Outcome Of Androgen Deprivation Therapy Research Articles

The comprehensive analysis of relationship between gut microbiome and treatment outcome of androgen deprivation therapy (ADT)-based treatment in patients with metastatic castration-sensitive and -resistant prostate cancer.

213 Background: Preclinical and clinical data from various types of cancer show that the gut microbiome can affect the outcome of treatments with immune checkpoint inhibitors or cytotoxic chemotherapies. However, the relationship between the microbiome and treatment outcomes in prostate cancer has remained unclear. Here, we present a comprehensive analysis of the relationship between the gut microbiome and treatment outcomes from a nationwide genome screening project (MONSTAR-SCREEN 1) in patients with metastatic castration-sensitive and -resistant prostate cancer (mCSPC and mCRPC). Methods: We performed 16S rRNA gene sequencing of fecal DNA from 73 mCSPC and 83 mCRPC patients before treatment. The microbiome data were compared using the Wilcoxon-Mann-Whitney test or Fisher’s exact test. Survival status and therapeutic efficacy of ADT based treatment were prospectively collected and estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival in different strata. Results: Fecal samples from mCRPC had more Klebsiella and Enterobacteriaceae than those from mCSPC, whereas mCSPC had more Akkermansia and Bifidobacterium compared to mCRPC. Prior and concurrent usage of anti-biotics did not affect diversity of the amplicon sequence variants (ASVs), KEGG orthology and metabolism pathway representation. Anti-biotics also did not influence time to treatment failure (TTF) in mCRPC (HR:0.81, 95%CI:0.36–1.78) and mCSPC (HR:1.35, 95%CI:0.55–3.34). mCRPC had more diverse KEGG orthology compared to mCSPC ( p=0.0009), however, no statistical differences were observed in the ASV ( p=0.77) and metabolism pathway representation ( p=0.35) between mCRPC and mCSPC. High ASV tended to be associated with longer TTF rather than low ASV in both mCRPC (Adjusted HR:0.63, 95%CI:0.34–1.10) and mCSPC (Adjusted HR:0.66, 95%CI:0.31–1.40). mCRPC patients with high AVS also showed significant longer PSA-progression free survival than patients with low ASV (HR:053, 95%CI:0.28–0.99). Conclusions: This investigation revealed significant differences in the microbiome status of mCRPC compared to mCSPC. These differences and diversity might influence the outcomes of ADT based treatment in prostate cancer.

Abstract 5053: Artificial intelligence (AI)-based multimodal framework predicts androgen-deprivation therapy (ADT) outcomes in non-metastatic castration resistant prostate cancer (nmCRPC) from SPARTAN

Abstract Objective: AI has demonstrated great promise in learning sophisticated features and relations in data that would otherwise remain hidden to the human eye. Here, we developed a proprietary AI-based multimodal approach to integrate clinical, digitized hematoxylin-eosin (H&E), and radiology bone scan (rBS) data for outcome prediction in ADT-treated nmCRPC patients. Identifying prostate cancer patients who may not benefit from ADT could improve the medical management of this disease beyond current definitive therapy. Methods: Patients in the ADT+placebo arm from SPARTAN clinical trial on nmCRPC with available clinical, H&E, and rBS were used (n=154). These patients were randomly divided into 70% (n=107) discovery and 30% (n=47) hold-out test datasets. Using the discovery set, we developed and trained a multimodal approach that combines survival convolutional neural networks (SCNNs1) and Cox proportional-hazards model (CPH) to learn ADT outcomes for overall survival (OS) and time to PSA progression (TTP) from the integration of imaging data and 11 traditional clinical features (e.g., tumor stage, Gleason score, PSA). The ability of the trained framework in predicting outcomes and risk stratification was evaluated on the hold-out set. Bootstrap analysis with Wilcoxon signed rank test was used to determine the significance of the multimodal framework’s performance improvement compared to clinical CPH. Results: The multimodal framework was predictive of ADT outcomes for OS and TTP in nmCRPC patients. In SPARTAN’s hold-out set, the multimodal framework significantly improved the predictive power of clinical CPH by 14%—16% across both outcomes (Wilcoxon signed rank P<0.0001). In particular, the multimodal framework’s concordance index (c-index) was 0.72 for OS and 0.73 for TTP, while clinical CPH’s c-index was 0.62 for OS, and 0.64 for TTP. Further, multimodal framework significantly stratified high- from low-risk nmCRPC patients for OS and TTP (log-rank P= 0.0049-0.0072), while clinical CPH failed to stratify risk for OS (log-rank P= 0.2891). Conclusion: AI-based framework that learns from the integration of different data types improves outcome prediction in ADT-treated nmCRPC. The multimodal approach demonstrates promise in treatment decision support for the early use of androgen receptor-directed therapy and patient selection for clinical trials with novel treatment combinations. Reference: 1. Mobadersany, Pooya, et al. "Predicting cancer outcomes from histology and genomics using convolutional networks." Proceedings of the National Academy of Sciences 115.13 (2018): E2970-E2979. Conflict of interest statement P.M., J.L., D.G., C.A., S.M., S.B., M.K.Y., K.T., N.H., J.Z., J.G., N.K., and S.S.F.Y., are employees of Janssen Pharmaceutical, LLC. Citation Format: Pooya Mobadersany, Justin Lucas, Darshana Govind, Clemente Aguilar-Bonavides, Sharon McCarthy, Sabine Brookman-May, Margaret K. Yu, Ken Tian, Natalie Hutnick, Jose Zamalloa, Joel Greshock, Najat Khan, Stephen S.F. Yip. Artificial intelligence (AI)-based multimodal framework predicts androgen-deprivation therapy (ADT) outcomes in non-metastatic castration resistant prostate cancer (nmCRPC) from SPARTAN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5053.

Immune system and intestinal microbiota determine efficacy of androgen depletion therapy against prostate cancer.

168 Background: Prostate cancer (PC) responds to androgen deprivation therapy (ADT) usually in a transient fashion, progressing from hormone-sensitive PC (HSPC) to castration-resistant PC (CRPC). While it is recognized that ADT has an immunomodulatory effect, little is known about the intestinal microbiome effect on therapeutic outcome of ADT. Methods: We investigated a mouse model of PC as well as specimens from PC patients to unravel an unsuspected contribution of thymus-derived T lymphocytes and the intestinal microbiota in the efficacy of ADT. Preclinical experiments were performed in PC-bearing mice, immunocompetent or immunodeficient. In parallel, we prospectively included 65 HSPC and CRPC patients to analyze their feces and blood specimen. Results: In PC-bearing mice, ADT increased thymic cellularity and output. PC implanted in T lymphocyte-depleted or athymic mice responded less efficiently to ADT than in immunocompetent mice. Moreover, depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT. Moreover, cohousing of PC-bearing mice with tumor-free mice, or oral gavage with Akkermansia improved the efficacy of ADT. This appear to be applicable to PC patients because long-term ADT resulted in an increase of thymic output, as demonstrated by an increase in circulating recent thymic emigrant cells (sjTRECs). Moreover, as compared to HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy. Conclusions: These findings suggest that reversing the intestinal dysbiosis and repairing acquired immune defects in PC patients have a potential impact on the therapeutic outcome of ADT.

Long-term outcomes of androgen deprivation therapy in prostate cancer among Japanese men over 80years old.

This study aimed to analyze the survival rate and to examine the risk of death from prostate cancer when accounting for competing risk of death, in men aged ≥80 y treated with primary androgen deprivation therapy (ADT). Data of patients with prostate cancer who had received ADT were extracted from a nationwide community‐based database established by the Japan Study Group for Prostate Cancer. Prognostic variables, including progression‐free survival, cancer‐specific survival, overall survival, and death rates were compared between men stratified by prostate cancer risk. Overall, 4760 patients older than 80 y were included. The proportion of low‐, intermediate‐, high‐, or very high‐risk, regional, and metastatic prostate cancer among super‐elderly men was 9.5%, 14.6%, 48.8%, 9.0%, 3.2%, and 24.9%, respectively. Survival rates decreased with increasing risk stratification. The cumulative 5‐y death rate by prostate cancer for low‐, intermediate‐, high‐, or very high‐risk, regional, and metastatic prostate cancer, was 0.92% (95% confidence interval [CI]: 0.2%‐3.6%), 1.6% (95% CI: 0.8%‐3.4%), 5.75% (95% CI: 4.25%‐7.75%), 15.6% (95% CI: 11.6%‐23.3%), 20.7% (95% CI: 13.1%‐31.7%), and 36.9% (95% CI: 32.8%‐41.4%), respectively. Our findings support that there is no need for immediate ADT for low‐ and intermediate‐risk groups. Conversely, in high‐ or very high‐risk, regional, and metastatic prostate cancer, more efforts for curative therapy and intensive therapy are needed in selected patients.

Primary metastatic prostate cancer between prognosis or adequate/proper medical therapy

PurposeTo define the efficacy of standard androgen deprivation therapy (ADT) in the treatment of metastatic prostate cancer (PCa).Materials and methodsFifty patients with mean age of 70.48 ± 9.95 years old (range 52–87) who had metastatic PCa and received ADT between 2014 and 2019 were retrospectively evaluated. Median values of pre-therapeutic PSA and Gleason scores were 50 ng/ml (range 8–1201) and 8 (range 6–9), respectively. All patients received luteinizing hormone-releasing hormone (LHRH) analogue and anti-androgen. The patients were evaluated in terms of age, pre-therapeutic PSA serum levels, Gleason scores, presence of metastasis, number and percentage of cores involved, nadir PSA, time to nadir PSA, duration of ADT, and PSA at last follow-up. Multivariate analysis was used to define the factors which have impact on ADT response. The mean follow-up period was 13.87 ± 7.78 months, (range 2–32).ResultsAll patients showed reduction in serum PSA level after initiation of ADT, and the median value of nadir PSA was 1.12 ng/ml (range 0.02–50). The mean value of time to nadir PSA was 3.85 ± 1.57 months (range 2–7). The median value of PSA at last follow-up was 2 ng/ml (range 0.02–50.21). Multi-variant analysis showed that nadir PSA have a significant correlation with pre-therapeutic PSA, PSA at last follow-up, age, and Gleason scores (p < .05).ConclusionStandard ADT is a feasible option in the treatment of metastatic PCa. Gleason scores, age, pre-therapeutic PSA, and PSA at last follow-up have significant impact on outcomes of ADT. Further studies of high number of patients with long-term follow-up including other chemo-hormonal therapy and androgen receptor blockers should be carried out to confirm and improve efficacy of ADT.

Does Physical Activity Regulate Prostate Carcinogenesis and Prostate Cancer Outcomes? A Narrative Review

Background: Prostate cancer (PCa) represents a common disease in men aged >65 years. The role of physical activity (PA) in patients at risk or diagnosed with PCa represents an evolving issue. We aimed to summarize available evidences about the impact of PA on the pathophysiology and clinical outcomes of PCa. Methods: We performed a narrative review. Evidences about the role of PA in elderly patients in terms of PCa biology, epidemiology, oncological and functional outcomes, as well as in terms of impact on the outcomes of androgen deprivation therapy (ADT) were summarized. Results: Potential pathophysiological pathways hypothesized to explain the benefits of PA in terms of prostate carcinogenesis include circulating levels of Insulin-like growth factor-1 (IGF-1), oxidative stress, systemic inflammation, sex hormones, and myokines. Clinically, emerging evidences support the hypothesis that PA is associated with decreased PCa risk, improved PCa-related survival, improved functional outcomes, and reduced ADT-related adverse events.

Lower urinary tract symptoms in patients with advanced prostate cancer: What are the outcomes of androgen deprivation therapy?

Androgen deprivation therapy (ADT) is accepted as the first-line treatment of advanced prostate cancer. This study sets out to determine the outcomes of ADT in reducing lower urinary tract symptoms (LUTS) in patients with advanced prostate cancer and also to determine the quality of life (QoL) of the patients. This was a prospective study carried out at Jos University Teaching Hospital. All consecutive patients who had LUTS due to advanced prostate cancer were recruited into the study. All patients completed the international prostate symptom score (IPSS) questionnaire, including QoL assessment. Post-void residual (PVR) urine, maximum flow rate (Qmax), prostate specific antigen and total prostate volume (TPV) were assessed. The parameters before and at 12 months were compared. Data from 65 patients were analysed. The mean age of the patients was 68.5 ± 8.67 years with an age range of 46-85 years. Four (6.2%) had mild LUTS before AD, and their symptoms remained mild at 12 months of ADT. Twenty-two (33.9%) patients had moderate urinary symptoms. Of this, 10 (18.5%) patients had symptomatic improvement at 12 months of ADT. Of 39 (60%) patients who presented with severe LUTS, 21 (32.3%) had improvement at 12 months of ADT. Before ADT and at 12 months of ADT, the mean IPSS score, mean TPV, Qmax, PVR and mean QoL score were 23 ± 8.8 and 15 ± 8.8 (P < 0.0001); 79.7 ± 51.4 and 73.4 ± 34.3 (P = 0.212); 8.0 ± 4.7 and 11.2 ± 4.4 (<0.001); 209.8 ± 127.8 and 163 ± 111.4 (<0.001); 4.23 ± 1.2 and 3.24 ± 1.2 (P < 0.001), respectively. Of the 39 patients (60%) with severe urinary symptoms, 18 (27.7%) of patients had urethral catheterization for either acute or chronic urinary retention before ADT. At 12 months on ADT, eight patients (12.3.7%) were still on catheter due to failed attempts at trial without catheter. ADT significantly improves urodynamic parameters, IPSS score and IPSS-related QoL. There remains a subset of patients, in whom LUTS persist with negative effects on QoL.

Relationship between body composition and hormone sensitivity for androgen deprivation therapy in patients with metastatic prostate cancer.

BackgroundTo evaluate the relationship between body composition and the oncological outcome of androgen deprivation therapy (ADT), we investigated whether body composition features including the psoas muscle may be predictive factors of ADT.MethodsThis study enrolled patients with hormone-naïve metastatic prostate cancer who were treated with primary ADT from April 1996 to November 2013 at Kyushu University Hospital and who underwent a computed tomography scan before primary ADT for calculating body fat percentage, psoas muscle ratio (psoas muscle, cm3/height, cm), and body mass index.ResultsOf the 178 patients enrolled, 60 patients died during follow-up. Median follow-up was 32 months, and progression-free survival and overall survival (OS) were 28 and 80 months, respectively. Multivariate analysis revealed that the psoas muscle ratio was correlated with OS (hazard ratio: 0.448; 95% confidence interval = 0.206–0.922; p = 0.028).ConclusionsThis study demonstrated that higher psoas muscle ratio predicts longer OS among patients with nonlocalized prostate cancer treated with primary ADT.

Abstract 1015: Molecular dissection of androgen receptor signaling in prostatic endothelial, epithelial, and stromal cells

Abstract Introduction and objectives: Androgen receptor (AR) is involved in development prostate cancer (CaP), and is a primary target for treatment of CaP. Androgen deprivation therapy (ADT) inhibits AR signaling by reducing AR ligands and/or blocking AR-ligand binding. ADT induces apoptosis of both endothelial cells and epithelial cells of human prostate, with apoptosis of endothelial cells preceding the apoptosis of epithelial cells. Further, the AR response to stimulation by androgen also differs between the 2 cell types. The current understanding of AR signaling was gained predominantly using CaP cell lines and samples prepared from whole tissue specimens. The present study sought to delineate AR signaling specifically in endothelial, epithelial, and stromal cells isolated from fresh clinical prostate tissue specimens and primary xenografts of human prostate tissue. Our results reveal the potentially different roles of AR signaling in different human prostate cell compartments, how AR regulates normal differentiated cell functions, and the biological consequences of ADT. Methods: Prostate tissue remnants were transplanted to male nude mice that were castrated and implanted with a sustained delivery device to maintain testosterone at human plasma levels. Endothelial and epithelial cells of both fresh prostate tissue and prostate tissue xenografts were isolated sequentially using magnetic beads conjugated with an antibody specific to epithelial cell or endothelial cell surface markers; the remaining cell fraction was defined as stromal cells. Transcriptomes were obtained using RNASeq, and were analyzed for differential expression of AR-regulated genes, AR co-regulators, and androgen metabolism enzymes. Results: Antibody-mediated cell type-specific enrichment isolated effectively the 3 cell types from the prostate from 16 patients. Among 1263 AR-regulated genes, 399, 313, and 223 were predominantly expressed in epithelial, endothelial or stromal cells, respectively. Among 179 AR co-regulators, 26, 26, and 18 were expressed predominantly in epithelial, endothelial or stromal cells, respectively. Among 128 potential androgen metabolic enzyme genes, 42, 15, and 12 were expressed predominantly in epithelial, endothelial or stromal cells, respectively. Conclusions: Differences in expression of genes associated with AR-mediated trans-regulation were apparent between the different cell types of prostate, whereas, the difference in expression of androgen metabolism genes was less striking. Therefore, the organ level outcome of ADT can only be understood by determining the response of the different cell types in CaP tissue. Citation Format: Nelson T. Gross, Jianming Wang, Gary Smith, Yue Wu. Molecular dissection of androgen receptor signaling in prostatic endothelial, epithelial, and stromal cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1015.

Abstract 5225: Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer

Abstract The Serine Peptidase Inhibitor, Kazal type 1 (SPINK1) overexpression represents the second-largest prostate cancer (PCa) subtype associated with increased risk of recurrence and poor prognosis. Regardless of molecular subtype, androgen-deprivation therapy (ADT) remains the mainstay treatment for locally advanced and metastatic PCa patients. However, majority of the treated individuals eventually progress to castration-resistant stage and a subset of these patients develop ADT-induced neuroendocrine prostate cancer. Despite evidences of detrimental effects of ADT on PCa, possible role of androgen signaling in SPINK1-mediated prostate oncogenesis remains unexplored. Here, we show that androgen receptor (AR) functions as a direct transcriptional repressor of SPINK1, and blocking AR signaling relieves its repression, leading to upregulation of SPINK1. In agreement, we observe an inverse association between SPINK1 levels and AR expression across multiple patient cohorts, and in neuroendocrine differentiated LNCaP cells. We show that AR and its corepressor, the RE1-silencing transcription factor (REST), occupy SPINK1 promoter and inhibits its transcription. On the other hand, in the absence of AR, lineage reprogramming factor SOX2 in turn binds to SPINK1 promoter leading to its positive transcriptional regulation in androgen-deprived conditions with concomitant increase in neuroendocrine markers. Additionally, stable knockdown of SPINK1 results in reduced epithelial-mesenchymal transition, decreased stemness and drug resistance. Collectively, our findings provide a plausible explanation to the paradoxical clinical outcomes of ADT, arising due to increase in SPINK1 levels. Finally, we emphasize the need to take a well-informed decision prior to ADT and develop alternative therapeutic strategies for castrate-resistant PCa patients. Citation Format: Ritika Tiwari, Nishat Manzar, Vipul Bhatia, Anjali Yadav, Shannon Carskadon, Nilesh Gupta, Amina Zoubeidi, Nallasivam Palanisamy, Bushra Ateeq. Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5225.

Gene Polymorphism-related Individual and Interracial Differences in the Outcomes of Androgen Deprivation Therapy for Prostate Cancer.

Among patients with prostate cancer, the prognosis after androgen deprivation therapy differs significantly among individuals and among races; however, the reasons underlying these differences are poorly understood. Several single nucleotide polymorphisms in genes associated with prostate cancer progression or castration resistance might serve as the host factor that influences prognosis and, thus, accounts for these individual and racial gaps in treatment outcomes. Accordingly, single nucleotide polymorphisms associated with treatment outcomes could be used as predictive and/or prognostic biomarkers for patient stratification and to identify personalized treatment and follow-up protocols. The present review has summarized the genetic polymorphisms that have been reported to associate with androgen deprivation therapy outcomes among patients with prostate cancer and compared the allele frequencies among different ethnic groups.

P021 - Long-term outcomes of androgen deprivation therapy plus estramustine phosphate combined with three-dimensional conformal radiotherapy for intermediate- to high-risk prostate cancer: A randomized study

P021 - Long-term outcomes of androgen deprivation therapy plus estramustine phosphate combined with three-dimensional conformal radiotherapy for intermediate- to high-risk prostate cancer: A randomized study

847 Impact of free testosterone levels on the outcome of androgen deprivation therapy in metastatic prostate cancer

847 Impact of free testosterone levels on the outcome of androgen deprivation therapy in metastatic prostate cancer

Zoledronic acid combined with androgen-deprivation therapy may prolong time to castration-resistant prostate cancer in hormone-naïve metastatic prostate cancer patients – A propensity scoring approach

ObjectiveTo clarify the oncological benefit of zoledronic acid for hormone-naïve metastatic prostate cancer, patient outcome of androgen deprivation therapy with zoledronic acid (ADT + Z) and androgen deprivation therapy alone (ADT) was compared. MethodsFifty-two patients with pathologically confirmed metastatic prostate cancer were prospectively enrolled and treated with combined androgen blockade (goserelin and bicalutamide) with zoledronic acid (4 mg every 4 weeks for 24 months). A propensity score-match with logistic regression analysis was applied to select 50 pair-matched cohorts (both from ADT + Z and from historical control cohorts who had undergone ADT alone), and patient outcomes were compared. ResultsPatients with ADT + Z had significantly longer time to progression (TTP) than those with ADT (median TTP; 24.2 vs. 14.0 months, p = 0.0092), while no significant difference of overall survival between two groups (p = 0.1502). Multivariate analysis for biochemical recurrence revealed treatment with ADT was the sole independent prognostic factor (HR: 1.724, 95% CI: 1.06–2.86, p = 0.0297). ConclusionCombination of zoledronic acid with ADT may prolong time to castration resistant prostate cancer.

The combination of the prodrugs perforin-CEBPD and perforin-granzyme B efficiently enhances the activation of caspase signaling and kills prostate cancer.

The survival of prostate cancer (PrCa) patients is associated with the transition to hormone-independent tumor growth and metastasis. Clinically, the dysregulation of androgen action has been associated with the formation of PrCa and the outcome of androgen deprivation therapy in PrCa. CCAAT/enhancer binding protein delta (CEBPD) is a transcription factor that has been reported to act as an oncogene or tumor suppressor, depending on the extra- and intracellular environments following tumorigenesis. We found that androgen can activate CEBPD transcription by direct binding of the androgen receptor (AR) to the CEBPD promoter region. Increases of suppressor of zeste 12 (SUZ12) and enhancer of zeste homolog 2 (EZH2) attenuated the androgen-induced transcription of CEBPD. Importantly, the increases in E2F1, SUZ12 and EZH2 as well as the inactivation of CEBPD were associated with the clinicopathological variables and survival of PrCa patients. We revealed that caspase 8 (CASP8), an apoptotic initiator, is responsive to CEBPD induction. Reporter and in vivo DNA-binding assays revealed that CEBPD directly binds to and activates CASP8 reporter activity. A prodrug system was developed for therapeutic application in AR-independent or androgen-insensitive PrCa to avoid the epigenetic effects on the suppression of CEBPD expression. Our results showed that the combination of a perforin (PF)-CEBPD prodrug (which increases the level of procaspase-8) and a PF-granzyme B prodrug (which activates CASP8 and caspase 3 (CASP3)) showed an additive effect in triggering the apoptotic pathway and enhancing apoptosis in PrCa cells.

Abstract 3922: 20(S)-protopanaxadiol-aglycone inhibition of the development and growth of castration-resistant prostate cancer

Abstract Recurrence with lethal castration-resistant prostate cancer after androgen deprivation therapy remains the major challenge in treatment of advanced prostate cancer. The main mechanism for the development of castration resistance is continuous androgen receptor signaling via promiscuous or hypersensitive androgen receptor, ligand-independent androgen receptor activation, expression of androgen receptor splice variants lacking the ligand-binding domain but remaining constitutively active, and/or de novo androgen synthesis in the prostate. Several new drugs targeting androgen receptor reactivation, such as abiraterone acetate, are showing benefit in prolonging survival in patients with castration-resistant prostate cancer. However, even this potent inhibitor of androgen synthesis has a relatively short time to disease progression. One potential mechanism is the prevalent upregulation of constitutively active, ligand-binding-domain-truncated androgen receptor splice variants in castration-resistant prostate cancer. Therefore, therapeutic approaches that can diminish the availability of both the full-length and the splice variants of androgen receptor should offer considerable benefit in preventing and inhibiting prostate cancer recurrence after androgen deprivation therapy. In the present study, we show that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD), a steroidal saponin from ginseng, effectively downregulates the abundance and activity of both the full-length and the splice variants of androgen receptor. The effect is manifested by an immediate drop in androgen receptor proteins, followed by a reduction in androgen receptor mRNAs. The initial decrease in androgen receptor proteins could be attributed to PPD induction of proteasome-mediated degradation, possibly as a result of disrupted androgen receptor N-C interaction. Our xenograft studies show that PPD inhibits not only the development of castration-resistant prostate cancer after androgen deprivation but also the growth of prostate tumors that are already castration resistant. The inhibition is accompanied by a pronounced decrease of tumor androgen receptor and serum prostate-specific antigen levels. Our findings therefore provide strong justification and lay the groundwork for an effective treatment modality to improve the therapeutic outcome of androgen deprivation therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3922. doi:1538-7445.AM2012-3922

The antiandrogenic effect of finasteride against a mutant androgen receptor

Finasteride is known to inhibit Type 2 5α-reductase and thus block the conversion of testosterone to dihydrotestosterone (DHT). The structural similarity of finasteride to DHT raises the possibility that finasteride may also interfere with the function of the androgen receptor (AR). Experiments were carried out to evaluate the antiandrogenic effect of finasteride in LNCaP, C4-2 and VCaP human prostate cancer cells. Finasteride decreased DHT binding to AR, and DHT-stimulated AR activity and cell growth in LNCaP and C4-2 cells, but not in VCaP cells. LNCaP and C4-2 (derived from castration-resistant LNCaP) cells express the T877A mutant AR, while VCaP cells express the wild type AR. When PC-3 cells, which are AR-null, were transfected with either the wild type or the T877A mutant AR, only the mutant AR-expressing cells were sensitive to finasteride inhibition of DHT binding. Peroxiredoxin-1 (Prx1) is a novel endogenous facilitator of AR binding to DHT. In Prx1-rich LNCaP cells, the combination of Prx1 knockdown and finasteride was found to produce a greater inhibitory effect on AR activity and cell growth than either treatment alone. The observation suggests that cells with a low expression of Prx1 are likely to be more responsive to the antiandrogenic effect of finasteride. Additional studies showed that the efficacy of finasteride was comparable to that of bicalutamide (a widely used non-steroidal antiandrogen). The implication of the above findings is discussed in the context of developing strategies to improve the outcome of androgen deprivation therapy.

Highlights of This Issue

Tran Cao and colleagues evaluated the efficacy of metronomic gemcitabine against metastasis formation in a highly-aggressive, RFP-labeled orthotopic nude mouse model of human pancreatic cancer. Metronomic gemcitabine reduced the spontaneous development of both solid metastases and ascites and significantly prolonged survival of mice without overt toxicity. These results suggest the clinical potential of adjuvant metronomic gemcitabine for the treatment of pancreatic cancer.Akt lies at a critical signaling node downstream of PI3K and is important in promoting cell survival and inhibiting apoptosis. Increased Akt signaling is associated with reduced sensitivity to cytotoxic agents or receptor tyrosine kinase inhibitors in preclinical models. The effect of a novel allosteric Akt inhibitor, MK-2206, was evaluated in combination with several anticancer agents. MK-2206 showed synergistic antitumor activities in combination with erlotinib, lapatinib, and cytotoxic agents, suggesting Akt inhibition may augment the efficacy of anticancer agents. MK-2206 (now in Phase I) is a promising agent to treat cancer patients who receive these cytotoxic and/or molecular targeted agents.Head and neck squamous cell carcinoma (HNSCC) is relatively resistant to chemotherapy-mediated apoptosis and frequently develops chemoresistance. Thus, improvement on conventional therapy is urgently needed to effectively treat HNSCC. In this study, Kim and colleagues found that the histone deacetylase inhibitor trichostatin A (TSA) significantly enhanced apoptosis in HNSCC induced by PS-341 (also known as bortezomib) in vitro and improved PS-341-mediated inhibition of HNSCC tumor growth in nude mice. Mechanistically, TSA increased PS-341-induced Noxa expression and caspase activation in HNSCC cells. These results provide an important rationale for the usage of a combination of both agents in patients with HNSCC.The development of castrationresistant prostate cancer after androgen deprivation therapy remains the major challenge in the treatment of advanced prostate cancer. Liu and colleagues showed that methylseleninic acid, an agent that effectively reduces androgen receptor abundance, significantly enhanced the cancer-killing efficacy of anti-androgen. Downregulation of telomerase as a result of androgen receptor signaling suppression is critically involved in mediating the combination effect. The findings indicate that methylseleninic acid in combination with anti-androgen could represent a viable approach to improve the therapeutic outcome of androgen deprivation therapy and that telomerase could serve as a tumor-specific biomarker to monitor the efficacy.

Abstract 1708: Telomerase as an important target of androgen-signaling blockade for prostate cancer treatment

Abstract As the mainstay treatment for advanced prostate cancer, androgen-deprivation therapy (ADT) targets the action of androgen receptor (AR) by reducing androgen level and/or by the administration of anti-androgen that competes with androgens for binding to AR. Albeit effective in extending survival, ADT is associated with dose-limiting toxicity and the development of castration-resistant prostate cancer (CRPC) after prolonged use. Since CRPC is generally lethal and incurable, developing effective strategies to enhance the efficacy of ADT and circumvent resistance becomes an urgent task. Continuous AR signaling constitutes one major mechanism underlying the development of CRPC. The present study showed that methylseleninic acid (MSA), an agent that effectively reduces AR abundance, could enhance the cancer-killing efficacy of the anti-androgen bicalutamide in both androgen-dependent and castration-resistant prostate cancer cells. We found that combination of MSA and bicalutamide produced a robust downregulation of prostate-specific antigen and a recently identified AR target, telomerase and its catalytic subunit, telomere reverse transcriptase (hTERT). The downregulation of hTERT occurs mainly at the transcriptional level, through reducing AR occupancy of the hTERT promoter. Furthermore, apoptosis induction by the two agents is significantly mitigated by restoration of hTERT. Our findings thus indicate that MSA in combination with anti-androgen could represent a viable approach to improve the therapeutic outcome of ADT. Given the critical role of hTERT/telomerase downregulation in mediating the combination effect and the fact that hTERT/telomerase could be measured in blood and urine, hTERT/telomerase could serve as an ideal tumor-specific biomarker to monitor the efficacy of the combination therapy non-invasively. (Supported by the Department of Defense Prostate Cancer Training grant No. W81XWH-08-1-0291 (SL); the National Cancer Institute grant No. K01 CA114252 (YD); the American Cancer Society grant No. RSG-07-218-01-TBE (YD)) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1708.

Clinical outcomes of androgen deprivation as the sole therapy for localized and locally advanced prostate cancer

To characterize the clinical outcomes of androgen deprivation therapy (ADT) as the sole therapy for localized prostate cancer, and to determine independent predictors of disease progression, as recent studies indicate an increasing use of ADT. The records of all patients with cT1-4NXM0 adenocarcinoma of the prostate treated with ADT as the primary initial therapy at the Portland Veterans Affairs Medical Center between 1993 and 2000 were reviewed. Age, race, Charlson Health Index, family history, prostate-specific antigen (PSA) level, PSA density, digital rectal examination (DRE) findings, Gleason score, and percentage of positive biopsy cores at diagnosis were recorded for 81 patients. Patients had a median (SD, range) age of 73 (5.6, 58-84) years, a PSA level of 14.3 (34.6, 1.4-252) ng/mL and tumours were classified as Gleason score < or = 5 in 9% of patients, 6 in 31%, 7 in 31% and 8-10 in 30%. Outcomes extracted were PSA progression, PSA nadir, bone fractures, local progression, distant progression and overall survival. With a median (range) follow-up of 54 (6-115) months, the incidence of local progression, distant progression, bone fractures, PSA progression, and death were 10%, 7%, 25%, 21% and 41% respectively. The percentage of positive biopsy cores > or = 83%, age < 70 years, Gleason score > or = 7, abnormal DRE, and PSA nadir > or = 0.2 ng/mL were significantly associated with PSA progression by univariate analysis. The multivariate analysis identified age < 70 years (hazard ratio 6.52, 95% confidence interval 2.29-18.55) and Gleason score > or = 6 (4.0, 2.0-12.0) as independent risk factors for PSA progression. ADT resulted in modest control of localized prostate cancer, but younger patients and those with Gleason > or = 6 cancers were at higher risk of treatment failure. Toxicity, principally in the form of bone fractures, was high.