Combination of androgen receptor inhibitor and cisplatin, an effective treatment strategy for urothelial carcinoma of the bladder

Tyagi, Ashish; Chandrasekaran, Balaji; Kolluru, Venkatesh; Rai, Samarpit; Jordan, Adrienne C.; Alatassi, Houda; Messer, Jamie; Ankem, Murali K.; Damodaran, Chendil; Haddad, Ahmed

doi:10.1016/j.urolonc.2019.03.008

Cited by 29 publications

(24 citation statements)

References 33 publications

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“…Tyagi et al. [ 60 ] further investigated the antitumor efficacy of combined treatment with enzalutamide and cisplatin in bladder cancer cell lines. Concurrent treatment with these agents synergistically inhibited tumor cell growth which was associated with increase in pro-apoptotic signaling and decrease in mesenchymal markers [ 56 ].…”

Section: Targeting Ar In Ucmentioning

confidence: 99%

Androgen receptor in bladder cancer: A promising therapeutic target

Tripathi

Gupta

2020

Asian Journal of Urology

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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.

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Section: Targeting Ar In Ucmentioning

confidence: 99%

Androgen receptor in bladder cancer: A promising therapeutic target

Tripathi

Gupta

2020

Asian Journal of Urology

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“…In a separate aspect of AR signaling, Miamoto's group [65] showed that androgens increased resistance to cisplatin-based chemotherapy of AR-expressing UBC cell lines. In a complementary fashion, AR blocking drugs increased cisplatin sensitivity [65,66]. Among the mechanisms responsible, Miamoto's group [67] found that androgens reduced expression of an RNA-and ribosome-processing protein, BRIX1 (BXDC2) in UBC cell lines.…”

Section: Investigators Have Shown a Correlation Between Ar Expression And Increasedmentioning

confidence: 99%

Gender Differences in Urothelial Bladder Cancer. Effects of Natural Killer Lymphocyte Immunity

Livas¹,

Presnell²,

Sexton³

et al. 2021

Preprint

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Men are more likely to develop cancer than women. In fact, male predominance is one of the most consistent cancer epidemiology findings. Additionally, men have a poorer prognosis and an increased risk of secondary malignancies compared to women. These differences have been investigated in order to better understand cancer and to better treat both men and women. In this review, we discuss factors that may cause this gender difference, focusing on urothelial bladder cancer (UBC) pathogenesis. We consider physiological factors that may cause higher male cancer rates, including differences in X chromosome gene expression. We discuss how androgens may promote bladder cancer development directly by stimulating bladder urothelium and indirectly by suppressing immunity. We are particularly interested in natural killer (NK) cells because they are important, but often overlooked anti-cancer lymphocytes.

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“…Total RNA was extracted from BPH1, Cd-exposed BPH1 (24, 48 and 72 h), CTBPH1, and ZIC2 siRNAtreated CTBPH1 cells and RT-qPCR performed for ZIC2, SOX2, Nanog, CD44, and Notch1 expressions as described previously 27 .…”

Section: Real-time Quantitative Pcr (Rt-qpcr)mentioning

confidence: 99%

Chronic exposure to cadmium induces a malignant transformation of benign prostate epithelial cells

et al. 2020

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Epidemiological evidence suggests that cadmium (Cd) is one of the causative factors of prostate cancer, but the effect of Cd on benign prostatic hyperplasia (BPH) remains unclear. This study aimed to determine whether Cd exposure could malignantly transform BPH1 cells and, if so, to dissect the mechanism of action. We deciphered the molecular signaling responsible for BPH1 transformation via RNA-sequencing and determined that Cd induced the expression of zinc finger of the cerebellum 2 (ZIC2) in BPH1 cells. We noted Cd exposure increased ZIC2 expression in the Cdtransformed BPH1 cells that in turn promoted anchorage-independent spheroids and increased expression of stem cell drivers, indicating their role in stem cell renewal. Subsequent silencing of ZIC2 expression in transformed cells inhibited spheroid formation, stem cell marker expression, and tumor growth in nude mice. At the molecular level, ZIC2 interacts with the glioma-associated oncogene family (GLI) zinc finger 1 (GLI1), which activates prosurvival factors (nuclear factor NFκB, B-cell lymphoma-2 (Bcl2), as well as an X-linked inhibitor of apoptosis protein (XIAP)) signaling in Cd-exposed BPH1 cells. Conversely, overexpression of ZIC2 in BPH1 cells caused spheroid formation confirming the oncogenic function of ZIC2. ZIC2 activation and GLI1 signaling induction by Cd exposure in primary BPH cells confirmed the clinical significance of this oncogenic function. Finally, human BPH specimens had increased ZIC2 versus adjacent healthy tissues. Thus, we report direct evidence that Cd exposure induces malignant transformation of BPH via activation of ZIC2 and GLI1 signaling. Oncogenesis 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,;

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Combination of androgen receptor inhibitor and cisplatin, an effective treatment strategy for urothelial carcinoma of the bladder

Cited by 29 publications

References 33 publications

Androgen receptor in bladder cancer: A promising therapeutic target

Androgen receptor in bladder cancer: A promising therapeutic target

Gender Differences in Urothelial Bladder Cancer. Effects of Natural Killer Lymphocyte Immunity

Chronic exposure to cadmium induces a malignant transformation of benign prostate epithelial cells

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