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Genetic variations represented by single-nucleotide polymorphisms (SNPs) could be helpful for choosing an effective treatment for patients with prostate cancer. This study investigated the prognostic and predictive values of SNPs associated with the prognoses of pharmacotherapy for prostate cancer through their pharmacological mechanisms. Patients treated with docetaxel or androgen receptor pathway inhibitors (ARPIs), such as abiraterone and enzalutamide, for castration-resistant prostate cancer were included. The SNPs of interest were genotyped for target regions. The prognostic and predictive values of the SNPs for time to progression (TTP) were examined using the Cox hazard proportional model and interaction test, respectively. Rs1045642 in ABCB1, rs1047303 in HSD3B1, rs1856888 in HSD3B1, rs523349 in SRD5A2, and rs34550074 in SLCO2A1 were differentially associated with TTP between docetaxel chemotherapy and ARPI treatment. In addition to rs4775936 in CYP19A1, rs1128503 in ABCB1 and rs1077858 in SLCO2B1 might be differentially associated with TTP between abiraterone and enzalutamide treatments. Genetic predictive models using these SNPs showed a differential prognosis for treatments. This study identified SNPs that could predict progression as well as genetic models that could predict progression when patients were treated with docetaxel versus ARPI and abiraterone versus enzalutamide. The use of genetic predictive models is expected to be beneficial in selecting the appropriate treatment for the individual patient., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

There are multiple reports on the value of complete blood count (CBC)-related parameters on prognosis in docetaxel-treated castration-resistant prostate cancer (CRPC) patients before the emergence of androgen receptor pathway inhibitors (ARPIs). We investigated the prognostic significance of CBC-related parameters in docetaxel-treated CRPC patients. Patients treated with docetaxel chemotherapy for CRPC between 2008 and 2018 were included. We analyzed the relevance of CBC-related parameters to oncological prognosis in docetaxel chemotherapy, associated with prior use of novel ARPIs. Among 144 Japanese men treated with docetaxel, 49 men (34.0%) had already received ARPI therapy. A high neutrophil-lymphocyte ratio (NLR) was a prognostic factor for poor progression-free survival and overall survival (OS) in both univariate and multivariate analyses. In addition, a low hemoglobin (Hb) level and a high systemic immune-inflammation index (SII) were prognostic factors of poor OS in univariate analysis. Hb level was a prognostic factor of OS in both ARPI-naive and ARPI-treated patients. However, a high NLR and SII were only associated with a poor prognosis in ARPI-naive but not in ARPI-treated patients. Hb, NLR, and SII have been suggested to be prognosticators in docetaxel-treated CRPC patients. The differential prognostic value of NLR and SII between ARPI-naive and ARPI-treated patients may require caution when using these markers in docetaxel-treated CRPC patients., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Although docetaxel (DTX) confers significant survival benefits in patients with castration-resistant prostate cancer (CRPC), resistance to DTX inevitably occurs. Therefore, clarifying the mechanisms of DTX resistance may improve survival in patients with CRPC. Claspin plays a pivotal role in DNA replication stress and damage responses and is an essential regulator for the S-phase checkpoint. CLSPN is an oncogenic gene that contributes to tumor proliferation in several human solid tumors. However, the clinical significance of claspin in prostate cancer (PCa) has not been examined. The present study aimed to elucidate the role of claspin and its relationship with DTX resistance in PCa. We immunohistochemically analyzed the expression of claspin in 89 PCa cases, of which 31 (35%) were positive for claspin. Claspin-positive cases were associated with higher Gleason score, venous invasion, and perineural invasion. Kaplan-Meier analysis showed that high claspin expression was related to poor prostate-specific antigen (PSA) relapse-free prognosis. In a public database, high CLSPN expression was associated with poor PSA relapse-free prognosis, Gleason score, T stage, lymph node metastasis, CRPC, and metastatic PCa. Claspin knockdown by siRNA decreased cell proliferation, upregulated DTX sensitivity, and suppressed the expression of Akt, Erk1/2, and CHK1 phosphorylation in DU145 and PC3 cell lines. Furthermore, claspin expression was much more upregulated in DTX-resistant DU145 (DU145-DR) than in parental DU145 cells. Claspin knockdown significantly upregulated the sensitivity to DTX in DU145-DR cells. These results suggest that claspin plays an important role in PCa tumor progression and DTX resistance., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: This study aimed to reveal the prognostic values of prior local therapy in first-line therapy using androgen receptor-axis targeting agents (abiraterone or enzalutamide) or docetaxel for castration-resistant prostate cancer (CRPC)., Methods: The study included 303 patients treated with first-line therapy for non-metastatic and metastatic CRPC. The association between prior local therapy and therapeutic outcome including progression-free survival and overall survival was investigated by univariate and multivariate analyses as well as propensity score-matched analysis., Results: In univariate analysis, local prior therapy was associated with a lower risk of all-cause mortality (hazard ratio, 0.56, 95% confidence interval, 0.40-0.79; P = 0.0009). Overall survival, but not progression-free survival, was better among patients with prior local therapy compared with patients without prior local therapy even after multivariate analysis and propensity score-matched analysis., Conclusions: This study robustly indicated that prior local treatment was prognostic for overall survival among patients with CRPC. This finding is useful to predict patient prognosis in CRPC., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

We investigated the efficacy and safety profiles of 4-weekly docetaxel for castration-resistant prostate cancer. Patients treated with ≥2 courses of docetaxel chemotherapy (median, 70 mg/m 2 ) between 2008 and 2018 were included. Among 125 Japanese men, 40 (32.0%) and 85 (68.0%) were treated with 3-weekly and 4-weekly regimens, respectively. In the 4-weekly regimen, the risks of progression, treatment failure, and any-cause mortality were comparable to those in the 3-weekly regimen. The incidences of severe adverse events were also similar between the 3-weekly and 4-weekly regimens. These data suggest that the 4-weekly regimen may be an acceptable option for selected patients.

Background/aim: The novel taxane cabazitaxel has been shown to exert excellent anticancer effects after androgen receptor axis-targeting (ARAT) agents in clinical data, but not in in vitro data. We investigated the clinical outcome of cabazitaxel chemotherapy after docetaxel according to use of ARAT agents., Patients and Methods: Prostate specific antigen (PSA) response, progression-free survival, and overall survival were compared between cases with and without prior use of ARAT agents in 74 Japanese patients with metastatic castration-resistant prostate cancer treated with cabazitaxel chemotherapy., Results: Background characteristics were comparable between patients with and without prior use of ARAT agents. PSA response, progression-free survival, and overall survival in cabazitaxel chemotherapy were comparable between patients with and without prior use of ARAT agents., Conclusion: No detrimental effects of prior ARAT agents on clinical outcome were observed for cabazitaxel chemotherapy in the post-docetaxel setting, suggesting that cabazitaxel can be expected to remain active even after ARAT agent therapy., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Recent studies have reported that TUBB3 overexpression is involved in docetaxel (DTX) resistance in prostate cancer (PCa). The aim of this study was to clarify the role of TUBB3 in DTX and cabazitaxel (CBZ) resistance, and cross-resistance between DTX and CBZ in PCa. We analyzed the effect of TUBB3 knockdown on DTX and CBZ resistance and examined the interaction between TUBB3 and PTEN. We also investigated the role of phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) in DTX and CBZ resistance. TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression. LY294002 suppressed TUBB3 expression in DTX-resistant and CBZ-resistant cell lines. LY294002 re-sensitized DTX-resistant cell lines to DTX and CBZ-resistant cell lines to CBZ. These results suggest that TUBB3 is involved in DTX resistance and CBZ resistance. A combination of LY294002/DTX and that of LY294002/CBZ could be potential strategies for PCa treatment.

Background/aim: Cabazitaxel use has usually been limited to up to 10 cycles in most countries according to the protocol in the TROPIC trial. Therefore, clinical data on cabazitaxel use beyond 10 cycles is limited. The aim of this study was to report the therapeutic outcome of cabazitaxel chemotherapy administered for >10 cycles., Patients and Methods: This study included 74 Japanese patients with prostate cancer between 2014 and 2017. Patients background, and treatment outcomes including PSA decline, progression-free survival, treatment-failure-free survival, overall survival, and adverse events were investigated, comparing patients treated with ≤10 and >10 cycles., Results: Patients characteristics were favorable as indicated by the higher number of cycles of prior docetaxel chemotherapy, absence of pain, and absence of bony and visceral metastases among men who received >10 cycles of cabazitaxel. PSA response, progression-free survival, treatment-failure-free survival and overall survival were better among patients treated with >10 cycles of cabazitaxel compared to those treated with ≤10 cycles. The incidence of severe adverse events was similar between the two groups., Conclusion: Taken together, this study suggested that continuous chemotherapy with cabazitaxel beyond 10 cycles may be beneficial., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

This multi-institutional study aimed to investigate the efficacy and safety profiles of cabazitaxel after prior docetaxel chemotherapy in patients with castration-resistant prostate cancer (CRPC). This study included 63 Japanese patients with CRPC who were treated with cabazitaxel from 2014 to 2017. The oncological outcomes and adverse events (AEs) were documented, and prognostic factors for oncological outcomes and predictive factors for AEs were analysed. PSA decline was observed in 68.3% of patients, including 25.4% who achieved a ≥ 50% decline. The median progression-free survival, treatment failure-free survival, and overall survival were 4.3, 4.1, and 9.0 months, respectively. More cycles of prior docetaxel therapy was identified as common favourable prognostic factors for progression-free survival, treatment failure-free survival, and overall survival. Severe neutropenia, febrile neutropenia, and severe non-haematological AEs were observed in 73.0%, 33.3%, and 23.8% of patients, respectively. However, > 10 cycles of docetaxel was not associated with increased incidence of AEs. In conclusion, cabazitaxel chemotherapy was still active in Japanese CRPC patients treated with > 10 cycles of docetaxel chemotherapy, with an acceptable risk of AE burden. Treatment with cabazitaxel after > 10 cycles of docetaxel may be an appropriate option when it can be administered.

Objectives: To investigate predictive factors of survival of metastatic castration‐resistant prostate cancer patients undergoing first‐line treatment with androgen receptor pathway inhibitors or docetaxel. Methods: Japanese patients with metastatic castration‐resistant prostate cancer treated with androgen receptor pathway inhibitor or docetaxel between 2008 and 2018 were included. The differential impact of various clinicopathological factors on the outcome, including progression‐free survival and overall survival, was compared between treatment with androgen receptor pathway inhibitor and docetaxel. Results: Of 254 patients with metastatic castration‐resistant prostate cancer, 119 (46.9%) and 135 (53.2%) were treated with androgen receptor pathway inhibitor and docetaxel, respectively. The multivariate analysis showed that androgen receptor pathway inhibitor was an independent prognostic factor for better progression‐free survival (hazard ratio 0.62, 95% confidence interval 0.42–0.92, P = 0.016) and overall survival (hazard ratio 0.61, 95% confidence interval 0.41–0.93, P = 0.021), compared with docetaxel. Pretreatment prostate‐specific antigen levels and time to castration‐resistant prostate cancer were differentially associated with progression‐free survival and overall survival between androgen receptor pathway inhibitor or docetaxel. In patients who presented <6 months to castration‐resistant prostate cancer, progression‐free survival was shorter in those treated with androgen receptor pathway inhibitor (median 1.1 months, 95% confidence interval 0.2–2.8 months) compared with those who received docetaxel (median 5.0 months, 95% confidence interval 1.8–6.7 months; P = 0.014). Conclusions: First‐line therapy with androgen receptor pathway inhibitor is associated with a better prognosis when compared with docetaxel, even after adjustment for prognostic factors. However, a shorter time to castration‐resistant prostate cancer is associated with better progression‐free survival for patients receiving docetaxel, suggesting that docetaxel is the preferred option for patients with a shorter time to castration‐resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Currently, the optimal sequential use of androgen receptor (AR) axis‐targeted agents and taxane chemotherapies remains undetermined. We aimed to elucidate the resistance status between taxanes and enzalutamide, and the functional role of the AR axis. Enzalutamide‐resistant 22Rv1 cells showed collateral resistance to taxanes, including docetaxel and cabazitaxel. However, taxane‐resistant cells showed no collateral resistance to enzalutamide; taxane‐resistant cells expressed comparable protein levels of full‐length AR and AR variants. Knockdown of both full‐length AR and AR variants rendered cells sensitive to taxanes, whereas knockdown of AR variants sensitized cells to enzalutamide, but not to taxanes. In contrast, overexpression of full‐length AR rendered cells resistant to taxanes. Consistently, the prostate‐specific antigen response and progression‐free survival in docetaxel chemotherapy were worse in cases with prior use of ARAT agents compared with cases without. Collateral resistance to taxanes was evident after obtaining enzalutamide resistance, and aberrant AR signaling might be involved in taxane resistance. [ABSTRACT FROM AUTHOR]

Objective To investigate the potential relationship of steroid usage with prostate-specific antigen ( PSA) flare as well as the prognostic impact of PSA flare, which is known to occur in 10-20% of patients with metastatic castration-resistant prostate cancer during docetaxel chemotherapy. Patients and Methods This study included 71 patients with metastatic castration-resistant prostate cancer treated by docetaxel chemotherapy with co-introduction of a steroid. PSA flare was defined as a transient PSA increase followed by a PSA decrease. Result s PSA flare was recognized in 7.0-23.9% of patients according to the definition used. Intriguingly, men with steroid intake before the initiation of docetaxel chemotherapy experienced significantly fewer PSA flares. The progression-free survival rate in men with PSA flare was equivalent to that of PSA responders, but significantly better than men with PSA failure. Conclusions Our results suggest that de novo steroid co-introduction with docetaxel chemotherapy induces the PSA flare phenomenon. This novel finding may account for the mechanism of PSA flare as well as being valuable for distinguishing PSA elevation attributable to PSA flare from that attributable to PSA failure. [ABSTRACT FROM AUTHOR]

Since 1941, androgen deprivation therapy has been the primary treatment for metastatic hormone-sensitive prostate cancer. Androgen deprivation therapy consists of several regimens that vary according to therapeutic modality, as well as treatment schedule. Androgen deprivation therapy initially shows excellent antitumor effects, such as relief of cancer-related symptoms, tumor marker decline and tumor shrinking. However, most metastatic hormone-sensitive prostate cancer cases eventually develop castration resistance and become lethal. Taxanes, such as docetaxel and cabazitaxel, as well as novel androgen receptor-targeting agents, such as abiraterone acetate and enzalutamide, have emerged for metastatic castration-resistant prostate cancer. The concept and principle of primary therapy for metastatic hormone-sensitive prostate cancer has remained unchanged for decades. Recently, upfront docetaxel chemotherapy has been shown to prolong overall survival in men with metastatic hormone-sensitive prostate cancer, and would lead to a paradigm shift in primary pharmacotherapy for metastatic hormone-sensitive prostate cancer. This raises the possibility of upfront use of taxanes, as well as novel androgen receptor-targeting agents combined with androgen deprivation therapy. The present review summarizes the current status of primary pharmacotherapy for metastatic hormone-sensitive prostate cancer, and discusses future perspectives in this field. [ABSTRACT FROM AUTHOR]

Prolonged survival of patients with castration-resistant prostate cancer has been demonstrated following treatment with a combination of docetaxel and prednisone. This combination has, therefore, become the standard first-line chemotherapy for castration-resistant prostate cancer. Median survival, however, does not exceed 20 months and there are currently no approved second-line treatments for patients who progress after docetaxel treatment. The development of effective and safe treatment strategies is urgently required. Several clinical trials are currently evaluating the use of cytotoxic, antiandrogenic and molecular targeting agents. Preclinical studies are identifying the mechanisms responsible for docetaxel resistance and means of enhancing docetaxel activity. The results of these studies will provide the basis for rationally designed therapeutic approaches. This article summarizes the results of recent preclinical and clinical studies and discusses future perspectives. [ABSTRACT FROM AUTHOR]

Purpose: Comorbidity with hypertension (HTN) may affect the outcome of castration-resistant prostate cancer (CRPC). In this study, we evaluated the prognostic impact of antihypertensive agents in patients with CRPC treated with androgen receptor axis-targeting (ARAT) agents or docetaxel chemotherapy.Patients and Methods: This study included 156 Japanese men with CRPC who were treated with ARAT agents (n = 85) or docetaxel (n = 71) at our hospital between 2008 and 2017. Associations between clinicopathological factors, HTN status, progression-free survival (PFS) and overall survival (OS) were evaluated by univariate and multivariate analysis.Results: When adjusted for age, prostate-specific antigen levels at pretreatment, Gleason score, and clinical M-stage, comorbid HTN was significantly associated with better OS (hazards ratio, 95% confidence interval: 0.41, 0.21-0.77; P = 0.0051), but not with PFS (hazards ratio, 95% confidence interval: 0.64, 0.38-1.11; P = 0.11) in patients treated with ARAT agent. However, HTN was not associated with PFS or OS for patients treated with docetaxel.Conclusions: Use of antihypertensive agents has prognostic significance for patients with CRPC treated with ARAT agent, but not docetaxel. [ABSTRACT FROM AUTHOR]

Purpose: Currently, several therapeutic options for castration-resistant prostate cancer (CRPC) are available, for which predictive biomarkers have not been established. Therefore, we aimed to reveal the association between pretreatment serum testosterone level and antitumor outcomes when treated with androgen receptor axis-targeting agents and taxane chemotherapies for CRPC.Patients and Methods: The present study included Japanese patients with metastatic prostate cancer whose serum testosterone levels during androgen-deprivation therapy were available. The antitumor outcomes when treated with enzalutamide, abiraterone, docetaxel, and cabazitaxel with clinicopathological parameters including serum testosterone levels during androgen-deprivation therapy, as well as prognoses including progression-free survival and overall survival, were examined.Results: Progression-free survival among men with higher serum testosterone level was superior to that among men with lower serum testosterone level when treated with enzalutamide. On the contrary, progression-free survival and overall survival among men with higher serum testosterone level were significantly inferior to those among men with lower serum testosterone level when treated with docetaxel and cabazitaxel, respectively.Conclusions: The present study indicated distinct prognostic values of serum testosterone level when treated with androgen receptor axis-targeting agent and taxane chemotherapy for CRPC, suggesting that serum testosterone level may be useful predictive biomarker to navigate the appropriate therapy in patients with CRPC. [ABSTRACT FROM AUTHOR]

Kinesin family member C1 (KIFC1) is a minus end-directed motor protein that plays an essential role in centrosome clustering. Previously, we reported that KIFC1 is involved in cancer progression in prostate cancer (PCa). We designed this study to assess the involvement of KIFC1 in docetaxel (DTX) resistance in PCa and examined the effect of KIFC1 on DTX resistance. We also analyzed the possible role of a KIFC1 inhibitor (CW069) in PCa. We used DTX-resistant PCa cell lines in DU145 and C4-2 cells to analyze the effect of KIFC1 on DTX resistance in PCa. Western blotting showed that KIFC1 expression was higher in the DTX-resistant cell lines than in the parental cell lines. Downregulation of KIFC1 re-sensitized the DTX-resistant cell lines to DTX treatment. CW069 treatment suppressed cell viability in both parental and DTX-resistant cell lines. DTX alone had little effect on cell viability in the DTX-resistant cells. However, the combination of DTX and CW069 significantly reduced cell viability in the DTX-resistant cells, indicating that CW069 re-sensitized the DTX-resistant cell lines to DTX treatment. These results suggest that a combination of CW069 and DTX could be a potential strategy to overcome DTX resistance. [ABSTRACT FROM AUTHOR]

Autophagy induction in cancer is involved in cancer progression and the acquisition of resistance to anticancer agents. Therefore, autophagy is considered a potential therapeutic target in cancer therapy. In this study, we found that long-chain fatty acids (LCFAs) have inhibitory effects on Atg4B, which is essential for autophagosome formation, through screening based on the pharmacophore of 21f , a recently developed Atg4B inhibitor. Among these fatty acids, docosahexaenoic acid (DHA), a polyunsaturated fatty acid, exhibited the most potent Atg4B inhibitory activity. DHA inhibited autophagy induced by androgen receptor signaling inhibitors (ARSI) in LNCaP and 22Rv1 prostate cancer cells and significantly increased apoptotic cell death. Furthermore, we investigated the effect of DHA on resistance to ARSI by establishing darolutamide-resistant prostate cancer 22Rv1 (22Rv1/Dar) cells, which had developed resistance to darolutamide, a novel ARSI. At baseline, 22Rv1/Dar cells showed a higher autophagy level than parental 22Rv1 cells. DHA significantly suppressed Dar-induced autophagy and sensitized 22Rv1/Dar cells by inducing apoptotic cell death through mitochondrial dysfunction. These results suggest that DHA supplementation may improve prostate cancer therapy with ARSI. [Display omitted] • LCFAs inhibit Atg4B, essential for autophagosome formation, particularly DHA. • Low concentrations of DHA inhibited ARSI-induced autophagy in prostate cancer cells. • Low concentrations of DHA enhanced ARSI sensitivity without being cytotoxic alone. • Low concentrations of DHA overcame Darolutamide resistance in 22Rv1/Dar cells. [ABSTRACT FROM AUTHOR]