Hormone-resistant Prostate Cancer Patients Research Articles

Comparative efficacy of radical prostatectomy and radiotherapy in the treatment of high-risk prostate cancer.

Both radical prostatectomy and radiation therapy are effective in controlling the condition of patients with hormone-resistant prostate cancer (HRPCa). However, there is limited research on the prognosis and quality of life of HRPCa patients after different treatment modalities. To explore the efficacy of radical prostatectomy (RP) and radiotherapy (RT), when treating high-risk prostate cancer (HRPCa). Overall 103 HRPCa patients were included and were divided into RP group and RT group according to different treatment methods. The propensity score matching method (PSM) was used to balance the baseline data of the two groups and match 34 patients in each group. The prognosis, quality of life, and basic efficacy of patients were compared. After intervention, the disease-free survival rate of the RT group was higher than that of the RP group (79.41% vs. 55.88%, p= 0.038). Quality of life scores between the two treatment methods had no difference before intervention (p> 0.05), but higher in RT group than that of the RP group after intervention (p< 0.05). After treatment, there was no statistically significant difference in total effective rate of treatment between two groups (44.12% vs. 58.82%, p> 0.05), but the disease control rate was significantly higher in RT group (94.12% vs. 76.47%, p= 0.040). Radical radiotherapy is effective in the clinical treatment of HRPCa patients, with a higher disease-free survival rate and improved quality of life after treatment, and is worth promoting.

Prevalence of oligoprogression in metastatic hormone-resistant prostate cancer patients on androgen targeted therapies: Could targeted radiotherapy improve patient outcomes?

110 Background: Androgen receptor-targeted therapies (ART) such as Abiraterone and Enzalutamide have shifted the management paradigm of metastatic castrate-resistant prostate cancer (mCRPC). These treatments are well-tolerated with less toxicities compared to chemotherapy, therefore methods to delay chemotherapy are beneficial to patients. Patients eventually become resistant to ARTs, and some patients will progress in a limited number of sites. This study investigated the prevalence of oligoprogressive disease (OPD) amenable to Stereotactic-body radiotherapy (SBRT). OPD is defined as ≤3 metastatic lesions which are progressing or new whilst all other sites of disease are well-controlled by ART. Methods: Retrospective analysis of electronic patient records and imaging studies of 95 patients treated with ART for mCRPC between April 2015 – 2017 from a single centre was undertaken. Data was analysed at the time of first tumour progression on ART. Results: The median (IQR) age of patients was 78.8 (74.4-83.6) years. OPD was found in 27 (28%) patients, 18 (19%) had lesions suitable for SBRT (Table). Seventeen (63%) patients were treated with abiraterone, 10 (27%) patients with enzalutamide. Median (IQR) time from starting ART to OPD was 16.4 (8.6-19.9) months. Five (19%) patients had 3 sites of OPD, 8 (29%) patients had 2 sites of OPD and 14 (52%) patients had 1 site of OPD. Nineteen patients continued ART beyond OPD for ≥3months. OPD was diagnosed using CT scan (56%), whole body diffusion-weighted MRI (22%), choline PET/CT (19%) and bone scan (3%). Six (22%) patients were treated with radiotherapy for OPD, 3 as participants of the TRAP trial (NCT03644303). Median time to subsequent progression after OPD for the 3 patients treated off trial with radiotherapy was 20.5 months. The OPD lesions treated with radiotherapy included the prostate (2 patients, 30 Gy in 5 and 24 Gy in 4 fractions) and para-aortic lymph node (1 patient, 30 Gy in 5 fractions). Median time to subsequent progression after OPD for those who did not receive radiotherapy was 6.4 months. There was no significant difference between median overall survival between patients with OPD and those who progressed with &gt; 3 lesions (7 vs 9.2 years, P= 0.54). Ten (66%) patients who progressed after initial OPD on continuation of ART progressed with further OPD (≤3 lesions including original OPD lesion). Conclusions: OPD is prevalent in patients on ART for mCRPC. The most frequent site of OPD was in bone and majority of patients had only 1 site of OPD at presentation. These results identify a cohort of patients who may benefit from SBRT to maximise ART treatment. Fourteen (14%) patients met entry criteria for TRAP trial which is currently testing the role of SBRT to sites of OPD in mCRPC. [Table: see text]

MP70-11 REVERSE OF DOCETAXEL RESISTANCE IN PROSTATE CANCER VIA NOTCH SIGNALING INHIBITION

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III1 Apr 2018MP70-11 REVERSE OF DOCETAXEL RESISTANCE IN PROSTATE CANCER VIA NOTCH SIGNALING INHIBITION Qiu Shi, Xiang Tu, Qiang Wei, and Lu Yang Qiu ShiQiu Shi More articles by this author , Xiang TuXiang Tu More articles by this author , Qiang WeiQiang Wei More articles by this author , and Lu YangLu Yang More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2255AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Chemotherapeutic Docetaxel (Doc) is the standard of care for the hormone resistant prostate cancer (HRPC). However, many HRPC patients do not respond to Doc chemotherapy in a long-term treatment because the cancerous tissue acquires resistance to Doc treatment. The molecular mechanism underlying the development of Doc resistance in HRPC remains unclear. METHODS Human prostate cancer cell line DU145 were purchased and Doc resistant human prostate cancer cell line DU145/adr were generated by culturing cells with Docetaxel in a dose-escalation manner. Cell viability was determined by MTT assay kit. After enumeration of tumor stem-like cells in 3D fibrin gels, CD133 positive cells were selected by fluorescence-activated cell sorting. A Notch signaling pathway inhibitor was applied to combine with Doc to overcome the Doc resistance in HRPC. The ability to release doxorubicin from DU145 and DU145/adr cells was detected by HPLC. Quantitative real-time PCR and western blotting were performed for the detection of the target genes and proteins. RESULTS A subpopulation of prostate cancer cells, owing enhanced stem-like properties, was found in both prostate cancer cell line and HRPC patient tumor tissues, showed high resistance to Doc. The subpopulation of Doc resistance cells has up-regulation of Notch2 and activation of Notch signaling pathway, leading to the high tumor initiating ability and colony formation capability. Most importantly, the Notch signaling pathway up-regulates the expression of drug resistant associated gene ABCB1, which encodes P-GP, resulting in the Doc resistance. CONCLUSIONS Our results illustrated the role of a stem cell-like subpopulation of prostate cancer cells in Doc-resistance that is dependent on Notch signaling pathway activation. Importantly, regulation of Notch signaling was evident in samples derived from the tumors of HRPC patients indicating the clinical relevance of Notch as a potential Doc resistance biomarker. Furthermore, inhibition of Notch signaling pathway in Doc treatment regimens can re-sensitize cancer cells, revealing a potential therapeutic strategy in cases of HRPC. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e938 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Qiu Shi More articles by this author Xiang Tu More articles by this author Qiang Wei More articles by this author Lu Yang More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

LINE-1-encoded reverse Transcriptase as a target in cancer therapy.

LINE-1 elements account for about 17% of the human genome and harbour two open reading frames: ORF1, encoding a 40 kDa RNA-binding protein, and ORF2, coding for a 150 kDa protein with reverse transcriptase (RT) activity. LINE-1s are highly expressed in embryos and tumor cells while being virtually silent in differentiated tissues and, consistently, both ORF-1p and ORF-2p have been detected in human cancers. RT-encoding ORF2 is expressed early in pre-neoplastic lesions suggesting that RT expression may be a potential cause, rather than a consequence, of cancer onset. Experimental data emerging from in vitro and in vivo studies confirm this view. Preclinical work showed that RT inhibition reduces proliferation, promotes differentiation of cancer cells and antagonizes tumor progression in murine models. Moreover, a recent phase II trial on metastatic hormone-resistant prostate cancer patients has confirmed the anticancer efficacy of RT inhibitors. Together, these data indicate that LINE-1-encoded RT emerges as a potential therapeutic target for a large spectrum of cancers and RT inhibitors as effective tools in a novel anti-cancer, non-cytotoxic, differentiation therapy.

Is the detection rate of 18F-choline PET/CT influenced by androgen-deprivation therapy?

To evaluate if the detection rate (DR) of (18)F-choline (18F-CH) PET/CT is influenced by androgen-deprivation therapy (ADT) in patients with prostate cancer (PC) already treated with radical intent and presenting biochemical relapse. We have retrospectively evaluated (18)F-CH PET/CT scans of 325 consecutive PC patients enrolled in the period November 2009 to December 2012 previously treated with radical intent and referred to our centre to perform (18)F-CH PET/CT for biochemical relapse. Two different groups of patients were evaluated. group A included the whole sample of 325 patients (mean age 70 years, range: 49-86) who presented trigger PSA between 0.1 and 80 ng/ml (mean 5.5 ng/ml), and group B included 187 patients (mean age 70 years, range 49-86) with medium-low levels of trigger PSA ranging between 0.5 and 5 ng/ml (mean PSA 2.1 ng/ml); group B was chosen in order to obtain a more homogeneous group of patients in terms of PSA values also excluding both very low and very high PSA levels avoiding the "a priori" higher probability of negative or positive PET scan, respectively. At the time of examination, 139 patients from group A and 72 patients from group B were under ADT: these patients were considered to be hormone-resistant PC patients because from their oncologic history (>18 months) an increase of PSA levels emerged despite the ongoing ADT. The relationship between (18)F-CH PET/CT findings and possible clinical predictors was investigated using both univariate and multivariate binary logistic regression analyses, including trigger PSA and ADT. Considering the whole population, overall DR of (18)F-CH PET was 58.2 % (189/325 patients). In the whole sample of patients (group A), both at the univariate and multivariate logistic regression analysis, trigger PSA and ADT were significantly correlated with the DR of (18)F-CH PET (p < 0.05). Moreover, the DR in patients under ADT (mean PSA 7.8 ng/ml) was higher than in patients not under ADT (mean PSA 3.9 ng/ml), (DR was 70.5 % and 48.9 %, respectively; p < 0.001), therefore, demonstrating the existence of a significant correlation between the DR of (18)F-CH PET and ADT. In group B patients only trigger PSA resulted a reliable predictor of the (18)F-CH positivity, since ADT was not correlated to the DR of (18)F-CH PET (p = 0.061). Also in group B the DR of (18)F-CH PET in patients under ADT was higher than in patients not under ADT (65.3 % and 51.3 %, respectively) but the difference was not significant without a statistically significant correlation in the Mann Whitney test (p = 0.456) therefore, suggesting the lack of correlation between DR (18)F-CH PET/CT and ADT. Similarly to previous published studies, in our series the overall DR of (18)F-CH PET/CT was 58 % and was significantly correlated to trigger PSA. The most important finding of the present study is that ADT does not negatively influence DR of (18)F-CH PET/CT in PC patients with biochemical relapse; therefore, it can be suggested that it is not necessary to withdraw ADT before performing (18)F-CH PET/CT.

S207 Comparing prostate specific antigen doubling time and prostate specific antigen velocity as predictors of prognosis and survival in hormone-resistant prostate cancer patients

S207 Comparing prostate specific antigen doubling time and prostate specific antigen velocity as predictors of prognosis and survival in hormone-resistant prostate cancer patients

Overall survival in hormone-resistant prostate cancer patients with different transition of care within the Veterans Affairs (VA) system.

5091 Background: Prostate cancer patients with locally advanced /metastatic disease have a poor prognosis and although hormonal therapy can induce long-term remission, development of hormone-resistant prostate cancer (HRPC) is inevitable. The goal of this study is to evaluate overall survival in HRPC patients with different transition of care in the Veterans Affairs (VA) system. We hypothesized that prostate cancer patients with late referral to medical oncologists were more likely to have decreased overall survival. Methods: This is a retrospective, observational analysis of patients enrolled in the Veterans Health Administration system from October 2003 to March 2011. Patients were followed from initial evaluation and treatment by urology until an endpoint of death or the end of the study period. VA patients with a diagnosis of HRPC were identified; prostate specific antigen (PSA), medical and pharmacy records were collected. HRPC was defined as PSA doubling after treatment with hormonal therapy. Transition of care was defined as two encounters with the medical oncology service and at least one encounter was a medical oncologist. Three cohorts were created: patients transitioned to oncology before HRPC, those transitioned to oncology after HRPC, and patients who were never transitioned to oncology. Primary outcome was overall survival (OS). The Charlson score was utilized for comorbidity assessment. Statistical analysis was conducted using chi square test for categorical variables. Results: Total number of patients evaluated was 8,281; 2,168 in transition before HRPC (tbHRPC) cohort, 2,052 in transition after HRPC (taHRPC), and 4,061 patients that never transitioned (tnHPRC). The mean ages for the respective cohorts were: 69.35, 69.69, and 71.64. The Charlson comorbidity scores were 3.79 (tbHRPC), 3.06 (taHRPC), and 3.14 (tnHRPC); p-values &lt; 0.05. Mortality rates among the cohorts were 57% tbHRPC, 69% taHRPC, and 62% tnHRPC; p-values &lt;0.001. PSA doubling within 10 months were: 57% tbHRPC, 60% taHRPC, and 54% tnHRPC; p-values &lt; 0.05. Conclusions: Overall survival was improved among prostate cancer patients that transitioned to oncology before becoming HRPC.

Abstract 5231: Zoledronic acid encapsulated into liposomes and nanoparticles: Enhanced antitumor activity in 3D-prostate carcinoma spheroids

Abstract Introduction: Zoledronic acid is currently used for the treatment of bone metastases in hormone-resistant prostate cancer patients. The rapid plasma half-life and the high affinity for Osteoclasts, the primary targets of bisphosphonates, limit the use for extra-skeletal tissues. Moreover, it remains still unclear, whether cancer-associated fibroblasts (CAF) influence the toxicity of ZOL. The use of nanomedicine is one promising strategy to improve the availability of drugs within the tumor tissue. To investigate the benefit of such approach, we used two different nanovectors encapsulating ZOL on 3D-spheroids from prostate carcinoma cells and CAF in combination with standard toxicity assays. Material and Methods: Stealth liposomes (PGNP_ZOL) and a new generation of nanovector, named self-assembly nanoparticles (NP_ZOL), were prepared using standard protocols already described. The prostate carcinoma cell lines PC-3, DU-145 and LNCaP were cultivated in 96-well MTP's and as Spheroids on agarose coated 96-well MTP's. Heterologous spheroids were prepared by mixing tumor cells with different ratios of normal (NAF) or tumor-associated (CAF) fibroblasts. Cell cultures/spheroids were incubated with ZOL, NP_ZOL/PGNP_ZOL for up to 120 h. Changes in growth behavior and toxicity (apoptosis/necrosis) were quantified from spheroid-cultures by modifications of standard assays (CDD+, LDH+). The adaptability of these techniques for 3D- cultures was assessed using thapsygargin/tunicamycin as apoptosis-inducing agents. Results: Standard-viability assays revealed a significant enhancement of antitumor activity of NP_ZOL/PGNP_ZOL as compared to the free drug in cell cultures of DU-145 and LNCaP, whereas these effects were less pronounced in PC-3 cells. The antitumor efficacy of NP_ZOL/PGNP_ZOL was caused by a strong inhibition of tumor cell proliferation as revealed by the BrDU-assay; on the other hand, both CDD+ and LDH+ failed to detect both apoptosis and necrosis after drug treatment for up to 120 h. The average IC50 values in the tumor cells ranges from 10-20µM/L, but the fibroblasts exhibit complete growth inhibition at concentrations between 2-5µm/L ZOL. Conclusion: These results confirm the hypothesis that the use of nanomedicine enables the extension in therapeutic applications of drugs such as bisphosphonates. In this context, ZOL seems to exert benefits even onto the primary tumor cells. Homo-/heterologeous 3D-spheroids offer advanced models mimicking the microenvironment within a tumor tissue grows thus bridging the gap between cell culture and live tissue. Moreover, the rapid generation of single-tumor spheroids allows for a high-throughput cell function and toxicity analysis. 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 5231. doi:1538-7445.AM2012-5231

Pilot phase II study with docetaxel in combination with curcuminoids in patients with hormone-resistant prostate cancer (HRPC).

e15069 Background: Prostate cancer is the most frequent tumor in men from developed countries. A previous phase I study showed the feasability of curcuminoids in association with docetaxel for advanced breast cancers. Despite several analogies, HRPC has a lower sensitivity to chemotherapy than breast cancer. Docetaxel (first-line reference treatment in HRPC) induces a PSA response in 45% of treated patients. However, the objective tumor response is limited to 12%. A pilot phase II study was conducted to assess the response of HRPC to docetaxel/curcuminoids combination. Methods: Docetaxel was given (75mg/m² + prednisolone, every 3 weeks for 6 cycles) in combination with curcuminoids orally at the dose of 6g/day according to previous phase I schedule (7 days/cycle: d-4 to d+2). The primary endpoint was the response rate assessed by clinical, biological and paraclinical examinations. The secondary endpoints included safety, time to progression (TTP) and compliance. Results: Among the 30 patients included (october 2009 to november 2010), data are available for 25 patients with a mean age of 69 years (range 58-83). Of 139 cycles, 122 (88%) were completed with perfect compliance. Twenty one patients received the 6 courses and 4 withdrew prematurely. No patient withdrew for toxicity. The most common grade-3-4 hematological toxicity was neutropenia and 2 patients presented with grade-2 anemia. For non-hematological toxicity, 4 grade-3 and 23 grade-2 adverse events were observed: mainly asthenia, diarrhea and ungueal toxicity. A PSA response was observed in 14 of the 24 evaluable patients (59%). The responses were complete (3 patients) or partial (11 patients) and were observed rapidly (before the 3rd cycle) in 12 patients. Fourteen of 25 patients had measurable or evaluable lesions (RECIST criteria), with 5 (36%) partial responses; 8 (57%) stable disease, 1 (7%) progressive disease. The median PSA TTP was 5.85 months (TTP on targets are not yet available). Conclusions: In HRPC patients, combination with curcuminoids tends to improve the response rate of docetaxel in terms of both PSA level and objective responses. This justify further randomized trials.

Assessment of the Effects of Zoledronic Acid Therapy on Bone Metabolic Indicators in Hormone-Resistant Prostate Cancer Patients with Bone Metastatasis

Purpose. Assessment of effects of zoledronic acid therapy on bone metabolic indicators in hormone-resistant prostate cancer patients with bone metastasis. Material and Methods. Hormone-resistant prostate cancer patients who were identified to have metastases in their bone scintigraphy were taken to trial group. Before administration of zoledronic acid, routine tests for serum calcium, total alkalen phosphates were studied. Sample sera for bone metabolic indicators BALP, PINP, and ICTP were collected. Bone pain was assessed via visual analogue scale and performance via Karnofsky performance scale. Four mg zoledronic acid was administered intravenously once a month. Results. When serum levels of bone forming indicators PINP; BALP were compared before and after therapy, there were insignificant decreases (P = .33, P = .21, resp.). Serum levels of bone destruction indicator ICTP was compared, and there was a significant decrease after zoledronic acid therapy (P = .04). When performances of the patients were compared during therapy period, performances decreased significantly due to progress of illness (P = .01). All patients had ostalgia caused by bone metastases at various degrees. Significant decrease in pain scores was observed (P < .01). Conclusion. Zoledronic acid therapy decreased bone destruction and was effective in palliation of pain in patient with bone metastasis. Using bone metabolic indicators during followup of zoledronic acid therapy might be useful.

A Review of the Patterns of Docetaxel Use for Hormone-Resistant Prostate Cancer at the Princess Margaret Hospital

Based on the TAX 327 phase III trial, docetaxel-based chemotherapy is the standard first-line treatment for hormone-resistant prostate cancer (HRPC); however, there is some heterogeneity in the use of this agent in routine clinical practice. The aim of the present study was to examine the patterns of docetaxel use in routine clinical practice at our institution and to compare them with docetaxel use in the TAX 327 clinical trial. We conducted a retrospective chart review of HRPC patients treated with first-line docetaxel between 2005 and 2007 at the Princess Margaret Hospital. In the first-line setting, 88 patients with HRPC received docetaxel. The main reasons for initiating docetaxel were rising prostate-specific antigen (PSA, 98%) and progressive symptoms (77%). The PSA response rate was 67%; median time to response was 1.5 months, and duration of response was 6.8 months. Median survival was 15.9 months (95% confidence interval: 12.4 to 20.5 months). Patients received a median of 7 cycles of treatment, and the main toxicities were fatigue (35%) and neuropathy (24%). Post docetaxel, 36 patients received second-line treatment with a 22% response rate. In routine clinical practice, HRPC patients received docetaxel mainly because of symptomatic disease progression. Overall response rates and toxicities were comparable to those in the TAX 327 trial. However, our patients received a median of only 7 cycles of treatment versus the 9.5 administered on trial, and survival was slightly shorter in our single-institution study. A larger prospective multicentre analysis, including performance status and quality-of-life parameters, may be warranted to determine if docetaxel performs as well in routine clinical practice as it does in the clinical trial setting.

Abstract C9: Utility of serological apoptosis biomarkers: Assessment in a phase II study of zibotentan (ZD4054) in patients with hormone-resistant prostate cancer

Abstract Serological apoptosis biomarkers, cytokeratin-18 (M65), cleaved cytokeratin 18 (M30) and nucleosomal DNA (nDNA) are frequently elevated above normal levels in patients with various cancers and are considered to reflect tumor burden.1 Moreover, these biomarkers appear to be dynamically modulated by cytotoxic therapy capable of inducing tumor response.2–4 We retrospectively investigated whether a non-cytotoxic agent, zibotentan, had any impact on serological levels of these apoptosis biomarkers. Zibotentan has shown survival benefit in hormone-resistant prostate cancer (HRPC) patients despite the lack of RECIST based responses.5 Serological samples were obtained from consented patients before the start and at 12 weeks after the assigned randomized treatment (placebo, zibotentan 10 or 15 mg daily oral doses) and were processed for M30, M65 and nDNA concentrations. Approximately 59% (N=184) and 42% (N=82) of the study intent to treat population (N=312 and N=195) had M30 values at baseline and at week 12, respectively. Similar numbers of M65 and nDNA values were available for analysis. No consistent dose-related trends in mean percentage change from baseline or at 12 weeks were observed for any of the biomarkers. However, there were trends towards reductions for M30 in patients receiving zibotentan 10 mg (−11%, 95% confidence interval [CI] −24%, +6%) and for nDNA in patients receiving zibotentan 15 mg (−15%, 95% CI −44%, +30%). Applying a Cox proportional hazards regression model for overall survival (OS) and including a treatment factor and baseline covariates, stratifying the apoptosis biomarkers on the basis of ‘high’ or ‘low’ concentrations (based on median baseline values) revealed a statistically significant difference for OS ± M65 (P value = &amp;lt;0.001). M30 and nDNA were without significant relationship. The M65 data suggest a potential utility for this marker in prognosis. Further evaluation of the clinical relevance of these findings is warranted with access to a larger patient dataset. The ongoing phase III clinical trials for zibotentan in HRPC patients will provide this opportunity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C9.

Pretreatment frequency of circulating IL‐17+CD4+ T‐cells, but not Tregs, correlates with clinical response to whole‐cell vaccination in prostate cancer patients

The aim of this study was to determine the prognostic implications of the pretreatment level of Th17 cells compared with regulatory T-cell status in prostate cancer patients receiving active whole cell immunotherapy. Ten-color flow cytometry was used to analyze IL-17-producing CD4(+) T-cells in the peripheral blood of hormone-resistant non-bone metastatic prostate cancer patients prior to immunotherapy with an allogeneic whole-cell vaccine. Surface expression of the chemokine receptors CCR4 and CCR6 was used to further subdivide IL-17-producing cells into subsets with distinct homing properties. The frequency of circulating regulatory T-cells (Tregs), defined as CD3(+)CD4(+)CD127(lo)Foxp3(+)CD25(+) was compared in the same patients. The frequency of CCR4(-)IL-17(+)CD4(+) T-cells prevaccination inversely correlated with time to disease progression (TTP) in 23 prostate cancer patients. Furthermore, responder (R) patients with statistically significant reductions in PSA velocity (PSAV) in response to the immunotherapy (n = 9), showed a Th17 profile similar to healthy male controls and significantly different from non-responder (NR) patients (n = 14) (i.e., those without any significant reduction in PSAV). In contrast, the frequency of Tregs in peripheral blood in PSA-R (n = 11) and -NR (n = 14) patients was similar (but in both cases, significantly higher than in age-matched healthy men). Accordingly, there was no significant correlation between frequency of Tregs and TTP in these late-stage prostate cancer patients undergoing active immunotherapy. These data imply an important role for IL-17-producing helper T-cells in cancer immunology and highlight their potential use as a pretreatment screen to ensure appropriate treatment is offered to hormone-resistant prostate cancer patients.

Long-term outcome of a phase II study of weekly docetaxel with a short course of estramustine and enoxaparine in hormone-resistant prostate cancer patients

The objective was to define the toxicity and activity of weekly docetaxel administered with a short course of estramustine and enoxaparine in patients with hormone-resistant prostate cancer (HRPC). Twenty-four patients were treated with the next regimen: weekly docetaxel 36 mg/m(2) iv for three consecutive weeks every 28 days, and estramustine 280 mg three times a day for three consecutive days beginning the day before docetaxel (days 1-3, 8-10 and 15-17). In order to prevent thromboembolic events, 40 mg of subcutaneous enoxaparine was administered daily sc on the same days as estramustine. Primary endpoints were: toxicity, especially the presence of thromboembolic events, PSA response rate and response in measurable disease. Secondary endpoints were: time to PSA progression and overall survival. Nineteen of 24 patients (79.1%, 95% CI 71-87%) had a PSA response = or >50%. Four of the eleven patients with measurable disease had a partial response. The median time to PSA progression was 7 months (CI 95%: 6.5-9) and the median survival was 19 months (IC 95%: 11-24). Toxicity was manageable with no treatment- related mortality. Only two patients had grade 4 neutropenia. Two patients had thrombotic events, one deep venous thrombosis and one stroke. The main grade 3 non-haematologic toxicity was diarrhoea and asthenia, both in 25% of patients. Weekly docetaxel with a short course of estramustine and enoxaparine is active and tolerable in HRPC patients. The observed incidence of thrombosis was lower than previously reported but the association of enoxaparine was not enough to completely prevent the thromboembolic events.

Elevated E2F1 inhibits transcription of the androgen receptor in metastatic hormone-resistant prostate cancer: Davis JN, Wojno KJ, Daignault S, Hofer MD, Kuefer R, Rubin MA, Day ML, Department of Urology, University of Michigan, Ann Arbor, MI

Activation of E2F transcription factors, through disruption of the retinoblastoma (Rb) tumor-suppressor gene, is a key event in the development of many human cancers. Previously, we showed that homozygous deletion of Rb in a prostate tissue recombination model exhibits increased E2F activity, activation of E2F-target genes, and increased susceptibility to hormonal carcinogenesis. In this study, we examined the expression of E2F1 in 667 prostate tissue cores and compared it with the expression of the androgen receptor (AR), a marker of prostate epithelial differentiation, using tissue microarray analysis. We show that E2F1 expression is low in benign and localized prostate cancer, modestly elevated in metastatic lymph nodes from hormone-naive patients, and significantly elevated in metastatic tissues from hormone-resistant prostate cancer patients (P = 0.0006). In contrast, strong AR expression was detected in benign prostate (83%), localized prostate cancer (100%), and lymph node metastasis (80%), but decreased to 40% in metastatic hormone-resistant prostate cancer (P = 0.004). Semiquantitative reverse transcription-PCR analysis showed elevated E2F1 mRNA levels and increased levels of the E2F-target genes dihydrofolate reductase and proliferating cell nuclear antigen in metastatic hormone-independent prostate cancer cases compared with benign tissues. To identify a role of E2F1 in hormone-independent prostate cancer, we examined whether E2F1 can regulate AR expression. We show that exogenous expression of E2F1 significantly inhibited AR mRNA and AR protein levels in prostate epithelial cells. E2F1 also inhibited an AR promoter-luciferase construct that was dependent on the transactivation domain of E2F1. Furthermore, using chromatin immunoprecipitation assays, we show that E2F1 and the pocket protein family members p107 and p130 bind to the AR promoter in vivo. Taken together, these results show that elevated E2F1, through its ability to repress AR transcription, may contribute to the progression of hormone-independent prostate cancer.

Chemotherapy for hormone-resistant prostate cancer: Where are we today?

Significant progress has been achieved in chemotherapy for hormone-resistant prostate cancer (HRPC) in the last five years. Although the disease was long considered to be chemoresistant, docetaxel-based regimens in particular have been shown to both palliate symptoms and prolong survival in HRPC patients. Docetaxel is now considered the best available chemotherapy for prostate cancer progressing on first-line hormonal treatment. Other cytotoxics including mitoxantrone, anthracyclines, vinorelbin and vinblastine can alleviate symptoms and improve progression-free survival in HRPC without affecting overall survival. The survival benefit from chemotherapy seen in randomized studies has been small or nonexistent. Results of a recent trial suggest that the survival benefit may have been underestimated as a result of crossover from the less active to the active arm.

Elevated E2F1 Inhibits Transcription of the Androgen Receptor in Metastatic Hormone-Resistant Prostate Cancer

Activation of E2F transcription factors, through disruption of the retinoblastoma (Rb) tumor-suppressor gene, is a key event in the development of many human cancers. Previously, we showed that homozygous deletion of Rb in a prostate tissue recombination model exhibits increased E2F activity, activation of E2F-target genes, and increased susceptibility to hormonal carcinogenesis. In this study, we examined the expression of E2F1 in 667 prostate tissue cores and compared it with the expression of the androgen receptor (AR), a marker of prostate epithelial differentiation, using tissue microarray analysis. We show that E2F1 expression is low in benign and localized prostate cancer, modestly elevated in metastatic lymph nodes from hormone-naïve patients, and significantly elevated in metastatic tissues from hormone-resistant prostate cancer patients (P = 0.0006). In contrast, strong AR expression was detected in benign prostate (83%), localized prostate cancer (100%), and lymph node metastasis (80%), but decreased to 40% in metastatic hormone-resistant prostate cancer (P = 0.004). Semiquantitative reverse transcription-PCR analysis showed elevated E2F1 mRNA levels and increased levels of the E2F-target genes dihyrofolate reductase and proliferating cell nuclear antigen in metastatic hormone-independent prostate cancer cases compared with benign tissues. To identify a role of E2F1 in hormone-independent prostate cancer, we examined whether E2F1 can regulate AR expression. We show that exogenous expression of E2F1 significantly inhibited AR mRNA and AR protein levels in prostate epithelial cells. E2F1 also inhibited an AR promoter-luciferase construct that was dependent on the transactivation domain of E2F1. Furthermore, using chromatin immunoprecipitation assays, we show that E2F1 and the pocket protein family members p107 and p130 bind to the AR promoter in vivo. Taken together, these results show that elevated E2F1, through its ability to repress AR transcription, may contribute to the progression of hormone-independent prostate cancer.

Nephrostomies in obstructive uropathy; how should hormone resistant prostate cancer patients be managed and can we predict who will benefit?

Current opinion advocates the use of nephrostomies in hormone naive patients with obstructive uropathy while hormone resistant patients require an individual approach. Patients undergoing a nephrostomy for uropathy were retrospectively analysed, with particular interest in hormone status and blood levels. Over a 46-month period, 26/112 nephrostomies were performed for prostate cancer induced uropathy. Survival was 226.5 days for hormone naive patients, 114.3 days in the responsive group and 100.2 days if resistant. Bilateral cases survived 72.1 days versus 157.6 days for unilateral patients. All patients should be considered for nephrostomy despite their hormone status.

Delayed Disease Progression after Allogeneic Cell Vaccination in Hormone-Resistant Prostate Cancer and Correlation with Immunologic Variables

There are a significant number of patients with asymptomatic hormone-resistant prostate cancer who have increasing prostate-specific antigen (PSA) levels but little or no evaluable disease. The immunogenicity and minimal toxicity associated with cell-based vaccine therapy makes this approach attractive for these patients. We have evaluated a vaccine comprising monthly intradermal injection of three irradiated allogeneic prostate cell lines (8 x 10(6) cells each) over 1 year. The first two doses were supplemented with bacille Calmette-Guérin as vaccine adjuvant. Twenty-eight hormone-resistant prostate cancer patients were enrolled. Patients were assessed clinically and PSA levels were measured monthly. Radiologic scans (X-ray, computed tomography, and bone scan) were taken at baseline and at intervals throughout the treatment period. Comprehensive monthly immunologic monitoring was undertaken including proliferation studies, activation markers, cytokine protein expression, and gene copy number. This longitudinal data was analyzed through predictive modeling using artificial neural network feed-forward/back-propagation algorithms with multilayer perceptron architecture. Eleven of the 26 patients showed statistically significant, prolonged decreases in their PSA velocity (PSAV). None experienced any significant toxicity. Median time to disease progression was 58 weeks, compared with recent studies of other agents and historical control values of around 28 weeks. PSAV-responding patients showed a titratable T(H)1 cytokine release profile in response to restimulation with a vaccine lysate, while nonresponders showed a mixed T(H)1 and T(H)2 response. Furthermore, immunologic profile correlated with PSAV response by artificial neural network analysis. We found predictive power not only in expression of cytokines after maximal stimulation with phorbol 12-myristate 13-acetate, but also the method of analysis (qPCR measurement of IFN-gamma > qPCR measurement tumor necrosis factor-alpha > protein expression of IFN-gamma > protein expression of interleukin 2). Whole cell allogeneic vaccination in hormone-resistant prostate cancer is nontoxic and improves the natural history of the disease. Longitudinal changes in immunologic function in vaccinated patients may be better interpreted through predictive modeling using tools such as the artificial neural network rather than periodic "snapshot" readouts.

Dendritic cells transfected with allo-tumor mRNA as cancer vaccine in treatment of hormone resistant prostate cancer patients

2541 Background: In this phase I/II trial, patients with hormone resistant prostate cancer and increasing PSA were vaccinated with autologous monocyte-derived dendritic cells (DCs) that have been transfected with mRNA from three prostate cancer cell lines (DU145, LNCaP and PC-3). By this strategy, we intend to make the DCs present a broad spectrum of tumor-associated antigens and elicit an immune response against tumor-associated proteins shared between the selected tumor cell lines and the individual patient. Methods: Twenty patients all with increasing PSA levels were included. Each patient received at least four weekly injections with 2x107 transfected DC. Ten patients had their DCs injected intranodally under ultrasonic guidance while 9 patients received the DCs intradermally. Safety and feasibility were evaluated, secondary end points were immune monitoring and PSA response. Immune responses were measured as DTH and by vitro immunoassays including ELISPOT, T cell proliferation test and cytotoxicity test in pre- and post-vaccination peripheral blood samples. Results: No grade II-IV toxicity and no serious adverse events were observed. Twelve patients developed a specific immune response to tumor mRNA transfected dendritic cells. In one patient HLA-A9 restricted CTL’s were generated that specifically killed an HLA-9 expressing prostate cancer cell line. Seven patients obtained stable disease by PSA evaluation (lPSA<50 % decrease and PSA< 25% increase). Ten patients showed a significant decrease in log slope PSA. Patients with lower PSA levels at inclusion had a better immunological response. Intranodal injection did not improve the results compared to intradermal vaccination. Conclusion: We conclude that our strategy of vaccinating with mRNA transfected DCs results in cellular immune responses specific for antigens encoded by mRNA derived from the prostate cancer cell lines. The observation that in some patients vaccination affected the PSA level, suggest that this approach might become potential useful as a treatment modality for prostate cancer patients. No significant financial relationships to disclose.