Recent trends in the management of advanced prostate cancer

Ritch, Chad R.; Cookson, Michael S.

doi:10.12688/f1000research.15382.1

Cited by 79 publications

(69 citation statements)

References 37 publications

(49 reference statements)

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“…Enzalutamide is approved for metastatic and nonmetastatic castration‐resistant prostate cancer . It showed weaker activity in comparison to darolutamide in several instances, for example, for the mutations W742C/L and M896V/T (Table and Supporting Information Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…Enzalutamide is approved for metastatic and nonmetastatic castration-resistant prostate cancer. 3,28,29 It showed weaker activity in comparison to darolutamide in several instances, for example, for the mutations W742C/L and M896V/T ( Table 1 and Supporting Information Table 2). When increasing the androgen concentrations, enzalutamide antagonism was reduced for AR wild type and several mutants.…”

Section: Resultsmentioning

confidence: 99%

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Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Sugawara

Baumgart

Nevedomskaya

et al. 2019

Intl Journal of Cancer

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Darolutamide is a novel androgen receptor (AR) antagonist with a distinct chemical structure compared to other AR antagonists and currently in clinical Phase 3 trials for prostate cancer. Using cell‐based transactivation assays, we demonstrate that darolutamide, its diastereomers and its main metabolite keto‐darolutamide are strong, competitive antagonists for AR wild type, and also for several mutants identified in prostate cancer patients for which other AR antagonists show reduced antagonism or even agonism. Darolutamide, its two diastereomers and main metabolite are also strong antagonists in assays measuring AR N/C interaction and homodimerization. Molecular modeling suggests that the flexibility of darolutamide allows accommodation in the W742C/L mutated AR ligand‐binding pocket while for enzalutamide the loss of the important hydrophobic interaction with W742 leads to reduced AR interaction. This correlates with an antagonistic pattern profile of coregulator recruitment for darolutamide. In vitro efficacy studies performed with androgen‐dependent prostate cancer cell lines show that darolutamide strongly reduces cell viability and potently inhibits spheroid formation. Also, a marked down‐regulation of androgen target genes paralleled by decreased AR binding to gene regulatory regions is seen. In vivo studies reveal that oral dosing of darolutamide markedly reduces growth of the LAPC‐4 cell line‐derived xenograft and of the KuCaP‐1 patient‐derived xenograft. Altogether, these results substantiate a unique antagonistic profile of darolutamide and support further development as a prostate cancer drug.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Sugawara

Baumgart

Nevedomskaya

et al. 2019

Intl Journal of Cancer

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“…Clinically, prostate cancer is frequently diagnosed and confirmed by biopsy, followed by medical imaging to evaluate the extent of potential metastasis. Management options for this disease greatly depend on tumor stage and general personal health conditions, and mainly consist of regular surveillance and combination of surgery, radiotherapy, chemotherapy and hormone therapy . The prognosis of prostate cancer is relatively favorable, and the 5‐year survival rate in the United States is more than 99%.…”

mentioning

confidence: 99%

TRIM66 promotes malignant progression of prostate carcinoma through the JAK/STAT pathway

et al. 2020

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Prostate cancer is the fifth leading cause of cancer‐related deaths in males globally. Tripartite Motif Containing 66 (TRIM66) functions as transcriptional repressor and exerts its effect at least partially through promotion of deacetylase. TRIM66 has been previously reported to play an oncogenic role in a number of human cancers. Here, we investigated the potential oncogenic properties of TRIM66 in prostate cancer. We report that shRNA‐mediated knockdown of TRIM66 significantly suppressed viability and proliferation of both PC‐3 and DU145 prostate cancer cell lines. Furthermore, TRIM66 deficiency inhibited migration and invasion of prostate cancer cells. Mechanistically, TRIM66 positively regulated signal transducer and activator of transcription 2 (STAT2) and interleukin‐2 (IL‐2) expression. The predominance of STAT2–IL‐2 in mediating the oncogenic properties of TRIM66 was determined using a rescue assay, wherein overexpression of either STAT2 or IL‐2 almost completely abolished the inhibitory effects on cell proliferation, migration and invasion elicited by TRIM66 deficiency in prostate cancer cells. Our study highlights the importance of the TRIM66–STAT2–IL‐2 signaling axis in the tumor biology of prostate cancer.

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“…Androgen deprivation therapy (ADT) is an effective treatment for advanced PCa as the androgen‐dependent growth manner. However, these tumors will eventually progress into the more aggressive castrate‐resistant prostate cancer (CRPC) after ADT failure, 3 which has an overall 5‐year survival rate of only 26% to 30% 4 . The pathogenesis of CRPC remains unclear 5 .…”

Section: Introductionmentioning

confidence: 99%

miR‐30a inhibits androgen‐independent growth of prostate cancer via targeting MYBL2, FOXD1, and SOX4

et al. 2020

The Prostate

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Background: Castrate-resistant prostate cancer (CRPC) is an aggressive and lethal disease. The pathogenesis of CRPC is not fully understood and novel therapeutic targets need to be identified to improve the patients' prognosis. has been demonstrated to be a tumor suppressor in many types of solid malignancies. However, its role in androgen-independent (AI) growth of prostate cancer (PCa) received limited attention as yet. Methods:The clinical association of miR-30a and its potential targets with AI growth was characterized by bioinformatics analyses. Regulation of cell proliferation and colony formation rates by miR-30a were tested using PCa cell models. Xenograft models were used to measure the regulation of prostate tumor growth by miR-30a.The real-time quantitative polymerase chain reaction was used to validate whether miR-30a and its targets regulate cell cycle control genes and androgen receptor (AR)-dependent transcription. Bioinformatics tools, Western blot, and luciferase reporter assays were utilized to identify miR-30a targets. Results: Bioinformatic analysis showed that low expression of miR-30a is associated with castration resistance of PCa patients and poor outcomes. Transfection of miR-30a mimics inhibited the AI growth of PCa cells in vitro and in vivo. Upregulation of miR-30a in 22RV1 cells altered the expression of cell cycle control genes and AR-mediated transcription, while downregulation of miR-30a in LNCaP cells had the opposite effects to AR-mediated transcription. MYBL2, FOXD1, and SOX4 were identified as miR-30a targets. Downregulation of MYBL2, FOXD1, and SOX4 affected the expression of cell cycle control genes and AR-mediated transcription and suppressed the AI growth of 22RV1 cells. Conclusions: Our results suggest that miR-30a inhibits AI growth of PCa by targeting MYBL2, FOXD1, and SOX4. They provide novel insights into developing new treatment strategies for CRPC. K E Y W O R D S castration-resistant prostate cancer, FOXD1, miR-30a, MYBL2, SOX4

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Recent trends in the management of advanced prostate cancer

Cited by 79 publications

References 37 publications

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

TRIM66 promotes malignant progression of prostate carcinoma through the JAK/STAT pathway

miR‐30a inhibits androgen‐independent growth of prostate cancer via targeting MYBL2, FOXD1, and SOX4

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