Biomarkers In Metastatic Prostate Cancer Research Articles

Prognostic value of bone scan index as an imaging biomarker in metastatic prostate cancer: a meta-analysis.

BackgroundThe prognostic value of the bone scan index (BSI) in metastatic prostate cancer (mPCa) remained controversial. Therefore, we performed a meta-analysis to determine the predictive value of BSI and survival in patients with mPCa.Materials and MethodsA literature search was performed in PubMed, Embase, Web of Science and Cochrane library databases. Hazard ratios (HRs), concordance indices (C-indices) were extracted to estimate the relationship between BSI and survival in patients with mPCa. Subgroup analyses were conducted on different types of mPCa, ethnics, cut-off values and sample sizes.Results14 high quality studies involving 1295 patients with mPCa were included in this meta-analysis. The pooled results indicated that high basline BSI and elevated BSI change on treatment (ΔBSI) were significantly predictive of poor overall survial (HR = 1.29, P < 0.001; HR = 1.27, P < 0.001, respectively). Baseline BSI was also significantly related to cancer specific survival (HR = 1.65, P = 0.019) and prostate specific antigen recurrence survival (HR = 2.26, P < 0.001). Subgroup analysis supported main results. Moreover, BSI could increase the C-indices of predictive models.ConclusionsBaseline BSI and ΔBSI may be beneficial to mPCa prognosis in clinical monitor and treatment. Further high quality studies with larger sample size are required in the future.

Comparative Proteomics Uncovers Correlated Signaling Network and Potential Biomarkers for Progression of Prostate Cancer

Background/Aims: Prostate cancer is one of the most common cancers for males worldwide, and it is prone to show the metastatic foci in lymph node and bone with high mortality. To date, the potential mechanism and the corresponding biomarkers for metastatic prostate cancer are still lacking. Hence, our study aims to clarify the mechanism of prostate cancer progression and identify the useful biomarkers for metastatic prostate cancer. Methods: The proteins and network tightly associated with tumor metastasis were identified using quantitative proteomics. Furthermore, the mRNA level of differential expressed proteins were confirmed using qRT-PCR, and the functional cluster analysis was performed using String and Cytoscape. Results: Totally, our study identified 203 differential proteins closely associated with tumor cell migration, and the mRNA expression of those proteins were verified by qPCR. Moreover, the migration associated molecular network was established using bioinformatics analysis. Conclusion: These data raveled the critical proteins for the cell migration of prostate cancer, and identified the potential markers for diagnosing the metastasis of prostate cancer.

A Treatment-Specific Predictive Biomarker in Metastatic Castration-Resistant Prostate Cancer

Despite the introduction of next-generation androgen receptor (AR)–targeted agents for patients with metastatic prostate cancer, resistance — either

SFMBT2 (Scm-like with four mbt domains 2) negatively regulates cell migration and invasion in prostate cancer cells.

Metastatic prostate cancer is the leading cause of morbidity and mortality in men. In this study, we found that expression level of SFMBT2 is altered during prostate cancer progression and has been associated with the migration and invasion of prostate cancer cells. The expression level of SFMBT2 is high in poorly metastatic prostate cancer cells compared to highly metastatic prostate cancer cells. We also found that SFMBT2 knockdown elevates MMP-2, MMP-3, MMP-9, and MMP-26 expression, leading to increased cell migration and invasion in LNCaP and VCaP cells. SFMBT2 interacts with YY1, RNF2, N-CoR and HDAC1/3, as well as repressive histone marks such as H3K9me2, H4K20me2, and H2AK119Ub which are associated with transcriptional repression. In addition, SFMBT2 knockdown decreased KAI1 gene expression through up-regulation of N-CoR gene expression. Expression of SFMBT2 in prostate cancer was strongly associated with clinicopathological features. Patients having higher Gleason score (≥ 8) had substantially lower SFMBT2 expression than patients with lower Gleason score. Moreover, tail vein or intraprostatic injection of SFMBT2 knockdown LNCaP cells induced metastasis. Taken together, our findings suggest that regulation of SFMBT2 may provide a new therapeutic strategy to control prostate cancer metastasis as well as being a potential biomarker of metastatic prostate cancer.

Non-coding RNAs as biomarkers for metastatic prostate cancer

Non-coding RNAs as biomarkers for metastatic prostate cancer

Identification of a long non-coding RNA as a novel biomarker and potential therapeutic target for metastatic prostate cancer

Metastatic prostate cancer (PCa) is still an incurable disease. Long non-coding RNAs (lncRNAs) may be an overlooked source of cancer biomarkers and therapeutic targets. We therefore performed RNA sequencing on paired metastatic/non-metastatic PCa xenografts derived from clinical specimens. The most highly up-regulated transcript was LOC728606, a lncRNA now designated PCAT18. PCAT18 is specifically expressed in the prostate compared to 11 other normal tissues (p<0.05) and up-regulated in PCa compared to 15 other neoplasms (p<0.001). Cancer-specific up-regulation of PCAT18 was confirmed on an independent dataset of PCa and benign prostatic hyperplasia samples (p<0.001). PCAT18 was detectable in plasma samples and increased incrementally from healthy individuals to those with localized and metastatic PCa (p<0.01). We identified a PCAT18-associated expression signature (PES), which is highly PCa-specific and activated in metastatic vs. primary PCa samples (p<1E-4, odds ratio>2). The PES was significantly associated with androgen receptor (AR) signalling. Accordingly, AR activation dramatically up-regulated PCAT18 expression in vitro and in vivo. PCAT18 silencing significantly (p<0.001) inhibited PCa cell proliferation and triggered caspase 3/7 activation, with no effect on non-neoplastic cells. PCAT18 silencing also inhibited PCa cell migration (p<0.01) and invasion (p<0.01). These results position PCAT18 as a potential therapeutic target and biomarker for metastatic PCa.

Highly functional natural killer (NK) cells as predictive biomarkers associated with long response to castration in newly diagnosed metastatic prostate cancer.

95 Background: Immunotherapy is now investigated as a promising alternative treatment for patients (pts) with metastatic prostate cancer (PC). Natural killer (NK) cells are powerful effector cells with antitumoral activity and their role have been explored in solid tumors but not yet in prostate cancer. NK cell cytotoxicity is regulated by a balance between activating and inhibitory receptors. Here, we performed a restrospective study to evaluate the link between NK cells and the time of castration response in newly diagnosed PC patients with metastases. Methods: Newly diagnosed metastatic PC pts were divided according the time of castration response, with an 18-months cutoff value: 18 pts with long castration response (LCR, median = 64.6 months), and 14 pts with short castration response ([SCR] median = 11.2 months), with a median overall survival of 97.7 months and 33.8 months respectively. Circulating NK cells from these patients were studied by flow cytometry to evaluate the expression of activating receptors and the NK cell functionality. Results: We observed thatNK cells from LCR pts express higher levels of the maturation marker CD57 (43.3% vs. 23.3% positive cells, p= 0.002), the receptor CD16 involved in cytotoxicity (29,124 vs. 16,806 MFI, p= 0.02), and the activating receptors NKp46 and NKp30 (17.5 vs. 11.4 RMFI, p= 0.0146 , and 10.9 vs. 6.3 RMFI, p = 0.0128 respectively) than NK cells from SCR pts. This suggests that LCR pts have powerful NK cells. Indeed, NK cells from LCR pts are highly efficient in CD107 functional assay than NK cells from SCR pts (28.9% vs. 19.4%, p =0.002). In vitro blocking experiments show that NKp46 is precisely one of the NK cell receptors involved in the NK-mediated recognition of prostate tumor cells, thus higher expression of NKp46 would help to control PC progression. Conclusions: Together our results show for the first time that efficient NK cells are associated to a long response to castration and prolonged survival in newly diagnosed metastatic PC. NK cell receptors might be useful as predictive biomarkers in metastatic PC, to help in stratification of patients and to design NK cell–based immunotherapeutic strategies for PC.

The role of IL-23 in regulating metastatic prostate cancer through STAT-3/ROR-gamma signaling.

142 Background: Interleukin-23 (IL-23) plays an important role in expanding the Th17 cell population and induce signal transducer and activator of transcription 3 (STAT-3) to up-regulates the expression of Retinoic Acid Receptor-Related Orphan Receptor Gamma-T (ROR-gamma). STAT-3 regulates the expression of a variety of genes in response to cellular stimuli, and thus plays a key role in cell growth and apoptosis. Furthermore, recent studies identified a critical role for ROR-gamma in lineage specification of uncommitted CD4+ T helper cells into Th17 cells. The goal of this study is to evaluate prospectively the prognostic importance of circulating IL-23 in patients with metastatic prostate cancer through downstream signaling. Methods: The study involved 140 men diagnosed with stages I to IV prostate cancer and 120 healthy controls. IL-23 serum concentration measure by a quantitative enzyme immunoassay technique associated with clinical-pathological variables. Blocking IL-23 with anti-p19 Ab in mice inoculation with two types of metastatic prostate cancer cell lines (LNCaP and DU-145) to study the pathway of IL-23 in vivo by using western blot and real-time RT-PCR. Results: We found a statistically significant higher systemic IL-23 level in the metastatic group in comparison with non-metastatic group (19.32±5.35 pg/ml vs. 7.25±3.42 pg/ml, p&lt;0.05). Patients with shorter overall survival presented higher IL-23 levels, suggesting a negative prognostic correlation. Furthermore, systemic delivery of blocking Abs directed against IL-23 completely inhibited STAT3/ROR-gamma levels in mice. Conclusions: These results demonstrate that STAT3/ROR-gamma, is a downstream mediator for IL-23–induced prostate metastasis in murine mice. IL-23 may represent an attractive therapeutic target or a biomarker in metastatic prostate cancer by blocking downstream effects. However, further studies are needed in larger samples to better investigate the implications of IL-23 in prostate cancer.

WS14-6 - Plasma Prosaposin: A New Potential Biomarker for Metastatic Prostate Cancer Regulated by Sphingosine Kinase 1

ABSTRACT Background Prosaposin is a neurotrophic secreted protein that stimulates specific G-coupled receptors and is involved in cancer progression, metastasis and chemoresistance through activation of the Raf-MAPK and uPA/uPAR pathways. Here we have investigated the crossregulation of prosaposin and sphingosine kinase 1 (SK1) pathways in hormone refractory prostate cancer (PCa) models. Methods and results Prosaposin knockout mice exhibited an involution of the prostate gland which correlated with a significant reduction of prostate SK1 activity. In PCa cell lines SK1 activity correlated with the amount of secreted, but not intracellular prosaposin, indicating a role for the prosaposin/GPCR signalling. The specific knockdown of prosaposin in PCa cells induced a significant decrease in SK1 activity and expression on mRNA and protein level. Additionally, a short prosaposin peptide TX14A enhanced SK1 activity and up-regulated SK1 mRNA expression via ERK1/2-mediated mechanism. Cytokine array showed that TX14A induced a significant upregulation of MIF and PAI-1 secretion, which was abrogated by pretreatment with psap- or SphK1-specific siRNA. Increased prosaposin secretion was detected in metastatic PCa cells lines and associated with increased cancer cell motility. Subsequently, SK1 activation was essential for prosaposin secretion and expression during serum deprivation. The effect was further amplified upon overexpression of SK1 and was drastically abrogated by specific knockdown or SK1 inhibitors, which could also abrogate prosaposin-induced cancer cell migration. Analysis of PCa patients plasma samples revealed increased levels of circulating prosaposin in comparison to cancer-free controls. Conclusions These data provide evidence that SK1-dependent prosaposin secretion promotes cancer cell migration and has potential diagnostic/prognostic and therapeutic value in PCa patients.

Bone Scan Index: A Quantitative Treatment Response Biomarker for Castration-Resistant Metastatic Prostate Cancer

There is currently no imaging biomarker for metastatic prostate cancer. The bone scan index (BSI) is a promising candidate, being a reproducible, quantitative expression of tumor burden seen on bone scintigraphy. Prior studies have shown the prognostic value of a baseline BSI. This study tested whether treatment-related changes in BSI are prognostic for survival and compared BSI to prostate-specific antigen (PSA) as an outcome measure. We retrospectively examined serial bone scans from patients with castration-resistant metastatic prostate cancer (CRMPC) enrolled in four clinical trials. We calculated BSI at baseline and at 3 and 6 months on treatment and performed univariate and bivariate analyses of PSA, BSI, and survival. Eighty-eight patients were scanned, 81 of whom have died. In the univariate analysis, the log percent change in BSI from baseline to 3 and 6 months on treatment prognosticated for survival (hazard ratio [HR], 2.44; P = .0089 and HR, 2.54; P < .001, respectively). A doubling in BSI resulted in a 1.9-fold increase in risk of death. Log percent change in PSA at 6 months on treatment was also associated with survival (HR, 1.298; P = .013). In the bivariate analysis, change in BSI while adjusting for PSA was prognostic at 3 and 6 months on treatment (HR, 2.368; P = .012 and HR, 2.226; P = .002, respectively), but while adjusting for BSI, PSA was not prognostic. These data furnish early evidence that on-treatment changes in BSI are a response indicator and support further exploration of bone scintigraphy as an imaging biomarker in CRMPC.

The PCCTC imaging data capture toolset: An analysis of its impact on prostate cancer clinical trial accuracy and workload.

4635 Background: Prostate Cancer Working Group 2 (PCWG2) Concensus Criteria proposed time-to-event endpoints in early-phase clinical trials. Chief among these was time to radiographic progression for bone scintigraphy, based on a standardized definition with additional specifications to distinguish early “flare” from true progression. The Prostate Cancer Clinical Consortium (PCCTC) created a bone scan data capture tool to standardize and operationalize these definitions in clinical trials. We tested the hypothesis that the tool would improve clinical trial workload and data accuracy. Methods: At Memorial Sloan-Kettering Cancer Center (MSKCC), the PCCTC bone scan tool was vetted through 9 versions over the course of 3 years. Reproducibility, ease-of-use and accuracy were tested over the course of 12 clinical trials. To assess workload, accruals at MSKCC of two phase III trials using the same drug, contracting research organization (CRO) and electronic data capture system were analyzed. The first trial did not use the PCCTC tool and the second incorporated it in its data collection plan and case report form. Workload and data capture adequacy for each trial were determined by examining the number of imaging queries from the CRO as a function of the number of scans and patients. Results: Data from this analysis are found in the table below. The relative number of queries per scan was reduced by 86.71% by use of the tool. The queries:scan ratios were 0.82 versus 0.11 before and after the use of the tool respectively; likewise, the ratios of queries:patient were 2.81 vs. 0.56. Conclusions: Using the PCCTC bone scan data capture tool, data are more completely reported and workload is decreased. The reproducibility and feasibility of the tool is further being tested in phase III studies in which PCWG2 criteria are being clinically qualified. These efforts to quantitate, standardize and qualify imaging data advance the goal of developing an imaging biomarker in metastatic prostate cancer. Support: DOD PC071610. 2008 phase III 2009 phase III without tool with tool Patients 16 41 Queries 45 23 Scans 55 211 Avg queries/patient 2.81 0.56 Avg scans/patient 3.44 5.15 Queries/scan 0.82 0.11 Reduction in queries/scan with tool -86.71%

Abstract 4173: Prostate derived Ets (E-twenty six) transcription factor (PDEF) as a prognostic biomarker for metastatic prostate cancer

Abstract While early stage prostate cancer (CaP) is unique in that many patients will take decades to progress to symptomatic disease; there exists a subset of patients whose disease may quickly become life-threatening. Unfortunately, due to the high incidence of CaP and clinicians’ inability to differentiate the majority of patients with disease that will never become symptomatic from the minority with aggressive life-threatening tumors, patients with CaP are often over-treated. Prognostic biomarkers, such as prostate specific antigen (PSA), have shown great efficacy in improving patients’ chances of surviving cancer by allowing physicians to identify the disease at an earlier stage, though there does not exist a biomarker for CaP that adequately differentiates disease that will quickly become metastatic. In order to facilitate prognosis, the expression of prostate derived Ets transcription factor (PDEF), a protein of significance to the progression of CaP, was studied. PDEF is expressed in normal epithelial cells and negatively regulates transcriptional networks controlling migration and invasion. Previous findings in breast cancer have also demonstrated that loss of PDEF expression results in upregulation of the antiapoptotic protein survivin, indicating a possible connection to growth and survival. Loss of PDEF expression has also been shown to increase the metastatic potential of several cancers. Patients PDEF expression was determined via immunohistochemistry staining of tissue microarray in set of over 700 archival CaP tissues taken at radical prostatectomy; and patients were subsequently stratified based on their tumor PDEF expression. The stratified CaP patients were then analyzed for the association of PDEF expression status with clinical outcomes. Univariate analysis showed that low PDEF expression is correlated with incidence of biochemical failure as defined by American Urological Association (AUA; OR=1.30, p=0.0493) or National Comprehensive Cancer Network (NCCN; OR=1.36, p=0.0164) definitions; and with metastatic disease incidence (OR=3.61, p=0.0047). Multivariate analysis also showed that low PDEF expression was associated with metastatic disease incidence (OR = 4.02, p=0.0146). Furthermore, Kaplan-Meier survival analysis showed that stratification of patients into subgroups based on PDEF expression (high, middle, low) was able to significantly predict relative time to biochemical failure (NCCN, p=0.0241) or metastatic disease (p=0.0084). This study demonstrates the potential usefulness of PDEF as a prognostic biomarker to differentiate those patients at the highest risk of developing life-threatening disease. We propose that the status of PDEF expression in CaP tissues could be used in conjunction with PSA to distinguish patients who are suitable for watchful waiting and patients who require aggressive treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4173. doi:10.1158/1538-7445.AM2011-4173

The Prostate Cancer Clinical Trials Consortium (PCCTC) bone scan data capture tool for clinical trials using Prostate Cancer Working Group 2 (PCWG2) criteria: Effect on data accuracy and workload.

121 Background: PCWG2 Concensus Criteria proposed time-to-event endpoints in early phase clinical trials. Chief among these was time to radiographic progression for bone scintigraphy (BS), based on a standardized definition with additional rulesets to account for early flare. The PCCTC created a tool to operationalize these definitions in clinical trials. We tested the impact of the tool on clinical trial workload and data adequacy. Methods: The BS capture tool was vetted and amended through nine versions by a multidisciplinary group from PCCTC participating institutions. Accruals at Memorial Sloan-Kettering Cancer Center on two phase III trials using the same drug, contracting research organization (CRO), and electronic data capture system were analyzed. The first trial did not use the PCCTC tool. The second incorporated the tool in its data collection plan and case report form. Workload and data capture adequacy for each trial were determine by examining the total number of imaging queries from the database query reports obtained from the CRO as a function of the total number of scans and patients. Results: Data from this analysis are found in the table . The relative number of queries per scan was reduced by 85.33% by use of the tool. The queries:scan ratios were 0.82 versus 0.12 before and after the use of the tool respectively; likewise, the ratios of queries: patient were 2.81 vs. 0.44. Conclusions: Using the PCCTC BS tool to standardize data capture and operationalize PCWG2 radiographic progression criteria, imaging data are more completely reported and workload for study research staff decreased. The reproducibility and feasibility of the BS tool is further being tested in two ongoing phase III studies in which PCWG2 criteria are being clinically qualified. These efforts to quantitate, standardize, and qualify imaging data advance the goal of developing an imaging biomarker in metastatic prostate cancer. [Table: see text] No significant financial relationships to disclose.

Urinary c-Met, a Novel Biomarker of Metastatic Prostate Cancer

Prostate cancer remains the second most common cause of cancer deaths of men in the United States, nearly all of which are from metastatic disease. c-Met, a receptor tyrosine kinase, is overexpressed in a number of malignancies including metastatic prostate cancer. c-Met ectodomain shedding in the urine of mice has been shown to correlate with tumor burden. We hypothesized that urinary c-Met in humans may correlate with metastatic prostate cancer and that c-Met may play a central role in the development of metastatic disease.