Androgen receptor in bladder cancer: A promising therapeutic target

Abstract

There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades. While immunotherapy with checkpoint inhibitors has revolutionized the treatment of urothelial carcinoma, unfortunately, only a minority of patients respond to immunotherapy. Treatment options for patients who do not respond and/or progress on immunotherapy are very limited and overall prognosis remains dismal in metastatic urothelial carcinoma. The first targeted therapy targeting the fibroblast growth factor receptor (FGFR) was recently approved for bladder cancer, but it is effective only in select patients harboring the FGFR2 and FGFR 3 mutations. Antibody drug conjugates like enfortumab vedotin have shown promising activity in clinical trials. Development of novel targeted therapies remains an area of investigation and an unmet need in bladder cancer. Exploitation of androgen receptor (AR) is a potential strategy for targeted drug development in bladder cancer. A significant proportion of urothelial carcinoma patients express AR irrespective of gender. AR signaling in urothelial carcinoma has been linked to progression through multiple mechanisms, including activation of human epidermal growth factor receptor-2 (EGFR or HER-2) signaling and epithelial to mesenchymal transition (EMT). Furthermore, AR is enriched in the luminal papillary mRNA subtype of urothelial carcinoma and also mediates resistance to cisplatin-based chemotherapy. Preclinical evidence suggests that AR inhibition can successfully inhibit urothelial carcinoma growth as monotherapy and is synergistic with cisplatin-based chemotherapy. We review the preclinical and clinical evidence supporting the putative role of AR signaling in urothelial carcinoma pathogenesis, progression and its role as a novel therapeutic target and future directions.

The Clinical Significance and Prognostic Value of HER2 Expression in Bladder Cancer: a Systematic Review and Meta-analysis

“…Zheng et al claimed that AR activation upregulated the expression of HER2 in bladder cancer cells [31]. It has been proved that inhibiting AR pathway can successfully control the occurrence and development of bladder cancer, and can be synergistic with cisplatin chemotherapy regimen [32]. These results of our own research and previous studies indicate that AR related pathway regulates HER2 expression in bladder cancer cells.…”

SLC35F2, a Transporter Sporadically Mutated in the Untranslated Region, Promotes Growth, Migration, and Invasion of Bladder Cancer Cells

“…In line with this, a high level of the SLC35F2 transporter might probably contribute to tumour progression through the increase of cancer metabolism. In addition, some studies show that stabilization of β-catenin and androgen receptor signaling can increase the expression of SLC35F2, providing new insights into the understanding of the regulation of this gene and potential targets for therapy [ 16 , 27 , 28 ]. Interestingly, the anti-cancer drug YM155 is a cargo of the SLC35F2 transporter, which has been reported to be involved in the drug resistance of YM155.…”

Copy number variations in primary tumor, serum and lymph node metastasis of bladder cancer patients treated with radical cystectomy

“…The MLPA assay did contain sequences to analyze a limited number of genes, but of several exons; some genes that may have an important role in bladder cancer progression were not included in this assay, e.g. the androgen receptor, which may contribute to disease progression by EGFR signaling 48 . Lastly, since the amount of cfDNA was low, we could not perform single analyses on every chromosomal region by real-time Taqman PCR.…”