Management of prostate cancer by targeting 3βHSD1 after enzalutamide and abiraterone treatment

Mei, Zejie; Yang, Tao; Liu, Ying; Gao, Yuanyuan; Hou, Zhufeng; Zhuang, Qian; He, Dongyin; Zhang, Xuebin; Tan, Qilong; Zhu, Xuyou; Qin, Yingyi; Chen, Xi; Xu, Chengdang; Bian, Cuidong; Wang, Xinan; Wang, Chenyang; Wu, Denglong; Huang, Shengsong; Li, Zhenfei

doi:10.1016/j.xcrm.2022.100608

Cited by 15 publications

(30 citation statements)

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“…The numbers of CTCs, AR-v7 expression, HSD3B1 genotype and expression level have been shown to be associated with abiraterone response. 10,24,25 Genetic testing evaluating a panel of genes also provides valuable information. 26 However, these methods are expensive and involve high technology, making it difficult to perform in a clinical laboratory.…”

Section: Discussionmentioning

confidence: 99%

“…Several biomarkers related to abiraterone response have been identified and have even entered clinical oncological practice. The numbers of CTCs, AR‐v7 expression, HSD3B1 genotype and expression level have been shown to be associated with abiraterone response 10,24,25 . Genetic testing evaluating a panel of genes also provides valuable information 26 .…”

Section: Discussionmentioning

confidence: 99%

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Serum prolactin level as a predictive factor for abiraterone response in patients with metastatic castration‐resistant prostate cancer

et al. 2022

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Background To investigate the prognostic value and potential therapeutic target of the baseline serum hormones in patients with metastatic castration‐resistant prostate cancer (mCRPC) treated with abiraterone. Methods This retrospective study was performed in patients with mCRPC receiving abiraterone acetate (AA) from July 2016 to September 2020. Patients who had serum hormone tests within 2 weeks before AA treatment were included. Univariate analysis and Cox regression were performed to evaluate the correlation of sex hormones with progression‐free survival (PFS) and overall survival (OS). Prolactin (PRL) expression in the clinical specimens was evaluated by immunohistochemistry. Bone metastases were quantified by automated Bone Scan Index (aBSI). Results The study included 61 patients with a median follow‐up of 19.0 months. Patients with lower baseline PRL levels (median) responded better to AA than those with higher baseline PRL levels as indicated by prostate‐specific antigen (PSA) reduction (PSA90, 66.7% vs. 25.8%, p = 0.001), PFS (19.6 vs. 7.9 months), and OS (52.8 vs. 19.2 months). Cox regression adjusted for clinical factors also confirmed that baseline PRL level was an independent predictive factor for PFS (hazard ratio = 1.096, p = 0.007). Prostatic PRL expression increased as the disease progressed. PRL expression was also detected in biopsy samples from bone metastasis but not in normal bone tissue, and the serum PRL levels were positively correlated with aBSIs (r = 0.28, p = 0.037). Conclusions Serum PRL levels are predictive of response to AA in patients with mCRPC. Serum PRL levels are positively correlated with the volume of metastatic bone disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Serum prolactin level as a predictive factor for abiraterone response in patients with metastatic castration‐resistant prostate cancer

et al. 2022

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“…Novel approaches are urgently required to meet the clinical challenges associated with abiraterone resistance (5,15,20). It is hypothesized that dutasteride might enhance abiraterone efficacy by regulating abiraterone metabolism (12).…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported recently that abiraterone metabolism accelerated and abiraterone concentration decreased in patients as disease progression, indicating the involvement of abiraterone metabolism in drug resistance (15). However, increasing abiraterone dose failed to elevate abiraterone concentration and overcome abiraterone resistance in patients (16).…”

Section: Introductionmentioning

confidence: 97%

The clinical efficacy and limitations of dutasteride-regulated abiraterone metabolism in abiraterone-resistant patients: a prospective single-arm clinical trial in Chinese patients

Liu¹,

Yang²,

Xu³

et al. 2022

Transl Androl Urol

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Background: The steroidal metabolism of abiraterone has been proposed to be involved in abiraterone resistance and limited approaches are available for abiraterone-resistant patients. Dutasteride regulates abiraterone metabolism in patients and might enhance the clinical efficacy of abiraterone. However, the function of dutasteride to overcome abiraterone resistance has not been investigated in clinic. Here we investigated the clinical efficacy and limitations of dutasteride in patients with abiraterone-resistant prostate cancer.Methods: Abiraterone-resistant patients with metastatic castration-resistant prostate cancer (mCRPC) were enrolled in this single-arm, open-label study, patients were treated with dutasteride (0.5 mg/day), abiraterone(1,000 mg/day), and prednisone (5 mg twice daily), prostate-specific antigen (PSA) was tested monthly. The primary objective was PSA response, and the secondary objectives were to assess symptom relief and safety.Kaplan-Meier analysis was used to assess the PSA progression free survival (PSA-PFS) of patients.Results: Twenty-two patients (median age: 75 years) were enrolled, and 19 patients completed the treatment. After a median treatment of 4.0 months, 7 (37%) patients showed a slight PSA reduction (−2% to −32%), and the median PSA-PFS was 2.0 months (1-7 months). No significant improvement was observed in Eastern Cooperative Oncology Group (ECOG) performance status. Bone pain was relieved in 6 patients after 1 month of treatment, but the improvement was not significant. No grade 3 or grade 4 adverse events were observed. Conclusions:The combination of dutasteride and abiraterone showed a mild effect in patients with abiraterone-resistant. The small sample size was the limitation of this study.

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“…Studies reported that genotype of the HSD3B1 gene can serve as a predictive biomarker for men treated with androgen-deprivation therapy [ 19 ], AA (steroidal CYP17A1 inhibitor) [ 20 ], ketoconazole (nonsteroidal CYP17A1 inhibitor) [ 21 ], and enzalutamide (androgen receptor blocker) [ 20 ] in mCRPC and in mHSPC with low-volume disease [ 22 ]. A preclinical study has shown that increased expression levels of 3βHSD1 were seen in VCaP-enz cells (enzalutamide-resistant cell lines) due to a gain of function mutation of HSD3B1 (A1245C), suggesting that steroidogenesis has an important role in abiraterone and enzalutamide drug resistance [ 23 ]. Targeting 3βHSD1 might reduce drug resistance [ 5 , 7 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Correlation Between Trough Level of Abiraterone and Prostate-Specific Antigen (PSA) Response in Metastatic Hormone-Sensitive Prostate Cancer

et al. 2022

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Background Prostate cancer growth is primarily driven by testosterone and 5α-dihydrotestosterone. Abiraterone is an irreversible inhibitor of CYP17, and CYP17 inhibition is a required step in testosterone biosynthesis. Previous studies have shown that abiraterone trough levels are predictive of prostate-specific antigen (PSA) response in metastatic castrate-resistant prostate cancer (mCRPC). It has not been demonstrated if this association exists for patients with metastatic hormone-sensitive prostate cancer (mHSPC). In this study, we aimed to explore the correlation and association between abiraterone trough levels and PSA levels in patients with mHSPC. Material/Methods This was a single-center, prospective, observational study of patients with mHSPC being treated with abiraterone acetate (AA) 1000 mg once daily. Abiraterone trough levels (22–26 h after drug administration) were drawn at 1, 3, and 7 months after treatment initiation. Results Thirteen patients with mHSPC were enrolled, and complete pharmacokinetic data were available for 8 patients. The mean trough levels at 1 month, 3 months, and 7 months were 34.49 ng/mL (3.36–240.46), 13.82 ng/mL (2.91–29.96), and 15.7 ng/mL (3.58–26.86), respectively. The correlation between the 1-month abiraterone trough level and 1-month PSA level was 0.29 ( P =0.38), between 3-month abiraterone trough and 3-month PSA was −0.61 ( P =0.08), and between 7-month abiraterone trough and 7-month PSA was −0.31 ( P =0.54). Conclusions This study demonstrated a trend toward a negative correlation between 3-month abiraterone trough levels and PSA levels, but the correlation was not statistically significant. A study with a larger prospective sample size is needed to validate these findings.

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Management of prostate cancer by targeting 3βHSD1 after enzalutamide and abiraterone treatment

Cited by 15 publications

References 60 publications

Serum prolactin level as a predictive factor for abiraterone response in patients with metastatic castration‐resistant prostate cancer

Serum prolactin level as a predictive factor for abiraterone response in patients with metastatic castration‐resistant prostate cancer

The clinical efficacy and limitations of dutasteride-regulated abiraterone metabolism in abiraterone-resistant patients: a prospective single-arm clinical trial in Chinese patients

Correlation Between Trough Level of Abiraterone and Prostate-Specific Antigen (PSA) Response in Metastatic Hormone-Sensitive Prostate Cancer

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