Untreated Prostate Cancer Research Articles

The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer

The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen-regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of α-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression). Patient summaryThis first-in-man study defines the rapid gene expression changes taking place in prostate cancer (PCa) following castration. Expression levels of the genes that the androgen receptor regulates are predictive of treatment outcome. Upregulation of oestrogen receptor 1 is a mechanism by which PCa cells may survive despite castration.

Mitochondrial DNA copy number in peripheral blood leukocytes and the aggressiveness of localized prostate cancer

We investigated whether low mitochondrial DNA copy number (mtDNAcn) in peripheral blood leukocytes at diagnosis was associated with an increased risk of the aggressive form of the tumor and disease progression among localized prostate cancer (PCa) patients. We recruited 1,751 non-Hispanic white men with previously untreated PCa from The University of Texas MD Anderson Cancer Center. mtDNAcn was categorized into three groups according to tertiles. We used multivariate logistic regression to estimate the odds ratios (ORs) and 95 percent confidence intervals (95% CIs) for the association of mtDNAcn with the risk of having aggressive PCa at diagnosis. We used Cox proportional hazards model to estimate hazard ratios (HRs) and 95% CIs for disease progression. We observed an inverse association between aggressiveness of PCa and mtDNAcn (P < 0.001). In multivariate analysis, compared to patients in the highest tertile of mtDNAcn, those in the second and lowest tertiles had significantly increased risks of presenting with the high-risk form of PCa, as defined by the D'Amico criteria, with ORs of 1.33 (95% CI, 0.89-1.98; P = 0.17) and 1.53 (95% CI, 1.02-2.30; P = 0.04), respectively. Furthermore, PCa patients in the lowest and second tertiles combined relative to those in the highest tertile had a 56% increased risk of disease progression (HR, 1.56; 95% CI, 0.96-2.54; P = 0.07). In summary, our results suggested that low mtDNAcn in peripheral blood leukocytes was associated with aggressive PCa at diagnosis and might further predict poor progression-free survival among localized PCa patients.

Nine-year Follow-up for a Study of Diffusion-weighted Magnetic Resonance Imaging in a Prospective Prostate Cancer Active Surveillance Cohort

BackgroundIn active surveillance (AS) for prostate cancer there are few data on long-term outcomes associated with novel imaging markers. ObjectiveTo determine long-term outcomes with respect to the apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (DW-MRI) in a prospective AS cohort. Early results have already been published; we now present findings with long-term follow-up. Design, setting, and participantsA subset of patients (n=86) underwent pre-enrolment DW-MRI in a prospective AS study between 2002 and 2006. Inclusion criteria were untreated prostate cancer, clinical T1/T2a/N0M0, Gleason ≤ 3+4, and prostate-specific antigen (PSA) <15 ng/ml. Protocol follow-up was by biopsy at 18–24 mo and then every 24 mo, with regular PSA measurement. InterventionMen underwent baseline DW-MRI in addition to standard sequences. ADC was measured from the index lesion on T2-weighted images. To avoid influencing treatment decisions, DW-MRI sequence results were not available to the AS study investigators. Outcome measurements and statistical analysisBaseline ADC was analysed with respect to time to radical treatment (TRT) and time to adverse histology (TAH). Kaplan-Meier analysis and univariate and multivariate regression analyses were performed. Results and limitationsThe median follow-up was 9.5 yr (interquartile range 7.9–10.0 yr). On univariate analysis, ADC below the median was associated with shorter TAH (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.17–3.89; p<0.014) and TRT (HR 2.54, 95% CI 1.49–4.32; p<0.001). Median TRT was 9.3 yr (95% CI 7.0–11.6 yr) for patients with ADC above the median and only 2.4 yr (95% CI 1.5–6.0 yr) for ADC below the median. For TRT, addition of ADC to a multivariate model of baseline variables resulted in a significant improvement in model fit (HR 1.33, 95% CI 1.14–1.54; p<0.001). Receiver operating characteristic analysis for TRT revealed an area under the curve of 0.80 (95% CI 0.70–0.88). The number of variables included in the multivariate model was limited by sample size. ConclusionsLong-term follow-up for this study provides strong evidence that ADC is a useful marker when selecting patients for AS. Routine DW-MRI is now being evaluated in our ongoing AS study for initial assessment and as an alternative to repeat biopsy. Patient summaryBefore entering a study of close monitoring for the initial management of prostate cancer, patients had a type of magnetic resonance imaging scan that looks at the movement of water within cancers. These scans may help in predicting whether patients should receive close monitoring or whether immediate treatment should be given.

Dysfunction of PSA-specific CD8+ T cells in prostate cancer patients correlates with CD38 and Tim-3 expression

The efficacy of immunotherapy in cancer patients is influenced by differences in their immune status. An evaluation of immunocompetence before therapy may help to predict therapeutic success and guide the selection of appropriate regimens. We assessed the preexisting cellular immunity against prostate-specific antigen (PSA) in untreated prostate cancer patients and healthy controls through measurement of the phenotype and function of CD8(+) T cells. Our data show that the majority of healthy men possess functional PSA-specific CD8(+) T cells in contrast to cancer patients, where <50 % showed a CD8(+) T cell response. PSA146-154-specific CD8(+) T cells of these patients had a higher expression of the activation marker CD38 and the exhaustion marker Tim-3, indicating that PSA-specific cells are exhausted. The heterogeneity of the CD8(+) T cell response against PSA in prostate cancer patients may influence their response to therapy and is a factor to be taken into account while designing and selecting treatment regimens.

Abstract 276: Recruitment of effector T cells into the tumor rim and center with neoadjuvant systemic GM-CSF in patients with localized prostate cancer

Abstract Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim) is a bone marrow growth factor that is often used as an adjuvant in cancer vaccine clinical trials and has the potential to enhance antitumor efficacy in combination with immune checkpoint blockade in preclinical studies and clinical trials. The effect of GM-CSF remains controversial, however. In this study, we sought to characterize the systemic and tissue-specific effects of GM-CSF in prostate cancer patients in the preoperative setting. Methods: Patients with localized prostate cancer were treated on an open-label phase I/II study of neoadjuvant GM-CSF prior to planned radical prostatectomy (NCT00305669). Patients received GM-CSF 250mcg/m2 subcutaneously on days 1-14 (cohort 1), days1-21 (cohort 2), or days 1-28 (cohort 3), and underwent radical prostatectomy (RP) within 5 days after the last dose of GM-CSF. Blood collected at baseline, day 14, pre-RP, and 6 weeks post-RP were analyzed for immune cell subsets by flow cytometry. Immune infiltration in RP tissue were evaluated by immunohistochemistry and quantified by digital image analysis with comparison to RP tissue from untreated prostate cancer patients as controls. Results: 18 patients were evaluated with 6 patients at each dose level. Treatment with GM-CSF was associated with an increase in the number of myeloid cells including myeloid dendritic cells. Treatment was also associated with increases in circulating conventional CD4 and CD8 T cells and NK cells. The number of FoxP3+ regulatory CD4+ T cells was also increased, but to a much lower magnitude. At the time of radical prostatectomy, treatment was associated with a recruitment of CD3+ T cells to the tumor rim, and with cohort 3, at the centers of tumor. These T cells were predominantly CD8+ T cells, although conventional CD4+ T cells were also increased. No increase in monocytes or dendritic cells was seen in the tissue. Conclusion: Daily injection of systemic GM-CSF induces an increase in circulating antigen presenting cells as well as T and NK cells. While this treatment does not enhance the frequency of antigen presenting cells in the tumor microenvironment, this treatment recruits effector CD8+ T cells into the tumor rims. Citation Format: Xiao X. Wei, Stephen Chan, Jera Lewis, Serena Kwek, Vinh Dao, Lawrence Fong. Recruitment of effector T cells into the tumor rim and center with neoadjuvant systemic GM-CSF in patients with localized prostate cancer. [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 276. doi:10.1158/1538-7445.AM2015-276

What is the correct staging and treatment strategy for locally advanced prostate cancer extending to the bladder?

In locally advanced prostate cancer with bladder invasion, frequently encountered problems such as bleeding, urinary retention, hydronephrosis, and pain create distress for the patients. Therefore patients' quality of life is disrupted and duration of hospitalization is prolonged. Relevant literature about accurate staging and treatment of locally advanced prostate cancer with bladder invasion was investigated. Locally advanced prostate cancer can present as a large-volume aggressive tumor extending beyond boundaries of prostate gland, and involving neighboring structures which can be involved as recurrence(s) following initial local therapy. Survival times of these patients can range between 5 and 8 years. Their common characteristics are adverse and severe local symptoms unfavorably affecting quality of life Control of local symptoms and their effective palliation are independent clinical targets influencing survival outcomes of these patients. The treatment outcomes of locally advanced prostate cancer into the bladder are currently debatable. Although in the current TNM classification, it is defined in T4a, we think that this may be categorized as a subgroup of T3 and thus encourage surgeons for the indication of radical surgeries (radical prostatectomy, radical cystoprostatectomy) in selected patient populations after discussing issues concerning consequences of the treatment alternatives, and expectations with the patients. Cystoprostatectomy followed by immediate androgen deprivation therapy may be a feasible option for selected patients with previously untreated prostate cancer involving the bladder neck because of excellent local control and long term survival.

Systematic dissection of phenotypic, functional, and tumorigenic heterogeneity of human prostate cancer cells.

Human cancers are heterogeneous containing stem-like cancer cells operationally defined as cancer stem cells (CSCs) that possess great tumor-initiating and long-term tumor-propagating properties. In this study, we systematically dissect the phenotypic, functional and tumorigenic heterogeneity in human prostate cancer (PCa) using xenograft models and >70 patient tumor samples. In the first part, we further investigate the PSA-/lo PCa cell population, which we have recently shown to harbor self-renewing long-term tumor-propagating cells and present several novel findings. We show that discordant AR and PSA expression in both untreated and castration-resistant PCa (CRPC) results in AR+PSA+, AR+PSA-, AR-PSA-, and AR-PSA+ subtypes of PCa cells that manifest differential sensitivities to therapeutics. We further demonstrate that castration leads to a great enrichment of PSA-/lo PCa cells in both xenograft tumors and CRPC samples and systemic androgen levels dynamically regulate the relative abundance of PSA+ versus PSA-/lo PCa cells that impacts the kinetics of tumor growth. We also present evidence that the PSA-/lo PCa cells possess distinct epigenetic profiles. As the PSA-/lo PCa cell population is heterogeneous, in the second part, we employ two PSA- (Du145 and PC3) and two PSA+ (LAPC9 and LAPC4) PCa models as well as patient tumor cells to further dissect the clonogenic and tumorigenic subsets. We report that different PCa models possess distinct tumorigenic subpopulations that both commonly and uniquely express important signaling pathways that could represent therapeutic targets. Our results have important implications in understanding PCa cell heterogeneity, response to clinical therapeutics, and cellular mechanisms underlying CRPC.

Association of NaF PET/CT findings with PSA and alkaline phosphatase in untreated castration-sensitive prostate cancer.

Association of NaF PET/CT findings with PSA and alkaline phosphatase in untreated castration-sensitive prostate cancer.

Nine-year follow-up for a study of diffusion-weighted MRI in a prospective active surveillance cohort for prostate cancer.

5043 Background: Active surveillance (AS) for untreated prostate cancer requires accurate selection of patients unlikely to need treatment in their lifetime. Most studies have selected patients on ...

Association of NaF PET/CT findings with PSA and alkaline phosphatase in untreated castration-sensitive prostate cancer.

122 Background: NaF PET/CT is an emerging imaging technique with potentially high sensitivity in detecting bone metastasis (mets), however, its role in castration-‐sensitive prostate cancer (CSPC) is undefined and it remains unclear which CSPC patients should have NaF PET/CT. Methods: We retrospectively reviewed NaF PET/CT scans done on 45 patients with untreated, high risk CSPC with the goal of determining which disease features were associated with positive findings. Two blinded radiologists reviewed each scan and determined by consensus if findings were negative for metastasis (0% liklihood of mets), possible (50%), probable (75%), or consistent with mets (90%). Prostate specific antigen (PSA) and alkaline phosphatase (AP) values were then evaluated at time of NaF scan when available. Results: Of the 45 patients 2 were Gleason 6, 5 were Gleason 7, 36 were Gleason 8 to 10, 2 unknown. When grouped by findings on NaF PET/CT, there were no substantial differences seen between median PSA or AP values. When patients with both PSA and AP values &gt; median were evaluated, there was no clear association with NaF PET/CT findings. Conclusions: Preliminary findings from this small retrospective analysis suggest that there may be limited associations between PSA and/or AP with findings on NaF PET/CT scan in untreated patients with CSPC. Further analysis in larger cohorts of pts is required. [Table: see text]

Whole transcriptome sequencing reveals extensive unspliced mRNA in metastatic castration-resistant prostate cancer.

Men with metastatic prostate cancer who are treated with androgen deprivation therapies (ADT) usually relapse within 2 to 3 years with disease that is termed castration-resistant prostate cancer (CRPC). To identify the mechanism that drives these advanced tumors, paired-end RNA-sequencing (RNA-seq) was performed on a panel of CRPC bone marrow biopsy specimens. From this genome-wide approach, mutations were found in a series of genes with prostate cancer relevance, including AR, NCOR1, KDM3A, KDM4A, CHD1, SETD5, SETD7, INPP4B, RASGRP3, RASA1, TP53BP1, and CDH1, and a novel SND1:BRAF gene fusion. Among the most highly expressed transcripts were 10 noncoding RNAs (ncRNAs), including MALAT1 and PABPC1, which are involved in RNA processing. Notably, a high percentage of sequence reads mapped to introns, which were determined to be the result of incomplete splicing at canonical splice junctions. Using quantitative PCR (qPCR), a series of genes (AR, KLK2, KLK3, STEAP2, CPSF6, and CDK19) were confirmed to have a greater proportion of unspliced RNA in CRPC specimens than in normal prostate epithelium, untreated primary prostate cancer, and cultured prostate cancer cells. This inefficient coupling of transcription and mRNA splicing suggests an overall increase in transcription or defect in splicing. Inefficient splicing in advanced prostate cancer provides a selective advantage through effects on microRNA networks but may render tumors vulnerable to agents that suppress rate-limiting steps in splicing.

Testosterone Replacement Therapy and Prostate Cancer Incidence.

While early studies demonstrated a positive association between testosterone and prostate cancer, evidence on the nature of the relationship has evolved with time and newer data. Studies examining links between baseline testosterone levels as well as testosterone therapy and incident prostate cancer, reveal a more complex relationship. Moreover, investigators have reported their initial experiences with supplementing testosterone in men with a history of both treated and untreated prostate cancer.

Combination of quercetin and hyperoside inhibits prostate cancer cell growth and metastasis via regulation of microRNA‑21.

Previous studies have reported that hyperoside and quercetin in combination (QH; 1:1) inhibited the growth of human leukemia cells. The aim of the present study was to investigate the anti‑cancer effect of QH on prostate cancer cells. The results demonstrated that QH decreased the production of reactive oxygen species (ROS) and increased antioxidant capacity in PC3 cells at various concentrations (2.5‑60 µg/ml) with peak inhibition and augmentation changes of 3.22‑ and 3.00‑fold, respectively. Following treatment with QH for 48 and 72 h, the IC50-values on PC3 cells were 19.7 and 12.4 µg/ml, respectively. Western blot analysis revealed that QH induced apoptosis in human prostate cancer cells via activation of caspase‑3 and cleavage of poly(adenosine diphosphate ribose) polymerase. In addition, QH significantly inhibited the invasion and migration of PC3 cells as well as reduced the expression of numerous prostate tumor‑associated microRNAs (miRs), including miR‑21, compared to that of untreated human prostate cancer cells. QH was also found to enhance the expression of tumor suppressor programmed cell death protein 4, which was negatively regulated by miR‑21. Furthermore, induced overexpression of miR‑21 using pre‑miR‑21 oligonucleotides attenuated the beneficial effect of QH on prostate cancer cells. In conclusion, the results of the present study indicated that QH exerted an anti‑cancer effect on human prostate cancer cells, the mechanism of which proceeded, at least in part, via the inhibition of the miR‑21 signaling pathway.

Phase IIa Clinical Trial of Trans-1-Amino-3-(18)F-Fluoro-Cyclobutane Carboxylic Acid in Metastatic Prostate Cancer.

We performed a phase IIa clinical trial of trans-1-amino-3-(18)F-fluoro-cyclobutane carboxylic acid (anti-(18)F-FACBC), a synthetic amino acid analog for PET, in patients with metastatic prostate cancer. The study subjects consisted of 10 untreated prostate cancer patients having lymph node and/or bone metastasis. Five patients underwent whole-body PET 5 and 30 min after intravenous injection of anti-(18)F-FACBC. The other five patients underwent 60 min dynamic PET of the pelvis. Safety assessment was performed before and 24 h after injection. PET/CT images were assessed visually, and time courses of anti-(18)F-FACBC uptake were evaluated from dynamic imaging. Two mild adverse events were observed and resolved without treatment. All 10 patients showed increased accumulation of anti-(18)F-FACBC in the primary prostate lesion. CT revealed five enlarged lymph nodes indicating metastasis, and all showed increased uptake. Additionally, anti-(18)F-FACBC PET delineated unenlarged lymph nodes as hot spots. Anti-(18)F-FACBC PET demonstrated metastatic bone lesions, similar to conventional imaging. In one of two patients with lung metastasis, some lesions showed increased uptake. Regarding the time course, increased uptake of anti-(18)F-FACBC in the lesion was demonstrated immediately after injection, followed by gradual washout. The results of this phase IIa clinical trial indicated the safety of anti-(18)F-FACBC in patients with prostate cancer and the potential of anti-(18)F-FACBC PET to delineate primary prostate lesions and metastatic lesions. This clinical trial was registered as JapicCTI-101326.

A longitudinal study on the impact of active surveillance for prostate cancer on anxiety and distress levels.

Patients with potentially indolent prostate cancer (PC) can be managed with active surveillance (AS). Our objective was to analyse how anxiety and distress develop in men with untreated PC and whether highly anxious men quit AS. One hundred and fifty Dutch patients who opted for AS in the Prostate cancer Research International: Active Surveillance Study were invited to participate in an additional prospective, longitudinal quality of life (QoL) study within 6 months after diagnosis. Participants completed questionnaires with validated measures on anxiety and distress at inclusion (t = 0), 9 (t = 9) and 18 (t = 18) months after diagnosis. We assessed changes in scores on depression (Center for Epidemiologic Studies Depression (CES-D) scale), generic anxiety (State-Trait Anxiety Inventory (STAI-6)), PC-specific anxiety (Memorial Anxiety Scale for Prostate Cancer (MAX-PC)) and decisional conflict (Decisional Conflict Scale (DCS)) about patients' treatment choice between t = 0, t = 9 and t = 18 using repeated measures analysis. Response rates for patients still on AS at t = 0, t = 9 and t = 18 assessments were 86%, 90% and 96%, respectively. Nine patients (7%, 9/129) between t = 0 and t = 9 and 33 of 108 patients (31%) between t = 9 and t = 18 stopped AS, mostly (86%) because of protocol-based reasons. CES-D, total MAX-PC and DCS scores did not change significantly (p > 0.05) when comparing t = 18 with t = 9 and t = 0 scores, but generic anxiety (STAI-6; p = 0.033) and fear of disease progression (sub-score of the MAX-PC; p = 0.007) decreased significantly. These differences, however, were clinically modest (0.089 SD and 0.281 SD). Overall, six of 129 men (5%) discontinued AS because of anxiety and distress. When men with low-risk PC are managed with AS, fear of disease progression and general anxiety decreased, and only few may discontinue AS because of anxiety and distress. This suggests that negative QoL effects are limited in men with favourable clinical characteristics who opted for AS. (Registered trial number, NTR1718) .

Utility of ERG Versus AMACR Expression in Diagnosis of Minimal Adenocarcinoma of the Prostate in Needle Biopsy Tissue

Adenocarcinoma of the prostate measuring <1 mm in needle core tissue can present a diagnostic challenge. The α-methylacyl-CoA racemase (AMACR) immunostain, a marker of neoplastic prostatic epithelial cells, may be used to evaluate these limited tumor cases, in needle biopsy, with a reported sensitivity ranging to a low of 80%. The use of the ERG immunostain in evaluating prostate cancer is becoming more common, but the utility of this marker in direct comparison with AMACR has not been examined. The purpose of our study was to investigate whether the ERG immunostain adds diagnostic value to AMACR expression in evaluating untreated prostate cancer foci measuring <1 mm in core needle biopsy. We identified 129 blocks from 113 patients with continuous tumor foci measuring <1 mm on core needle biopsy. ERG and AMACR immunostaining analyses were performed on serial sections from the blocks, and expression was assessed by intensity and proportion scores assigned to each stain. Sixty-five of the selected blocks from 63 patients retained tumor foci measuring <1 mm after obtaining deeper sections. Of these 65 tumor foci, 36 were positive for AMACR alone, 28 were positive for AMACR and ERG, and 1 was positive for ERG alone. AMACR had a sensitivity of 99%, and ERG had a sensitivity of 45%. Most cases displayed strong AMACR expression, and only 7 of 65 foci (11%) exhibited weak or negative AMACR expression. Of these 7 foci with weak or negative AMACR expression, only 2 foci were ERG positive. This is the first study to our knowledge that examines the diagnostic utility of ERG expression in comparison with AMACR expression in minimal usual acinar adenocarcinoma of the prostate in core needle biopsy. Our findings suggest that AMACR should be the first-line positive marker for confirmation of a diagnosis of minimal adenocarcinoma of the prostate, when needed. ERG immunohistochemistry is potentially indicated only in uncommon cases of minimal adenocarcinoma when AMACR staining is negative or weak, and in these cases ERG is informative in only a minority (29%) of cases. Evidence-based utilization of diagnostic markers, without their routine overutilization, such as ERG expression in minimal adenocarcinoma, that do not provide added diagnostic value in most cases, is an important principle in application of immunohistochemistry in this era of cost-consciousness.

Living with untreated prostate cancer

To summarize the literature on the predictors of quality of life (QoL) of patients with prostate cancer (PCa) on active surveillance and to highlight both risk factors of poor QoL and resilience factors that facilitate decision-making and promote adherence to active surveillance. Four main clusters of predicting variables have been highlighted: decision-making-related issues (patient's perception of the influence of physicians on the choice of active surveillance was related to higher decisional conflict; smaller amount of time to make a decision was predictive of poor QoL); demographic variable (such as marital status, age, and education level); psychological individual and interpersonal characteristics (neuroticism and impaired mental health were found to be associated with poor QoL, whereas positive outlook toward cancer was predictive of considering active surveillance as an effective management option for PCa); and patients' perceptions of cancer characteristics (prostate-specific antigen and number of positive cores). Men who choose active surveillance may present unique care needs. Identification of the most relevant risk factors for poor QoL can be useful to physicians who aim to target the psychosocial issues that patients and their families may need to address promptly. Predictive models could be used to identify active surveillance patients who present features of psychosocial vulnerability and to develop tailored psychoeducational interventions.

MP52-20 POST-TRANSLATIONAL MODIFICATION MEDIATED BY THE PROLYL ISOMERASE PIN1 ACCERELATE CANCER PROGRESSION IN CASTRATION RESISTANT PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2014MP52-20 POST-TRANSLATIONAL MODIFICATION MEDIATED BY THE PROLYL ISOMERASE PIN1 ACCERELATE CANCER PROGRESSION IN CASTRATION RESISTANT PROSTATE CANCER Yota Yasumizu, Takeo Kosaka, Yasumasa Miyazaki, Eiji Kikuchi, Akira Miyajima, and Mototsugu Oya Yota YasumizuYota Yasumizu More articles by this author , Takeo KosakaTakeo Kosaka More articles by this author , Yasumasa MiyazakiYasumasa Miyazaki More articles by this author , Eiji KikuchiEiji Kikuchi More articles by this author , Akira MiyajimaAkira Miyajima More articles by this author , and Mototsugu OyaMototsugu Oya More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1630AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives The prolyl isomerase Pin1 regulates phosphorylated status of proteins by catalyzing the cis-trans isomerization of phosphorylated Ser/Thr and Pro motifs, and plays an important role in cancer progression. The aim of this study was to establish a new treatment strategy for docetaxel resistant CRPC with a special focus on inhibition of Pin1. Methods Human CRPC cell lines: C4-2 and C4-2AT6 cell lines were used in this study. The C4-2AT6 cell line was established from C4-2 cells grown in androgen ablated serum for six months. The efficacy of Pin1 inhibitor: juglone was examined in CRPC cell lines. Human untreated prostate cancer tissues were obtained during radical prostatectomy at Keio University Hospital. Results We compared the cytotoxic effect of docetaxel (DTX) on C4-2 and C4-2AT6 cells by cell viability assay. In C4-2 and C4-2AT6 cells, the relative cell viability treated with 5nM DTX was 38.0% ± 5.2% and 59.1% ± 6.3%, respectively. These results indicated that C4-2AT6 cells showed significantly higher resistance to DTX than C4-2 cells. Next we evaluated the cytotoxic effect of juglone on C4-2AT6. The relative cell viability was 51.2 ± 3.2% with 30µM Juglone and 34.9 ± 3.8% with combined 5nM DTX and 30µM Juglone. Juglone significantly inhibited cell proliferation of C4-2AT6. When combined with DTX, Juglone showed significantly higher cytotoxicity than monotherapy (p<0.05). We previously demonstrated the efficacy of dual PI3K/mTOR inhibitor: NVP-BEZ235 against C4-2AT6. Pin1 regulates phosphorylated status of PI3K/Akt/mTOR pathway. Therefore, we examined the synergic effect of Juglone and NVP-BEZ235. The relative cell viability treated with 300nM NVP-BEZ235 was 49.3 ± 3.2% and 43.0 ± 3.8% with combined 300nM NVP-BEZ235 and 30µM Juglone. The combination of Juglone and NVP-BEZ235 shows little synergic effect on C4-2AT6 cells. In vivo, we examined a mouse xenogrftmodel of C4-2AT6 cells treated with DTX (2mg/kg) or NVP-BEZ235 (12.5mg/kg/day). In immunohistochemistry, tumors treated with DTX showed up-regulation of Pin1, while tumors treated with NVP-BEZ235 showed little expression of Pin1. These results suggest that Pin1 inhibitor shows the significant effect on tumors with up-regulation of Pin1. We confirmed the expression of Pin1 in human samples by immunohistochemistry. Specimens with a high Gleason score (>8) and a high pathological classification (pT3) showed significantly elevated Pin1 expression (p>0.05). Conclusions The combination of Juglone and DTX showed significant anti-tumor effects in CRPC. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e587 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Yota Yasumizu More articles by this author Takeo Kosaka More articles by this author Yasumasa Miyazaki More articles by this author Eiji Kikuchi More articles by this author Akira Miyajima More articles by this author Mototsugu Oya More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Commentary on “Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: Long-term results of a randomised controlled trial (EORTC trial 22911).” Bolla M, van Poppel H, Tombal B, Vekemans K, Da Pozzo L, de Reijke TM, Verbaeys A, Bosset JF, van Velthoven R, Colombel M, van de Beek C, Verhagen P, van den Bergh A, Sternberg C, Gasser T, van

BackgroundWe report the long-term results of a trial of immediate postoperative irradiation versus a wait-and-see policy in patients with prostate cancer extending beyond the prostate, to confirm whether previously reported progression-free survival was sustained. MethodsThis randomised, phase 3, controlled trial recruited patients aged 75 years or younger with untreated cT0-3 prostate cancer (WHO performance status 0 or 1) from 37 institutions across Europe. Eligible patients were randomly assigned centrally (1:1) to postoperative irradiation (60Gy of conventional irradiation to the surgical bed for 6 weeks) or to a wait-and-see policy until biochemical progression (increase in prostate-specific antigen>0·2μg/L confirmed twice at least 2 weeks apart). We analysed the primary endpoint, biochemical progression-free survival, by intention to treat (two-sided test for difference at α = 0.05, adjusted for one interim analysis) and did exploratory analyses of heterogeneity of effect. This trial is registered with ClinicalTrials.gov, number NCT00002511. Findings1005 patients were randomly assigned to a wait-and-see policy (n = 503) or postoperative irradiation (n = 502) and were followed up for a median of 10·6 years (range 2 months to 16·6 years). Postoperative irradiation significantly improved biochemical progression-free survival compared with the wait-and-see policy (198 [39·4%] of 502 patients in postoperative irradiation group vs 311 [61·8%] of 503 patients in wait-and-see group had biochemical or clinical progression or died; HR 0·49 [95% CI 0·41-0·59]; p<0·0001). Late adverse effects (any type of any grade) were more frequent in the postoperative irradiation group than in the wait-and-see group (10 year cumulative incidence 70·8% [66·6-75·0] vs 59·7% [55·3-64·1]; p = 0.001). InterpretationResults at median follow-up of 10·6 years show that conventional postoperative irradiation significantly improves biochemical progression-free survival and local control compared with a wait-and-see policy, supporting results at 5 year follow-up; however, improvements in clinical progression-free survival were not maintained. Exploratory analyses suggest that postoperative irradiation might improve clinical progression-free survival in patients younger than 70 years and in those with positive surgical margins, but could have a detrimental effect in patients aged 70 years or older. FundingLigue Nationale contre le Cancer (Comité de l'Isère, Grenoble, France) and the European Organisation for Research and Treatment of Cancer (EORTC) Charitable Trust.

Metabolomic evaluation of the response to endocrine therapy in patients with prostate cancer

Timely evaluation of the response to endocrine therapy in patients with prostate cancer (PCa) may optimize treatment regimens and improve long-term prognosis. We used the liquid chromatography–mass spectrometry (LC–MS)-based metabolomic technique to identify serum biomarkers indicative of disease progression and therapeutic benefit.The mean serum levels of seven metabolites, including deoxycholic acid (DCA), glycochenodeoxycholate (GCDC), l-tryptophan, docosapentaenoic acid (DPA), arachidonic acid, deoxycytidine triphosphate, and pyridinoline, differed significantly between untreated PCa patients and healthy controls. In patients who did not develop castration-resistant prostate cancer (CRPC) for at least 2 years (good responders), these metabolite levels reverted to near healthy control levels during endocrine therapy. In contrast, the metabolite levels remained abnormal in patients who developed CRPC within 1 year (poorly responsive patients). Three of these biomarkers (DCA, GCDC, and DPA) are mainly involved in cholesterol metabolism, underscoring the importance of elevated cholesterol to PCa progression. These metabolites may serve as predictive biomarkers for assessing the therapeutic response of PCa patients to endocrine therapy.