Survival In Castration-resistant Prostate Cancer Patients Research Articles

Developing New Treatment Options for Castration-Resistant Prostate Cancer and Recurrent Disease.

Prostate cancer (PCa) is a major diagnosed cancer among men globally, and about 20% of patients develop metastatic prostate cancer (mPCa) in the initial diagnosis. PCa is a typical androgen-dependent disease; thus, hormonal therapy is commonly used as a standard care for mPCa by inhibiting androgen receptor (AR) activities, or androgen metabolism. Inevitably, almost all PCa will acquire resistance and become castration-resistant PCa (CRPC) that is associated with AR gene mutations or amplification, the presence of AR variants, loss of AR expression toward neuroendocrine phenotype, or other hormonal receptors. Treating CRPC poses a great challenge to clinicians. Research efforts in the last decade have come up with several new anti-androgen agents to prolong overall survival of CRPC patients. In addition, many potential targeting agents have been at the stage of being able to translate many preclinical discoveries into clinical practices. At this juncture, it is important to highlight the emerging strategies including small-molecule inhibitors to AR variants, DNA repair enzymes, cell survival pathway, neuroendocrine differentiation pathway, radiotherapy, CRPC-specific theranostics and immune therapy that are underway or have recently been completed.

Appropriate Patient Status for Ra-223 Treatment in the Treatment Sequence for Castration-resistant Prostate Cancer.

Radium (Ra)-223 is widely used for treating castration-resistant prostate cancer (CRPC) with bone metastasis based on evidence of increased survival and decreased skeletal-related events. However, the timing of Ra-223 use in the treatment sequence of CRPC remains controversial. Therefore, this study aimed to explore the appropriate patient status for Ra-223 use in the CRPC treatment sequence by examining patients treated with Ra-223 from the time of CRPC diagnosis until death. The medical records of 67 CRPC patients with bone metastasis who were treated with Ra-223 at two institutes were retrospectively analysed. The impact of 13 factors from the time of CRPC diagnosis until death was analysed using univariate and multivariate Cox hazard ratio models to evaluate the appropriate patient status for Ra-223 treatment. The median survival time following CRPC diagnosis for all the patient groups was 3.82 years. Univariate analysis identified a higher-than-normal alkaline phosphatase (ALP) level, bone scan indexes ≥2, and prostate-specific antigen (PSA) doubling time <3 months before Ra-223 treatment as predominant adverse prognostic factors. Ra-223 therapy discontinuation was not a significant factor. The survival of CRPC patients with these factors was significantly worse than that of patients without these factors. In the multivariate analysis, a higher-than-normal ALP level at the start of treatment was identified as a poor prognostic factor for mortality. The appropriate patient status for Ra-223 use includes low bone metastasis burden and well-controlled PSA levels.

Prostate-Specific Antigen and Time to PSA Nadir as Prognostic Significance in Castration-Resistant Prostate Cancer

Highlight:Assessing the survival rate in castration-resistant prostate cancer was descriptived.PSA level between survivor and non survivor was significant but not for PSA nadir level, TTN and TTC.Initial PSA level can predict survival prognosis rate of castration-resistant prostate cancer patients. Abstract:High mortality rates was often found in castration-resistant prostate cancer (CRPC). Our aim on this research was to assess the PSA level and time to PSA nadir as a prognostic tool for survival in CRPC patients. Several factors are considered to be useful as prognostic marker in CRPC patients. This study was a descriptive study assessing the survival rate in castration-resistant prostate cancer. Evaluation data included sex, age, initial PSA level, final PSA level, time to PSA nadir (TTN), time to CRPC progression (TTC), and survival status. A total of 24 patients with CRPC were evaluated in this study. There was significant difference found of initial PSA level between survivor (445.7 + 165.6 ng/mL) and non-survivor (200.7 + 144.9 ng/mL). There were no significant differences were also found in PSA nadir level, TTN and TTC between survivor and non-survivor groups. This study revealed that there was association between initial PSA level on survival rate of CRPC patients. Initial PSA level could be used to predict survival prognosis in CRPC patients.

EFFECT OF NEW ANDROGEN RECEPTOR AXIS-TARGETED AGENTS ON SURVIVAL OF CASTRATION-RESISTANT PROSTATE CANCER

(Background)The real world's effect of new androgen receptor axis-targeted agents (ARATs) on survival of castration-resistant prostate cancer (CRPC) remains unclear in Japan. (Aims)The primary aim was to determine the clinical benefit of ARATs on survival of CRPC patients. The secondary aim was to evaluate predictive factors affecting the survival of CRPC patients. (Patients and results)Among 236 patients treated with androgen deprivation therapy (ADT), 68 patients developed CRPC; two groups of 34 patients were treated with ARATs (A cases) or conventional ADT (V cases). In a median follow-up of 61.5 months, 20 A and 22 V cases died of cancer. Median survival time (MST) from diagnosis was 99 and 66 months for A and V cases, respectively, and MST from CRPC to death were 50.5 and 44.5 months, respectively. There were no significant differences between both cases. The hazard ratio for death from diagnosis or CRPC progression of the A cases to V cases was 0.711; 95% confidence interval (CI), 0.371 to 1.362; P = 0.3037, or 0.805; 95% CI, 0.434 to 1.491; P=0.4899, respectively. Multivariable analysis revealed that a unique and significant independent prognostic factor from diagnosis was time to CRPC. (Conclusions)In this small retrospective study, we could not determine the clinical benefit of new ARATs compared with conventional ADT on survival of CRPC patients, and a unique and significant independent prognostic factor from diagnosis was time to CRPC. We need to validate these results in a future multi-institutional study.

THE PROGNOSTIC VALUE OF PROSTATE SPECIFIC ANTIGEN AND TIME TO PSA NADIR IN CASTRATION-RESISTANT PROSTATE CANCER

High mortality rates was often found in castration-resistant prostate cancer (CRPC). Our aim on this research was to assess the PSA level and time to PSA nadir as a prognostic tool for survival in CRPC patients. Several factors are considered to be useful as prognostic marker in CRPC patients. This study was a descriptive study assessing the survival rate in castration-resistant prostate cancer. Evaluation data included sex, age, initial PSA level, final PSA level, time to PSA nadir (TTN), time to CRPC progression (TTC), and survival status. A total of 24 patients with CRPC were evaluated in this study. There was significant difference found of initial PSA level between survivor (445,7 + 165,6 ng/mL) and non-survivor (200.7 + 144.9 ng/mL). There were no significant differences were also found in PSA nadir level, TTN and TTC between survivor and non-survivor groups. This study revealed that there was association between initial PSA level on survival rate of CRPC patients. Initial PSA level could be used to predict survival prognosis in CRPC patients.

Muscle Characteristics Obtained Using Computed Tomography as Prognosticators in Patients with Castration-Resistant Prostate Cancer

Limited studies have investigated the correlation between body composition and prostate cancer outcomes. We analyzed the effect of muscle mass and quality on castration-resistant prostate cancer (CRPC) outcomes. Skeletal muscle index (SMI) and skeletal muscle attenuation (SMA) were measured for 411 patients at the L3 vertebral level using computed tomography at CRPC diagnosis and were dived to low and high groups at the value of median. Analysis of the skeletal phenotypes and age (<70 and >70 years) was performed to evaluate the effect of SMI and SMA. The median survival rates for patients with low and high SMI were 19 and 24 months (p = 0.015), and those with low and high SMAs were 15 and 26 months (p < 0.001), respectively. In the subgroup analysis by age, SMA was a significant prognosticator in both groups, while SMI was a significant prognosticator only in patients aged >70 years. Patients with low SMA + low SMI had the worst prognosis. Muscle characteristics seems to be a prognosticator in survival of CRPC patients and may be considered in treatment planning.

Intratumoral and subcutaneous injection of HVJ-E (GEN0101) for metastatic castration-resistant prostate cancer: Open-label, phase I, dose escalation study.

e16511 Background: Inactivated Sendai virus particles (hemagglutinating virus of Japan envelope (HVJ-E)) have a novel antitumor effect: HVJ-E fused to prostate cancer cells via cell surface receptor causes apoptosis of prostate cancer cells in vitro and in vivo. HVJ-E also induces antitumor immunity by activating natural killer (NK) cells and cytotoxic T cells and suppressing regulatory T cells in vivo. We conducted an open-label, phase I, dose-escalation study in patients with castration-resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and subcutaneous injection of HVJ-E (GEN0101). Methods: Patients with CRPC who were resistant to standard of care or could not receive standard of care were eligible. GEN0101 was injected directly into the prostate on day 1 and subcutaneously on days 5, 8 and 12 in two 28-day treatment cycles using a modified 3+3 dose-escalation design to determine the recommended dose of GEN0101. The primary end points were to evaluate safety and tolerability of GEN0101 and determine the recommended dose. The secondary end points were to analyze antitumor effect and tumor immunity. The study is registered at UMIN Clinical Trials Registry, number UMIN000017092. Results: Of the 9 patients treated, 3 received 30,000mNAU of GEN0101 and 6 received 60,000mNAU. There were no dose-limiting toxicities, and the recommended dose of GEN0101 was defined as 60,000mNAU. Radiographically, one patient had stable disease and 2 had progressive disease in the low-dose group, and 5 patients had stable disease and one had progressive disease in the high-dose group. Four patients in high dose group had reductions in lymph node metastasis after 2 treatment cycles. Final PSA increase rates in high-dose group were more suppressed than those in low-dose group. NK cell activity was enhanced in 2 patients (66%) in low-dose group and 5 patients (83%) in high-dose group, Serum interleukin-6, and IFN-γ levels were not affected by GEN0101 treatment. Conclusions: Intratumoral and subcutaneous injections of GEN0101 were well tolerated and feasible. Antitumor effect in lymph node metastasis were observed in CRPC patients. It is necessary to test whether the treatment with GEN0101 improves the survival of CRPC patients. Clinical trial information: UMIN000017092.

MicroRNA-200a suppresses prostate cancer progression through BRD4/AR signaling pathway.

Prostate cancer is still considered a significant health care challenge worldwide due in part to the distinct transformation of androgen‐dependent prostate cancer (ADPC) into treatment‐refractory castration‐resistant prostate cancer (CRPC). Consequently, there is an urgent need to explore novel molecular mechanisms underlying treatment resistance in ADPC. Although numerous studies have alluded to the role of miR‐200a in several cancers, the biological significance of miR‐200a in prostate cancer remains unknown. After performing microarray analysis and reanalysis of the publicly available Memorial Sloan Kettering Cancer Center dataset, miR‐200a expression was found higher in ADPC tissues and its expression was positively associated with survival of CRPC patients. In vitro studies showed that miR‐200a overexpression in CRPC cells markedly suppressed cellular proliferation and facilitated apoptosis. In vivo studies indicated that overexpression of miR‐200a inhibited growth and metastasis of prostate cancer. The luciferase reporter assay demonstrated that BRD4 is a direct target gene of miR‐200a and it could reverse miR‐200a‐mediated biological effects in prostate cancer cells. Most importantly, our findings indicated that miR‐200a suppresses the progression of CRPC by inhibiting the activation of BRD4‐mediated AR signaling. This finding provides the foundation for the development of more personalized therapeutic approaches for CRPC patients.

Identification of LIMK2 as a therapeutic target in castration resistant prostate cancer

This study identified LIMK2 kinase as a disease-specific target in castration resistant prostate cancer (CRPC) pathogenesis, which is upregulated in response to androgen deprivation therapy, the current standard of treatment for prostate cancer. Surgical castration increases LIMK2 expression in mouse prostates due to increased hypoxia. Similarly, human clinical specimens showed highest LIMK2 levels in CRPC tissues compared to other stages, while minimal LIMK2 was observed in normal prostates. Most notably, inducible knockdown of LIMK2 fully reverses CRPC tumorigenesis in castrated mice, underscoring its potential as a clinical target for CRPC. We also identified TWIST1 as a direct substrate of LIMK2, which uncovered the molecular mechanism of LIMK2-induced malignancy. TWIST1 is strongly associated with CRPC initiation, progression and poor prognosis. LIMK2 increases TWIST1 mRNA levels upon hypoxia; and stabilizes TWIST1 by direct phosphorylation. TWIST1 also stabilizes LIMK2 by inhibiting its ubiquitylation. Phosphorylation-dead TWIST1 acts as dominant negative and fully prevents EMT and tumor formation in vivo, thereby highlighting the significance of LIMK2-TWIST1 signaling axis in CRPC. As LIMK2 null mice are viable, targeting LIMK2 should have minimal collateral toxicity, thereby improving the overall survival of CRPC patients.

Abstract A080: Caveolin-1 detected in tumor-derived exosomes induces cancer stem cell phenotypes in castration-resistant prostate cancer

Abstract Prostate cancer (PCa) is by far the most common male malignancy and the third leading cause of cancer-related death in the US. Regardless of a great response of hormonal therapy for metastatic PCa patients, eventually PCa relapses to an end-stage castration-resistant prostate cancer (CRPC) leading to mortality. Although introducing newer androgen receptor (AR) pathway inhibitors is encouraging, treatment resistance in CRPC continues to remain a clinical problem. Clinical evidence of treatment resistant CRPC indicates carcinoma cell undergoing transdifferentiation. However, the mechanism as well as cell lineage are not fully characterized, which highlights an unmet clinical need to uncover potential therapeutic targets for targeted therapy to improve the overall survival of CRPC patients. Exosome is characterized as nano-grade small extracellular vesicle derived from the endosomal system from many kinds of cells. Therefore, exosome can carry many kinds of message molecules as a delivery vehicle in a paracrine or endocrine manner. Overall, tumor-derived exosomes (TDE) has been shown to play a critical role in promoting cancer progression or drug resistance. Our recent data have shown that TDE from PCa cells is able to induce neuroendocrine differentiation of CRPC, which leads us to further elucidate the role of PCa-derived exosome. Previously by using xenograft model, we have reported that elevated caveolin-1 (Cav-1) in LNCaP cell can accelerate its tumor growth but also increase the tumor incidence of low tumorigenic cells in a paracrine manner, implying that Cav-1 can be secreted extracellualrly. However, the functional role of secreted Cav-1 in PCa is still being debated. The expression of Cav-1 was considered to function as a suppressor of cell transformation and as preventing the development and metastases of mammary tumor; on the other hand, Cav-1 served as an oncogene that correlates with PCa progression. Furthermore, recent studies have shown that Cav-1 expression is associated with chemoresistance in multiple cancers as well as cancer stem cell (CSC) property in lung cancer. CSC theory has raised significant attention in recent years because of its self-renewal and quiescent nature, which underlies its role as a cancer-initiating cell population responsible for recurrent tumor with treatment resistance. In this study, we purified TDE from various PCa cell lines including either Cav-1 positive (Cav-1High) or negative (Cav-1low) cells using membrane-based affinity chromatography, and further characterized its size and number using Zetaview (Particle Matrix, Mebane, NC) and Exocet quantitation kit (SBI, Palo Alto, CA) separately. We found that TDE derived from metastatic PCa cells without AR expression is capable of inducing CSC phenotypes in AR-expressing recipient cells. Further analyses demonstrated that the high accumulation of Cav-1 in TDE appears to be a potential candidate. Indeed, Cav-1High cells or exogenous Cav-1-treated PCa cell lines can increase CSC phenotypes in vitro and in vivo. Mechanistically, the presence of Cav-1 is able to increase stem cell transcription Yamanaka factors, including KLF4, SOX2, OCT4, and Nanog. Furthermore, from microarray screening, we found RPC32 as another potential Cav-1 downstream effector, which is characterized as a subunit of RNA polymerase III (Pol III). RPC32 has two different isoforms (α and β), and only RPC32α is known to be highly regulated and expressed in stem cell and transformed cells. Therefore, we hypothesize that RPC32α is responsible for the elevated Yamanaka factors protein expression leading to CSC development. Nevertheless, we conclude that the presence of Cav-1 in PCa TDE plays an inductive role in the appearance of treatment-resistant CRPC in a paracrine manner, which provides a potential prognostic marker and therapeutic target. Citation Format: Chun-Jung Lin, Andrew Dang, Elizabeth Hernandez, Jer-Tsong Hsieh. Caveolin-1 detected in tumor-derived exosomes induces cancer stem cell phenotypes in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A080.

125I seeds implantation in patients with castration resistant prostate cancer

Objective To evaluate the clinical efficacy of brachytherapy with 125I seeds implantation in patients with castration resistant prostate cancer (CRPC). Methods Twenty-eight patients with CRPC from February 2010 to December 2015 in Northern Jiangsu People′s Hospital were analyzed retrospectively. Patients were divided into 2 groups according to different treatment methods. Control group (n=13) received endocrine therapy, and study group (n=15) underwent brachytherapy combined with endocrine therapy. The progression was defined as posttreatment prostate specific antigen (PSA)≥ 125% PSA of baseline level. PSA-progression-free survival (PFS), overall survival (OS) and quality of life (physical functioning, social functioning, general health, general physical discomfort, urinary symptoms and treatment-related symptoms) of 2 groups were compared using Kaplan-Meier analysis and log-rank test. Results The median PSA-PFS and OS of study group were 29(24, 37) months and 37(32, 50) months respectively, both of them were longer than those of control group (13(7, 21) months, 19(14, 23) months; χ2=13.300, 19.362, both P<0.01). Comparing with control group, the physical functioning, social functioning, general health and general physical discomfort of study group were improved. Conclusion Brachytherapy can effectively prolong the survival of CRPC patients and improve the patients′ life quality. Key words: Prostatic neoplasms; Brachytherapy; Iodine radioisotopes

Abstract 4948: miR-375 induces docetaxel resistance in prostate cancer by targeting SEC23A and YAP1

Abstract Background: Castration-resistant prostate cancer (CRPC) patients are commonly treated with the chemotherapy drug, docetaxel. We previously reported that elevated miR-375 was significantly associated with poor overall survival of CRPC patients. However, the biological role and mechanism of action of miR-375 in CRPC chemotherapy remain unknown. In this study, we evaluated if miR-375 induced chemo-resistance through regulating target genes associated with multiple drug resistance. Methods: We first compared miR-375 expression level between prostate cancer tissues and normal prostate tissues using TCGA prostate cancer data. To examine the role of miR-375 in docetaxel sensitivity, we then transfected miR-375 using a pre-miRNA lentiviral vector and examined the effect of the exogenously overexpressed miR-375 on cell growth in two prostate cancer cell lines, DU145 and PC3. To determine the effect of overexpressed miR-375 on tumor growth and chemo-resistance in vivo, we subcutaneously injected cells with miR-375 overexpression into mice. Lastly, we utilized qRT-PCR and western blot assay to examine two miR-375 target genes, SEC23A and YAP1, for their expression changes after miR-375 transfection. Results: By comparing 495 tumor tissues and 52 normal tissues, we found that miR-375 was significantly overexpressed in prostate cancer tissues (8.45 fold increase, p value = 1.98E-23). Docetaxel treatment induced higher expression of miR-375 with 5.83 and 3.02 fold increases in DU145 and PC3, respectively. Interestingly, miR-375 appeared to play a contradictory role in determining prostate cancer fate. We found that miR-375 overexpression caused cell proliferation inhibition, cell cycle arrest and cell apoptosis. However, we also found that the elevated miR-375 significantly reduced cell sensitivity to docetaxel treatment in vitro, evidenced by less apoptotic cells and higher cell proliferation. Mouse models also showed that the increased miR-375 expression was resistant to docetaxel treatment, demonstrated by greater tumor weight and sizes in miR-375 transfected cells than in empty vector controls. In addition, previous studies in other laboratories have shown that SEC23A and YAP1 are miR-375 target genes and are able to reduce cancer cell growth. We therefore examined expression levels of the two genes and observed significant expression reduction of both proteins and mRNAs in the miR-375 transfected prostate cancer cell lines. TCGA dataset analysis further confirmed the negative correlations between miR-375 and the two target genes (r = -0.62 and -0.56 for SEC23A and YAP1, respectively; p&amp;lt;0.0001). Conclusions: miR-375 may confer chemo-resistance to docetaxel treatment during prostate cancer chemotherapy through directly targeting SEC23A and YAP1. Our study implies that miR-375 or its target genes, SEC23A or YAP1 might serve as potential diagnostic and/or therapeutic targets to overcome chemo-resistance in CRPC treatment. Citation Format: Yuan Wang, Rachel Lieberman, Jing Pan, Qi Zhang, Meijun Du, Ming You, Liang Wang. miR-375 induces docetaxel resistance in prostate cancer by targeting SEC23A and YAP1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4948.

Abstract 3342: Galiellalactone derivative targets stem cell population in ENZ-resistant prostate cancer through inhibition of STAT3

Abstract Background: Androgen ablation remains the most effective therapy for patients with advanced disease. Unfortunately, most patients progress to castrate resistant prostate cancer (CRPC) characterized with hyper-activation of the androgen receptor (AR). Enzalutamide, a potent AR inhibitor showed efficacy by prolonging survival in CRPC patients. However, ENZ resistance (ENZR) rapidly occurs in patients and in our pre-clinical model targeting AR in ENZ resistant tumors with a 3rd generation AR inhibitor is short lived. The role of signal transducer and activator of transcription (STAT) 3 in the progression of prostate cancer is well established and has been repeatedly linked with maintenance of a stem cell phenotype across cancers. Additionally, drug resistance has been hypothesized to occur via enrichment of cancer stem-like cells (CSC), a phenotype associated with poor survival in patients. Therefore, we propose a shift of focus to target CSC phenotype using small molecule inhibitor of STAT3 called GPA500, instead of the AR axis to deal with ENZ resistance. Methods and Results: We developed a unique model of ENZ-resistance and found that cell lines derived from serially passaged ENZR tumors displayed broad genetic diversity and differential AR activity. Notably, the cell lines 42DENZR and 42FENZR are PSAlow, harbor an expanded CSC population and have STAT3 hyper-activation compared to CRPC controls measured by STAT3-luc reporter. Accordingly, Crystal Violet and MTT proliferation assays showed that 42DENZR and 42FENZR cell lines were more sensitive to the STAT3 inhibitor GPA500 compared to CRPC control. Targeting the ENZ-R cells with GPA500 reduced mRNA levels of CD133, CD44, SOX2, OCT4 and Nanog. The reduction of these CSC markers was accompanied by reduced self-renewal capacity measured by spheroid assay. Cytometry analysis revealed that treatment with GPA500 reduced α2β1+, CD44+ and CD133+ (CSC) population in the 42D and 42F cells. Conclusion: In this study, we provide pre-clinical proof that targeting the STAT3 pathway using GPA500 in ENZ resistance as well as CRPC reduces cell proliferation as well as expression of stem cell markers. Impact: Exploring mechanisms of ENZR resistance serves a critical unmet need in PCa oncology, as the number of men with ENZ resistant CRPC continues to rise. Targeting STAT3 with the small molecule inhibitor GPA500 may provide an effective method to treat ENZR patients or delay the emergence of ENZ resistance in CRPC by reducing the emergence of stem cells. Citation Format: Sepideh Vahid, Daksh Thaper, Alistair Davies, Micaela Janse Van Rensburg, Kate Gibson, Krisi Ketola, Martin Johansson, Jennifer L. Bishop, Amina Zoubeidi. Galiellalactone derivative targets stem cell population in ENZ-resistant prostate cancer through inhibition of STAT3. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3342.

Abstract 3486: Dissecting the mechanism of AR-v7 nuclear translocation in prostate cancer

Abstract Continuous androgen receptor (AR) signaling is the key driver of castration-resistant prostate cancer (CRPC), despite prior androgen deprivation therapy (ADT). Potent, next-generation AR signaling inhibitors, such as abiraterone and enzalutamide have been recently added to the standard of care in the treatment of prostate cancer. However, resistance to these drugs inevitably emerges and is mediated by adaptive mechanisms that restore AR function, in the form of constitutively active, ligand-independent AR-variant (AR-V) overexpression. The microtubule-targeting drugs Docetaxel (DTX) and Cabazitaxel (CTX) are the only chemotherapy that significantly improves survival of CRPC patients. We have shown that full-length AR (AR-fl) binds microtubules (MTs) via its hinge domain, and utilizes them as tracks to facilitate its nuclear translocation. Taxanes keep AR-fl inactive in the cytoplasm as a result of MT stabilization. Of the two most prevalent AR-Vs, ARv567 contains the hinge region and is sensitive to taxane treatment while AR-v7, expressed in 60% of CRPC patients, lacks the hinge region and does not depend on MTs for its nuclear translocation. Therefore, ARv7 nuclear translocation is MT-independent and neither taxane treatment nor the disruption of dynein motor complex inhibited its nuclear localization. Thus, AR-v7 expression confers taxane resistance in vivo, in addition to next-generation AR inhibitors. Hence, inhibition of AR-v7 nuclear translocation and activity is critical to overcome drug resistance to current therapeutic modalities. However, the mechanism of ARv7 nuclear translocation is not clearly understood. Previously, we showed that ARv7 exhibited faster kinetics of nuclear translocation compared to AR-fl. Additionally, AR-v7 nuclear import is independent of the importin-α/β pathway, which is utilized by the MT-dependent, AR-fl and ARv567. Upon disruption of the Ran-GTPase nuclear import pathway, by overexpression of the catalytic mutant Q69L form of Ran, we observed that the nuclear import of both AR-fl and AR-V567 was significantly impaired, while ARv7 nuclear import was only partially affected. In this study, we hypothesized that molecular dynamics of AR nuclear import and export determines overall spatiotemporal localization of AR and its activity. To test this hypothesis, we generated photo-convertible AR-fl and AR-Vs (AR-v567 and AR-v7) fused to mEos4b construct, which enables us to track protein mobilization in the region of interest after photo-conversion in live cells. We are currently studying the nuclear import and export kinetics of both AR-fl and AR variants (AR-v567 and AR-v7) alone and in combination using the photo-conversion methodology. Elucidation of the distinct pathway(s) that mediate ARv7 nuclear import and/or export will allow the rationale design of effective ARv7 inhibitors or the development of co-targeting strategies in combination with taxanes and AR signaling inhibitors. Citation Format: Seaho Kim, Mohd Azrin Jamalruddin, Luigi Portella, Paraskevi Giannakakou. Dissecting the mechanism of AR-v7 nuclear translocation in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3486.

Should We Try Antiandrogen Withdrawal in Castration-Resistant Prostate Cancer Patients? Insights From a Retrospective Study

BackgroundIt remains uncertain whether those with response to antiandrogen withdrawal (AAW) have a better prognosis. We investigated the predictors of a better response to AAW and overall survival after acquiring resistance to first-line androgen deprivation therapy inpatients with castration-resistant prostate cancer (CRPC). Patients and MethodsWe retrospectively reviewed the medical records of 87 CRPC patients treated at Keio University Hospital. Sixty-seven of 87 CRPC patients underwent AAW. We analyzed clinicopathologic parameters to identify predictors of survival in CRPC patients and investigated predictors of good response to AAW. ResultsYounger age, longer duration of androgen deprivation therapy before CRPC development, and better response to AAW were independent favorable prognostic factors for overall survival. Although better response to AAW was a favorable prognostic factor in this study, trying AAW was not significantly related to overall survival. Duration of hormone therapy was significantly longer in those whose disease responded to AAW (69.9 ± 11.0 months) than those with no response (45.3 ± 5.2 months). ConclusionThe prognostic benefit of AAW was not clearly determined in this study. However, AAW might be beneficial in patients who have favorable prognostic factors for a response to AAW—that is, those who have received hormone therapy for a long period. However, AAW should not be done in patients who do not have favorable factors and who had a high prostate-specific antigen level at the time of their prostate cancer diagnosis.

Abstract 728: New derivative of galiellalactone inhibits the STAT3 activity and suppresses ENZ-resistant Prostate Cancer in vitro

Abstract Background: The role of signal transducer and activator of transcription (STAT) 3 in the progression of Prostate Cancer (PCa), the most common male cancer in North America, is well established. Although androgen ablation remains the most effective therapy for patients with advanced disease, most progress to castrate resistant prostate cancer (CRPC). Despite the development of new potent anti-androgens, like Enzalutamide (ENZ), which prolongs survival in CRPC patients, ENZ resistance rapidly occurs. Re-activation of the androgen receptor (AR) is a hallmark of CRPC and can occur via different mechanisms, including STAT3 activation. Furthermore, STAT3 can promote CRPC independently of AR activity, however whether STAT3 promotes resistance to ENZ in CRPC remains unknown. We have found that our LNCaP xenograft derived ENZR cell lines exhibit higher activity of the STAT3 pathway compared to CRPC. Additionally, in this model further targeting the AR using novel anti-androgens is short lived or ineffective. Therefore, we propose that targeting STAT3 using the small molecule inhibitor GPA500, alone or in combination with anti-androgens may delay or treat ENZR CRPC. Methods and Results: We developed a unique model of ENZ-resistance and found that cell lines derived from serially passaged ENZR tumors displayed broad genetic diversity and differential AR activity but consistent STAT3 hyper-activation compared to CRPC controls. WB analysis showed that all ENZR cell lines had increased pSTAT3Y705 compared to CRPC. Accordingly, Crystal Violet and MTT proliferation assays showed that ENZR cell lines were more sensitive to the STAT3 inhibitor GPA500 compared to CRPC control. The reduction in growth of GPA500 treated ENZR cells was independent of PARP cleavage, whereas GPA500 induced PARP cleavage in CRPC cells. Moreover, in ENZR cell lines with high AR activity and CRPC control cells, inhibition of STAT3 reduced AR activity as shown with WB and qRT-PCR for AR downstream targets like PSA and an AR-luciferase reporter assay. In ENZR cells with low AR activity and a stem cell phenotype, GPA500 treatment reduced surface expression of α2β1, CD44 and CD133. Inhibition of STAT3 activity was confirmed by WB as well as qRT-PCR analysis of STAT3 regulated genes like c-Myc, MCL1, BCL-XL. Conclusion: In this study, we provide pre-clinical proof that targeting the STAT3 pathway using GPA500 in ENZ resistance as well as CRPC reduces cell proliferation and AR activity as well as expression of stem cell markers. Impact: Exploring mechanisms of ENZR resistance serves a critical unmet need in PCa oncology, as the number of men with ENZ resistant CRPC continues to rise. Targeting STAT3 with the small molecule inhibitor GPA500 may provide an effective method to treat ENZR patients or delay the emergence of ENZ resistance in CRPC via reduction of AR activity and/or by suppressing aggressive tumor cell phenotypes such as cancer stem cells. Citation Format: Daksh Thaper, Sepideh Vahid, Jennifer L. Bishop, Martin Johansson, Amina Zoubeidi. New derivative of galiellalactone inhibits the STAT3 activity and suppresses ENZ-resistant Prostate Cancer in vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 728. doi:10.1158/1538-7445.AM2015-728

Abstract 366: A novel transcript variant of androgen receptor identified in circulating tumor cells from castration-resistant prostate cancer patients as a potentially prognostic biomarker

Abstract Circulating tumor cells (CTCs) are rare cancer cells in the bloodstream thought to have a key role in cancer metastasis. There are enormous interests in their analysis for castration-resistant prostate cancer (CRPC) due to their tendency to metastasize to bone. In this study, we applied a surface marker-independent microfluidic device for CTCs capture and retrieval that is based on cell size and deformability. Our device was able to capture 90% and recover 30% of tumor cells in spike experiments. We also developed and validated assays capable of detecting the transcript levels of selected molecular markers in single cells prepared with C1TM Single-Cell AutoPrep System. Blood samples drawn from 34 CRPC patients and 10 primary prostate cancer patients (PPC) were preceded for CTC isolation and molecular characterization. We found that 73% CRPC patients and 10% PPC patients were positive for EpCAM, and only about half of the EpCAM-positive CRPC cases were PSA or AR positive. It is interesting that while there is a strong association between AR and PSA expression in CTC samples, there is no correlation between AR or PSA transcripts in CTCs and serum PSA protein levels in CRPC patients. The positive detection of AR or PSA, but not EpCAM is statistically associated with poor prognosis of the CRPC patients. Very intriguingly, we identified a novel androgen receptor (AR) transcript variant -ARv from four CRPC patients’ CTCs. This ARv lacks a 554bp sequence region in the ligand binding domain (LBD), resulting in a loss of the entire LBD. Clinical data analysis revealed that the ARv is significantly associated with worse survival of CRPC patients (p&amp;lt;0.0001). In vitro functional studies showed this novel ARv is constitutively active in the absence of testosterone. Our findings suggest that this AR variant might contribute to the late stage progression of the diseases and could be used as a potential indicator for alternative therapies. In summary, our new fluidic device is capable of isolating CTC to enable molecular marker analysis, providing value in prognosis and guidance to therapy. Citation Format: Zhigang Kang, Avani Shah, Yunkai Yu, Yuelin Zhu, Ali Asgar Bhagat, Kyra Zhao, Andrew Wu, James Gao, Ravi Madan, James Gulley, William Dahut, Paul Meltzer, Liang Cao. A novel transcript variant of androgen receptor identified in circulating tumor cells from castration-resistant prostate cancer patients as a potentially prognostic biomarker. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 366. doi:10.1158/1538-7445.AM2015-366

MP87-07 PROGNOSTIC FACTORS FOR OVERALL SURVIVAL IN PATIENTS WITH CASTRATION-RESISTANT PROSTATE CANCER TREATED BY INTERMITTENT CHEMOTHERAPY WITH DOCETAXEL AND PREDNISOLONE

You have accessJournal of UrologyProstate Cancer: Advanced III1 Apr 2015MP87-07 PROGNOSTIC FACTORS FOR OVERALL SURVIVAL IN PATIENTS WITH CASTRATION-RESISTANT PROSTATE CANCER TREATED BY INTERMITTENT CHEMOTHERAPY WITH DOCETAXEL AND PREDNISOLONE Shintaro Narita, Takuya Koie, Shigeyuki Yamada, Kazuhiko Orikasa, Shigeki Matsuo, Hiroshi Aoki, Shigeto Ishidoya, Senji Hoshi, Norihiko Tsuchiya, Chikara Ohyama, Yoichi Arai, and Tomonori Habuchi Shintaro NaritaShintaro Narita More articles by this author , Takuya KoieTakuya Koie More articles by this author , Shigeyuki YamadaShigeyuki Yamada More articles by this author , Kazuhiko OrikasaKazuhiko Orikasa More articles by this author , Shigeki MatsuoShigeki Matsuo More articles by this author , Hiroshi AokiHiroshi Aoki More articles by this author , Shigeto IshidoyaShigeto Ishidoya More articles by this author , Senji HoshiSenji Hoshi More articles by this author , Norihiko TsuchiyaNorihiko Tsuchiya More articles by this author , Chikara OhyamaChikara Ohyama More articles by this author , Yoichi AraiYoichi Arai More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1952AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Optimal schedule of docetaxel chemotherapy for castration-resistant prostate cancer (CRPC) is unknown, although the continuous administration has been accepted as a standard. Here, we conducted a phase II trial to evaluate the outcome of intermittent docetaxel and prednisolone (DP) in CRPC and assessed the feasibility of intermittent chemotherapy in patients having various prognostic factors. METHODS The patients were treated with a 28-day cycle of docetaxel (70 mg/m2 on day 1) and oral prednisolone (10 mg/day). After 3 consecutive administration of docetaxel, the holiday was taken until PSA level returned to the baseline. The therapy was continued intermittently until disease progressed, the drug became markedly toxic and the presence of patient's refusal. Adverse events, duration of chemotherapy holidays, overall survival, scores of quality of life (QOL), were statistically assessed. Cox proportional hazards regression was used to identify independent prognostic factors for overall survival. RESULTS A total of 120 patients were enrolled. The median age and pretreatment PSA level were 72 years and 37.5 ng/mL, respectively. 61 (50.8%) patients resumed chemotherapy after the first holiday, and maximally 6 courses (-18 docetaxel administration) were administered in four patients. The mean period of first, second and third to fifth holiday was 5.9, 3.3 and 2.1 months, respectively. Toxicity was moderate except for two fatal adverse events. The median time to treatment failure and overall survival from initiation of DP therapy were 18.4 and 35 months, respectively. All QOL scores were statistically unchanged from the start of DP therapy to the beginning of the second course. In univariate analyses, ECOG-PS, pretreatment PSA level, completion of first cycle, and 50% or greater of PSA decline in first course were significant prognostic factors for overall survival. Multivariate analyses showed that ECOG-PS and pretreatment PSA level was strong prognostic factors for overall survival in CRPC patients treated with the intermittent DP therapy (HR 6.52, 95% CI 1.97 -12.80, p=0.001; HR 2.97, 95% CI 1.08 -5.77, p=0.032, respectively). CONCLUSIONS Intermittent DP therapy may be one of the feasible options for CRPC treatment with comparable outcome, successful chemotherapy holidays and maintaining QOL. Patients with good PS and low pretreatment PSA level may be good candidates for intermittent DP therapy. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e1086-e1087 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shintaro Narita More articles by this author Takuya Koie More articles by this author Shigeyuki Yamada More articles by this author Kazuhiko Orikasa More articles by this author Shigeki Matsuo More articles by this author Hiroshi Aoki More articles by this author Shigeto Ishidoya More articles by this author Senji Hoshi More articles by this author Norihiko Tsuchiya More articles by this author Chikara Ohyama More articles by this author Yoichi Arai More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MP87-02 PROGNOSTIC VALUE OF NEUTROPHIL-TO-LYMPHOCYTE RATIO AND ESTABLISHMENT OF NOVEL RISK STRATIFICATION MODEL IN CASTRATION-RESISTANT PROSTATE CANCER PATIENTS TREATED WITH DOCETAXEL CHEMOTHERAPY

You have accessJournal of UrologyProstate Cancer: Advanced III1 Apr 2015MP87-02 PROGNOSTIC VALUE OF NEUTROPHIL-TO-LYMPHOCYTE RATIO AND ESTABLISHMENT OF NOVEL RISK STRATIFICATION MODEL IN CASTRATION-RESISTANT PROSTATE CANCER PATIENTS TREATED WITH DOCETAXEL CHEMOTHERAPY Yoshihiro Nakagami, Jun Nakashima, Yoshio Ohno, Ohori Makoto, and Masaaki Tachibana Yoshihiro NakagamiYoshihiro Nakagami More articles by this author , Jun NakashimaJun Nakashima More articles by this author , Yoshio OhnoYoshio Ohno More articles by this author , Ohori MakotoOhori Makoto More articles by this author , and Masaaki TachibanaMasaaki Tachibana More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1947AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Docetaxel (DTX) therapy is the standard treatment for castration-resistant prostate cancer (CRPC). The present study was undertaken to investigate independent prognostic factors and develop a stratification model of survival in CRPC patients treated with DTX therapy. METHODS The present study included 101 CRPC patients treated with DTX therapy from December 2003 to October 2013 in a single institution. We used the combination of docetaxel (DTX), estramustine phosphate (EMP) and hydrocortisone every 3 weeks. Associations of clinical factors with survival were analyzed using univariate and multivariate analyses. RESULTS The average number of treatment courses was 11. Median overall survival (OS) time was 21 months. In univariate analyses, patients with pain, impaired performance status, hemoglobin (Hb) ≤ 11 mg/dl, neutrophil-to-lymphocyte ratio (NLR) ≥ 2.6, lactate dehydrogenase ≥ 230 IU/L, PSA (at the initiation of DTX therapy) ≥ 110 ng/ml, alkaline phosphatase ≥ 650 IU/L and C-reactive protein (CRP) ≥ 2 mg/dl showed significantly lower survival rates than their respective counterparts. On the other hand, bone metastasis, age, PSA doubling time and lymph node metastasis were not significantly associated with OS. Multivariate analysis showed that presence of pain (hazard ratio [HR] 3.60, p < 0.001), CRP ≥ 2 mg/dl (HR 3.49, p = 0.002), impaired performance status (HR 2.75, p = 0.004), Hb ≤ 11 mg/dl (HR 1.93, p = 0.021), and NLR ≥ 2.6 (HR 1.98, p = 0.031) were independent predictors of OS. Using these 5 statistically significant variables, patients were stratified into 3 risk groups: low (HR = 1 – 3.60), intermediate (HR = 3.82 – 34.55), and high (HR = 34.68 – 132.03). The differences among the three groups were statistically significant CONCLUSIONS Elevation of NLR was an independent prognostic factor as were presence of pain, elevated CRP, impaired performance status and low Hb and the combination of these factors can stratify OS risks in CRPC patients treated with DXT therapy. Our risk stratification model may be useful to identify patients with poor prognosis, who might be good candidates for innovative treatment. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e1084 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yoshihiro Nakagami More articles by this author Jun Nakashima More articles by this author Yoshio Ohno More articles by this author Ohori Makoto More articles by this author Masaaki Tachibana More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Constitutively active AR-V7 plays an essential role in the development and progression of castration-resistant prostate cancer.

This study aimed to investigate the role of AR-V7 in development of castration-resistant prostate cancer (CRPC) and to determine whether the AR-V7 expression in CRPC tissues can predict cancer-specific survival. We enrolled 100 localized prostate cancer (PCa) (cohort 1), 104 newly diagnosed metastatic PCa (cohort 2), and 46 CRPC (cohort 3) patients treated at our institution. The expression of AR-V7 in PCa was assessed by immunohistochemistry. Cox regression models were used to evaluate the predictive role of all covariates for the development of CRPC in cohort 2 and for cancer-specific survival in cohort 3. Time to CRPC and cancer-specific survival curves were estimated using the Kaplan-Meier method. AR-V7 expression rate in cohort 3 was significantly elevated compared with other two cohorts (p < 0.001). Multivariate analysis revealed that AR-V7 was an independent predictive factor for CRPC development (HR = 2.627, p = 0.001) and for cancer specific survival (HR = 2.247, p = 0.033). Furthermore, the AR-V7 expression was associated with shorter survival in CRPC patients. Our results demonstrated protein AR-V7 levels in primary tumors can be used as a predictive marker for the development of CRPC and as a prognostic factor in CRPC patients. Therapy targeting AR-V7 may help prevent PCa progression and improve the prognosis of CRPC patients.