptor-signaling bypass mechanisms, and androgen receptor-independent clonal evolution The latter mechanism is thought to cause the lethal form of CRPC called treatment-emergent neuroendocrine prostate cancer (t-NEPC) [10].

Results

87 NEPC specimens

Limitations

Conclusions

Disclosures