Advanced Prostate Cancer Disease Research Articles

Advances in Research on Risk Factors for Disease Progression in Advanced Prostate Cancer

Advanced prostate cancer has mostly lost the chance of surgery, and has a low 5-year survival rate and high mortality rate. Therefore, exploring the risk factors for advanced prostate cancer disease progression can help formulate scientific and standardized treatment plans and strategies for advanced prostate cancer disease progression. Intervention measures provide evidence to improve the quality of life and survival rate of patients. Based on the existing research reports at home and abroad, I reviewed the risk factors related to the progression of advanced prostate cancer.

Epidemiology and Diagnostics of Prostate Cancer During COVID-19 Pandemic

Background: Prostate cancer (PCa) is the second most common cancerin the male population and represents a major health problem, especially in developed countries, where older men are more prevalent in the general population. Analyzing recent data for European countries, the incidence is highest in Northern and Western Europe (>200 per 100,000), while the rate is lower in Eastern and Southern Europe, but shows a continuous increase. Globally, about 450,000 Europeans are diagnosed with prostate cancer each year, and prostate cancer was the second most common cause of cancer-related deaths in 2018, when it was the cause of death for 107,000 men in Europe. Global data for BiH indicate that PCa is the second most common cancer in the male population, or the third leading cause of death in men due to cancer. Objective: The aim of this study was to analyze (PCa) how PCa screening is the most controversial topic regarding statements described in the urological literature searching most important biomedical on-line databases. Methods: Authors used descriptive method for this systematic study based on the published literature, summarized through meta-analysis, to show that screening was associated with an increase in PCa diagnosis. Results and Discussion: Most of autghors written about this topic and concluded that the greater detection of localized and less advanced PCa disease, but without benefits in the field of PCa “specific survival” and “overall survival”, “overdiagnosis” and “overtreatment”, leading to recommendations against systematic population screening in all countries, including Europe. The main diagnostic tools for diagnosing PCa are digitorectal examination (DRE), serum specific antigen concentration (PSA), transrectal ultrasonography (TRUS) and mp MRI, and the definitive diagnosis is based on pathohistological verification of cancer in prostate biopsy specimens or operative specimen. The indication for biopsy should be determined based on PSA levels and/or suspected DRE, depending on age, potential comorbidities and therapeutic consequences, and the indication for repeated biopsy is an increase or persistently elevated PSA, suspected DRE, “atypical small acinar proliferation” (ASAP), extensive high grade “prostatic intraepithelial neoplasia” (PIN) and positive multiparametric MRI of the prostate (PI-RADS ≥3). Conclusion: PCa volume assessment is based on DRE and PSA with the addition of multiparametric MRI, bone scan and CT, although there are new imaging modalities, such as PET/CT scan and Diffusion-weighted whole-body MRI. However, the cost-effectiveness” of these new approaches needs to be further assessed. Given that COVID-19 has imposed other priorities on all health systems, we hope that the diagnosis of clinically significant prostate cancer and adequate treatment is not questionable at this time.

IMPACT of putative chemopreventative agents on prostate cancer diagnosis.

e16553 Background: Prostate cancer (PC) is the most common non-cutaneous cancer in men and the third most common cause of cancer death in males. Several studies have shown that use of commonly prescribed medications, is associated with improved survival in various malignancies, including PC. There has not been any large population-based study, examining the effects of these and other commonly prescribed medications, such as proton pump inhibitors (PPI), on the rate of PC diagnosis, PC advanced disease and PC-specific death. Methods: A retrospective population-based study using data from the institute of clinical evaluative sciences, including all male patients aged 65 and above in Ontario who have had a negative first prostate biopsy between 1994 and 2016. We assessed the impact of commonly prescribed medications on PC outcomes. The analyzed medications included Statins (hydrophilic and hydrophobic), most commonly used diabetes drugs (metformin, insulins, sulfonylureas, and thizolidinedions), PPIs, 5 alpha reductase inhibitors, and alpha blockers. Time dependent Cox regression proportional hazards models were performed to determine predictors of PC diagnosis, PC advanced disease (defined as usage of hormonal therapy), and PC-specific death. Medication exposure was time varying and modelled as “ever” vs. “never” use or as cumulative exposure. Results: A total of 21,562 men were analyzed over a mean (SD) follow-up time of 8.06 (5.44) years. Overall, 5,187 patients (24%) were diagnosed with PC, 7861 (36.5%) had died, and 647 (3%) died of PC. On multivariable analysis usage of hydrophilic statins modelled as “ever vs. never” was associated with a lower diagnosis rate (OR 0.832, 95% CI 0.732-0.946, p = 0.005) and a significantly decreased PC-specific death (OR 0.676, 95% CI 0.528-0.871, p = 0.0024). In contrast, Pantoprazole was associated with a higher rate of advanced PC disease when modelled as cumulative exposure of 6 months (OR 1.03, 95% CI 1.003-1.06, P = 0.031), and PC-specific death, when modeled as “ever vs. never” (OR 1.26, 95% CI 1.02-1.576, p = 0.031). Conclusions: Hydrophilic statins were associated with a clinically and statistically significant lower PC diagnosis and PC-specific death, while pantoprazole was associated with a higher rate of advanced PC disease and PC-specific death.

The impact of plasma zinc status on the severity of prostate cancer disease.

PurposeThe severity of prostate cancer (PCa), which determines the disease progression, is theorized to be a function of zinc status. Hence, this study was structured to determine the impact of zinc status on the severity and progression of PCa disease.Materials and MethodsThis was a descriptive cross-sectional study of 220 histologically-confirmed PCa patients and 220 age-matched controls, conducted prospectively in a Nigerian tertiary hospital. Plasma zinc, prostate-specific antigen, creatinine, fasting glucose, and estimated glomerular filtration rate were determined for both study groups. The International Society of Urological Pathology (ISUP) grades and the American Joint Committee on Cancer clinical staging were employed as indices for PCa severity (grade) and progression (stage) respectively.ResultsThe PCa patients had markedly reduced plasma zinc status compared to controls (cases: 9.42±3.02 µmol/L versus controls: 15.23±4.47 µmol/L; p<0.001). Low zinc status was more pronounced within the severe grade and advanced PCa disease subgroups (p<0.001). Inverse relationships existed between zinc status and ISUP grades among the entire PCa patient (p<0.001) and the categorized PCa grade and stage subgroups (p<0.001). Low zinc status had significant impact of predicting severe (crude=odds ratio [OR], 8.714; p<0.001; age-adjusted=OR, 11.152; p<0.001) and advanced (crude=OR, 17.160; p<0.001; age-adjusted=OR, 18.927; p<0.001) PCa disease.ConclusionsThis study suggests that low plasma zinc status is associated with severe grade and advanced PCa disease. However, further well-designed studies with large sample sizes are warranted to confirm these associations.

Fibroblast growth factor signaling as a bypass mechanism of the androgen receptor pathway: new perspectives for castrationresistant prostate cancer

Till now, prostate cancer (PC) appears among the most critical public health concerns in men in developed as well as developing countries. Androgens operating through androgen receptor (AR) nourish the development and function of normal prostate and may pathologically contribute to PC in case of any deformation or deregulation (1). Based on this, inhibiting the production of androgens by castration or their effects by using anti- AR agents is employed as a treatment of advanced PC disease. However, in most instances, upon therapy, cancer will develop in a form called castrate-resistant prostate cancer (CRPC).

Targeting aggressive prostate cancer-associated CD44v6 using phage display selected peptides.

There is a crucial need to identify new biomarkers associated with aggressive prostate cancer (PCa) including those associated with cancer stem cells (CSCs). CD44v6, generated by alternative splicing of CD44, has been proposed as a CSC biomarker due to its correlation with aggressive PCa disease. We hypothesized that phage display selected peptides that target CD44v6 may serve as theranostic agents for aggressive PCa. Here, a 15 amino acid peptide (“PFT”) was identified by affinity selection against a peptide derived from the v6 region of CD44v6. Synthesized PFT exhibited specific binding to CD44v6 with an equilibrium dissociation constant (Kd) of 743.4 nM. PFT also bound CD44v6 highly expressed on human PCa cell lines. Further, an aggressive form of PCa cells (v6A3) was isolated and tagged by a novel CSC reporter vector. The v6A3 cells had a CSC-like phenotype including enriched CD44v6 expression, enhanced clonogenicity, resistance to chemotherapeutics, and generation of heterogeneous offspring. PFT exhibited preferential binding to v6A3 cells compared to parental cells. Immunohistofluorescence studies with human PCa tissue microarrays (TMA) indicated that PFT was highly accurate in detecting CD44v6-positive aggressive PCa cells, and staining positivity was significantly higher in late stage, metastatic and higher-grade samples. Taken together, this study provides for the first time phage display selected peptides that target CD44v6 overexpressed on PCa cells. Peptide PFT may be explored as an aid in the diagnosis and therapy of advanced PCa disease.

Urokinase plasminogen activator receptor (uPAR) as a novel biomarker in prostate cancer.

183 Background: New biomarkers are warranted to distinguish between indolent and aggressive prostate cancer (PCa). The urokinase plasminogen activator receptor (uPAR) plays an important role in pericellular proteolysis by binding urokinase plasminogen activator (uPA). This is required for degradation of the extracellular matrix and for cancer invasion. In addition to binding uPAR, uPA cleaves uPAR liberating uPAR(I) and uPAR(II-III). Intact, uPAR(I-III), and uPAR(II-III) can be liberated from the cell surface resulting in three different uPAR forms in circulation. The different uPAR forms are strong prognostic markers in several cancers. We measured the uPAR forms in plasma from patients with different stages of PCa. Methods: Between February 1, 2012 and October 1, 2014, 400 patients with PCa (se table) had plasma samples obtained. The levels of intact uPAR [uPAR(I-III)], intact uPAR + cleaved uPAR domains II+III [uPAR(I-III) + uPAR(II-III)], and cleaved uPAR domain I [uPAR(I)] were determined in citrated plasma samples with two-site sandwich time-resolved fluorescence immunoassays (TR-FIAs). Results: Plasma uPAR(I-III) + uPAR(II-III) and uPAR(I) were significantly higher in hormone naïve patients and CRPC patients compared to patients with localized disease (see table). Quantification of intact uPAR(I-III) revealed no significant differences between the three groups. Conclusions: Our findings suggest that uPAR(I-III) + uPAR(II-III) and uPAR(I) are associated with higher tumor stage as well as advanced PCa disease. These associations suggest that uPAR domains in plasma harbour prognostic value for PCa patients. Further studies are warranted to validate the use of uPAR forms as biomarkers for PCa. [Table: see text]

Abstract A38: Maternal embryonic leucine zipper kinase (MELK) is upregulated in high-grade prostate cancer

Abstract Loss of cell cycle control is a prerequisite for cancer onset and progression. In prostate cancer, increased activity of cell cycle proliferating genes has been associated with prognostic parameters such as biochemical relapse and survival. The identification of novel oncogenic and druggable targets in patient subgroups with poor prognosis may help to develop targeted therapy approaches. We analyzed prostate cancer and corresponding benign tissues (n = 98) using microarrays. The comparison of high and low grade tumors (Gleason score ≥ 4+3 vs. ≤ 3+4) revealed 144 differentially expressed genes (p &amp;lt; 0.05), which are associated with a severe disease course. Out of these, 15 genes are assigned to cell cycle process. The gene maternal embryonic leucine zipper kinase (MELK) was identified to be highly correlated with cell cycle and prostate cancer associated genes like UBE2C, TOP2A, CCNB2 and AURKB, and was therefore further included into validation and functional experiments. The association between MELK gene expression and high-risk prostate cancer was validated in an independent patient cohort (p &amp;lt; 0.005, n = 79). Furthermore, our finding was supported by a public microarray dataset showing a higher MELK expression in prostate cancer patients with biochemical relapse. Immunohistochemical analysis using a tissue microarray (n = 94) revealed increased MELK protein expression in prostate cancer tissues of high Gleason scores. Knockdown of MELK decreased cell viability in PC3 and LNCaP cells. Microarray analysis upon MELK knockdown experiments revealed downstream processes like chromatin modification, embryonic development and cell migration. Our findings indicate that the protein serine/threonine kinase MELK represents a promising marker for advanced prostate cancer disease. Citation Format: Ruprecht Kuner, Holger Sültmann, Maria Fälth, Nicole Chui Pressinotti, Jan Christoph Brase, Sabrina Balaguer-Puig, Georg Schäfer, Georg Bartsch, Eberhard Steiner, Helmut Klocker. Maternal embryonic leucine zipper kinase (MELK) is upregulated in highgrade prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A38.

Expression of hypoxia inducible factor-1 alpha in matched hormone naive and castrate resistant prostate cancer specimens

Hypoxia inducible factor-1 alpha (HIF-1α) is known as an important transcription factor in endocrine tumours. It is elevated in hypoxic tumour microenvironment, increasing angiogenesis and enabling tumour cells to enter the circulation. We therefore hypothesised that patients with advanced prostate cancer disease have high tumoural HIF-1α xpression and worse disease specific survival. Aim of this study was to assess expression of HIF-1α in prostate cancer specimens taken before and after castrate resistance to address its cellular location and to examine if this is associated with clinicopathological features and clinical outcome of the particular prostate cancer cohort. 50 pairs of hormone naive and castrate resistant prostate cancer specimens were analysed employing tissue microarray technology. Immunohistochemistry was performed using an antibody to HIF-1α.HIF-1α expression was observed in both, cytoplasm and nucleus. Cytoplasmic HIF-1α expression correlated positively with metastases at diagnosis (p=0.005), whereas nuclear HIF-1α expression correlated with metastases at relapse (p=0.041). Cytoplasmic and nuclear HIF-1α expression did not change from hormone naive to hormone castrate resistant tumours. No significant association was observed in this study between tumoural HIF-1α expression, biochemical relapse and patient survival. HIF-1α was associated with the presence of metastases at time of diagnosis and time of relapse. HIF-1α is likely to play a role in progressive prostate cancer.

RHAMM (CD168) Is Overexpressed at the Protein Level and May Constitute an Immunogenic Antigen in Advanced Prostate Cancer Disease

Localized prostate cancer (CaP) can be cured using several strategies. However, the need to identify active substances in advanced tumor stages is tremendous, as the outcome in such cases is still disappointing. One approach is to deliver human tumor antigen-targeted therapy, which is recognized by T cells or antibodies. We used data mining of the Cancer Immunome Database (CID), which comprises potential immunologic targets identified by serological screening of expression libraries. Candidate antigens were screened by DNA microarrays. Genes were then validated at the protein level by tissue microarrays, representing various stages of CaP disease. Of 43 targets identified by CID, 10 showed an overexpression on the complementary DNA array in CaP metastases. The RHAMM (CD168) gene, earlier identified by our group as an immunogenic antigen in acute and chronic leukemia, also showed highly significant overexpression in CaP metastases compared with localized disease and benign prostatic hyperplasia. At the protein level, RHAMM was highest in metastatic tissue samples and significantly higher in neoplastic localized disease compared with benign tissue. High RHAMM expression was associated with clinical parameters known to be linked to better clinical outcome. Patients with high RHAMM expression in the primaries had a significantly lower risk of biochemical failure. The number of viable cells in cell cultures was reduced in blocking experiments using hormone-sensitive and hormone-insensitive metastatic CaP cell lines. Acknowledging the proven immunogenic effects of RHAMM in leukemia, this antigen is intriguing as a therapeutic target in far-advanced CaP.

RHAMM (CD168) is overexpressed on the protein level and may constitute an immunogenic antigen in advanced prostate cancer disease

5129 Introduction: Treatment options for early stage prostate cancer are well defined, and localized prostate cancer can be cured by several strategies. However therapeutic outcome in advanced tumor stages is still disappointing. One approach is to deliver targeted therapy based on identified human tumor antigens, specifically expressed in neoplastic tissue and recognised by CD4/CD8 T-cells or antibodies. Materials and Methods: We employed serological identification of antigens by recombinant expression cloning (SEREX) and data mining in SEREX related databases to identify potential immunological target structures. Consequently, candidate antigens were screened by DNA microarrays consisting of approximately 20K genes, designed to profile benign and malignant prostate tissues. Genes overexpressed on the cDNA level were evaluated on the protein level by tissue microarrays representing various disease stages including about 900 tissue cores. Protein expression was measured by the Chromavision system. Results: Ten of the targets identified by SEREX and data mining showed a significant overexpression on the 20k cDNA array in localized prostate cancer compared to benign prostatic hyperplasia and in metastases compared to localized prostate cancer. One gene which has been identified earlier as an immunogenic antigen in leukemia by our group, CD168, showed a highly significant overexpression in prostate cancer metastases compared to localized disease (p=0.007). On the protein level CD168 was highest in metastatic tissue samples and significantly higher in neoplastic localized disease compared to benign tissue (p=0.03). High CD168 expression had an association to clinical parameters known to be associated with better clinical outcome. Patients with high CD168 expression in the primaries had a significantly lower risk for biochemical failure (log rank p=0.023; RR:0.621). In cell culture experiments, the number of viable cells was reduced in blocking experiments using hormone sensitive (LNCaP) and hormone insensitive metastatic (PC3 and DU 145) prostate cancer cell lines. Conclusion: Acknowledging the proven immunogenic effects of CD168 in leukemia, this antigen is an intriguing therapeutic target in advanced prostate cancer disease. No significant financial relationships to disclose.

Metabolic susceptibility genes and prostate cancer risk in a southern European population: the role of glutathione S-transferases GSTM1, GSTM3, and GSTT1 genetic polymorphisms.

Glutathione S-transferase (GST) metabolic enzymes may be involved in the development of human cancer. Genetic polymorphisms have been reported in GSTM1, GSTM3, and GSTT1 with functional alterations and influencing cancer risk. We analyzed DNA samples from 335 (670 alleles) unrelated individuals, 185 community control subjects, and 150 prostate cancer (PC) patients, for GSTM1, GSTM3, and GSTT1 genotypes using polymerase chain reaction (PCR). The analysis of the frequencies from the 670 alleles indicates that men carrying two B-alleles (GSTM3) have increased risk for PC (OR = 5.50, 95% confidence interval (CI) 1.2-25.8; P = 0.016). Multivariate logistic regression analysis confirmed this association (OR = 5.2, 95% CI 1.1-25.0; P = 0.036). No increased PC risk was observed for men carrying any of the GSTM1 or GSTT1 genotypes (OR = 1.20, 95% CI 0.75-1.90; P = 0.420 for GSTM1 null and OR = 0.87, 95% CI 0.50-1.51; P = 0.550 for GSTM1 null). However, GSTT1 null was overrepresented in men with advanced PC disease (P = 0.038). Our results indicate that polymorphism in the GSTM3 may be an important biomarker for PC risk, especially in the definition of the genetic risk profile of populations of southern Europe.

Long-term treatment results of elderly patients with prostate cancer in Japan: an analysis of prognostic factors.

The management of elderly patients with prostate cancer is an important issue because the incidence of prostate cancer is high in old men, and people are also living longer today. The present retrospective study was therefore conducted to evaluate the long-term clinical outcome of elderly patients with prostate cancer and to analyze the prognostic factors. Between 1980 and 1992, 151 patients aged 75 to 89 years old were diagnosed as having prostate cancer. The patients were initially managed by hormonal therapy in 117, radical prostatectomy in 11, external radiotherapy in 20, chemotherapy in 1 and no treatment in 2 cases. The clinical outcome of the patients was analyzed in relation to clinical stage, histological grade and treatment methods received. By univariate analysis, the stage and treatment methods were significant variables for overall and cause-specific survival rates, and grade was a significant variable for cause-specific survival rate of the patients. However, multivariate analysis revealed that stage was the only independent prognostic factor for overall as well as cause-specific survival of the patients. Among the patients with stage A2-B disease, a comparison between those treated definitively and non-definitively revealed no difference in terms of overall and relative survival rates. The presence of advanced prostate cancer disease had the greatest impact on the survival of the elderly patients. On the other hand, localized prostate cancer was satisfactorily managed with non-definitive almost as well as with definitive treatment.