Clinical development of immunotherapy for prostate cancer

Prostate cancer is the most common cancer in men, and the second leading cause of cancer‐related death in Western countries. Prostate cancer‐related death occurs in patients with metastatic castration‐resistant prostate cancer. Although several new drugs for castration‐resistant prostate cancer have been approved, each of these has prolonged survival by just a few months. Consequently, new therapies are sorely needed. Recently, it has been recognized that immunotherapy is an effective treatment for prostate cancer patients. Several strategies, such as cancer vaccines and immune checkpoint inhibitors, have been investigated in clinical studies for prostate cancer patients. In the present review, the results of the most recent clinical studies investigating immunotherapy in prostate cancer patients are reported, and the future clinical development of immunotherapy for prostate cancer is discussed.     

Brachytherapy: Update and results

Prostate cancer is the most common noncutaneous malignancy and the second most common cause of cancer mortality in American men. Treatment options for these patients include radical prostatectomy, external beam radiation therapy, hormonal therapy, and prostate brachytherapy. Patients with clinically and radiographically localized disease, especially young patients with few comorbid illnesses, are good candidates for prostate brachytherapy. Prostate brachytherapy has gained widespread acceptance throughout the past two decades and data from several large series of patients are now available. This article describes current techniques, treatment issues, and clinical results of permanent seed implants.     

Molecular detection of prostate cancer: a role for GSTP1 hypermethylation

OBJECTIVE: Prostate cancer is a leading cause of cancer-related mortality and morbidity in Western world. Curative treatment is feasible provided the disease is diagnosed in its earliest stages, but current screening methodologies are characterized by low specificity. DNA-based markers are a class of new and promising tools for cancer detection. Promoter hypermethylation is a common epigenetic alteration affecting cancer-related genes. METHODS: We critically reviewed the most relevant reports on prostate cancer detection using DNA methylation analysis in prostate tissue and body fluids. RESULTS: The epigenetic silencing of the glutathione-S-transferase P1 (GSTP1) gene is the most common (>90%) genetic alteration so far reported in prostate cancer. Methylation-specific PCR (MSP) methods allowed for the successful detection of GSTP1 methylation in body fluids (serum, plasma, urine, and ejaculates) from prostate cancer patients. In addition, the development of highly specific quantitative MSP assays augmented standard histopathology for the diagnosis of prostate cancer in tissue biopsies, accurately distinguishing benign from malignant prostate lesions. CONCLUSIONS: Further advances in the epigenetic characterization of prostate cancer are likely to yield powerful tools for patient diagnosis and management.     

Prognostic factors in localised prostate cancer with emphasis on the application of molecular techniques

Prostate cancer is the most prevalent malignancy in males in the Western world and the second leading cause of male cancer death. Prostate specific antigen (PSA) based screening and case finding leads to identification of early stage prostate cancer. It is often difficult to discriminate between patients that need curative treatment and those that can be managed conservatively. Prognostic factors are used to make this clinical decision.Based on the classification proposed by the American College of Pathologists and the World Health Organisation, selected prognostic factors in prostate cancer are described. Clinical applicable factors are stage, grade and serum PSA. Prognostic factors that are not routinely used (for various reasons) are ploidy, histological type and cancer volume in needle biopsies. All other factors (including circulating tumour cells, angiogenesis, growth factors, proliferation rate, apoptosis, nuclear morphometry, neuroendocrine differentiation, loss of chromosomal regions, tumour suppresser genes and adhesion molecules) are promising as prognostic factor although currently their use in clinical decisions is not recommended. The role of these factors in prostate cancer growth and their predictive value are discussed.The rapid developments in molecular techniques allow assessment of structure or function of thousands of genes in a prostate biopsy sample. We expect that molecular characterisation of tumour material will become a clinically important tool to predict prognosis in patients with localised prostate cancer.     

前列腺癌干细胞研究进展

前列腺癌是男性患者中最常见的癌症,严重危害男性的健康.目前关于前列腺癌的发病理论并不能完全解释该疾病异质性、转移性生长、耐药性和肿瘤复发的机制.前列腺干细胞是前列腺中具有自我再生和增殖功能的异质亚群,能产生构成前列腺上皮的所有细胞谱系.根据癌症干细胞假说,前列腺癌可能是一种干细胞疾病.前列腺癌干细胞具有明显的克隆形成性...     

Localised and Locally Advanced Prostate Cancer: Who to Treat and How?

Prostate cancer is the third most common cause of male death in Europe. In 2004, prostate cancer accounted for 85,200 deaths, equating to 8.9% of all male cancer deaths. In recent years, heightened awareness of the disease and increased prostate-specific antigen screening have resulted in an overall rise in the incidence of prostate cancer detection, with more young men presenting with earlier stage (ie, localised or locally advanced) disease. For many patients diagnosed with prostate cancer, especially for those who wish to maintain an active life, quality of life is of paramount importance. The challenge, therefore, is to identify which patients will benefit most from the different treatment options available. In this article we present two clinical scenarios to facilitate discussion of the treatment options available for two patients—one with localised disease and another with asymptomatic locally advanced disease—who are both anxious to avoid death from prostate cancer.     

Prostate imaging modalities that can be used for complementary and alternative medicine clinical studies

This article provides an overview of imaging modalities that aid in diagnosing, staging, and assessing therapeutic response in prostate cancer. Prostate cancer is the second most common type of cancer in American men and the second leading cause of cancer death among men. Prostate cancer is difficult to diagnose in early stages, and advanced disease often recurs after treatment. To localize sites of recurrence many imaging modalities have been used with varying success. This article presents case studies of PET scanning using carbon 11 acetate and discusses intravenously infused ascorbate, a complementary and alternative medicine therapy for prostate cancer.     

Gene polymorphisms and prostate cancer: the evidence

OBJECTIVE

Prostate cancer is still the most frequent noncutaneous male malignancy and is the second most common cause of cancer death. Genetic factors have been extensively studied in different countries. In addition, numerous genome–wide association studies have been performed in developed countries. Genetic tests will be applied in the near future for diagnosis, therapeutic, and prognostic significance. Therefore, we reviewed the association of several important pathways and genes with critical functions in prostate cancer development or progression.

MATERIALS AND METHODS

We performed a PubMed® search using several key words such as prostate cancer, names of important genes with critical function, and polymorphisms. Then, we reviewed retrieved articles as well as relevant articles from 1997 to 2009.

RESULTS

There are conflicting results of studies on some gene polymorphisms in association with prostate cancer. Most of the inconsistent results have been reported in studies investigating the vitamin D receptor gene polymorphism in association with prostate cancer. Genes related to angiogenesis and cell adhesion genes are more promising. Following results of future studies, the use of antibodies blocking over‐expressed genes or proteins may be supported in patients with prostate cancer.

CONCLUSIONS

The difference between the results of studies on gene polymorphisms in prostate cancer may be explained partly by ethnic differences, limited sample size, and other risk or protective factors modifying these effects. Genome‐wide studies are currently performed in developed countries and extensive use of this type of analysis may merit consideration in other countries. Furthermore, future studies are needed to further investigate environmental and diet factors interactions with genetic factors.     

The prostate: an increasing medical problem.

The prostate gland is the major site of medical problems in the U.S. male. Surgery for benign prostatic hyperplasia is the most common surgical procedure performed in males, and the total cost for this surgery exceeds 1 billion dollars per year. The incidence of and mortality from prostate cancer are increasing yearly. Prostate cancer now exceeds lung cancer as the most commonly diagnosed cancer in males and is the second leading cause of male cancer deaths. Of all tumors, the prevalence of prostate cancer increases the most rapidly with age. A shift in age distribution favoring an older population will lead to an increase in the number of patients diagnosed with prostate cancer in the United States. It is estimated that by the year 2000 there will be a 37% increase in prostate cancer deaths per year and a 90% increase in prostate cancer cases per year. Although the factors responsible for the development and progression of prostate cancer to a clinically manifest form are not known, there is evidence that environmental factors may play a role. It will be important for the future to focus on the etiological factors that may lead to a decrease in the prevalence of prostatic tumors.     

Screening of differentially expressed genes and identification of AMACR as a prognostic marker in prostate cancer

Prostate cancer, the second most common cancer found in male over the world, was estimated to have 191,930 new cases and 33,330 deaths in 2020 in the United States. Prostate cancer is very common in male, about 12.1% of men will acquire this cancer in their lifetime, and a higher risk was reported in older men and African American men. Gene deregulations have been found to be extensively associated with cancer development. To gain further insight into how gene deregulation affects prostate cancer, we analysed three gene profiling datasets of prostate cancer from Gene Expression Omnibus (GEO) applying bioinformatic tools in our study. Firstly, we identified common differently expressed genes (DEGs) shared by the three gene profiling datasets, constructed protein–protein interaction network and determined top 10 hub genes. Further DEGs validation in TCGA and Human Protein Atlas Database identified AMACR as the core gene. We then analysed the role of AMACR in prostate cancer cell lines and found that AMACR-knockdown resulted in the decreased cell proliferation and increased apoptosis. These results suggest an oncogenic role of AMACR in prostate cancer, and it could be a potential biomarker for the diagnosis of prostate cancer.     

Cancer immunomics: using autoantibody signatures in the early detection of prostate cancer

Prostate cancer remains the most common malignancy among men and the second leading cause of cancer death of men in the United States. Although measurement of prostate-specific antigen (PSA) has led to earlier detection of many prostate cancers, new serum biomarkers are still needed to improve the accuracy of prostate cancer detection. Considerable evidence has shown that an immune response in the form of autoantibodies to various tumor antigens develops in many patients with cancer. By using phage-epitope microarray analysis, we were able to identify peptides expressed by prostate cancer tissue, which commonly induce formation of autoantibodies in the sera of patients with prostate cancer. Using a panel of 22 peptides, we were able to detect prostate cancer with a specificity of 88.2% and a sensitivity of 81.6%. These results were significantly better than PSA, especially among men with a PSA between 4 and 10 ng/ml. Measurement of the immune response to prostate cancer, as well as other malignancies, has the potential to improve significantly the detection of these cancers and possibly assist in the determination of prognosis.     

Biopsy-proven brain metastases from prostate cancer: a series of four cases with review of the literature

Aims

Prostate cancer is very common and is the second most common cause of cancer death in males in Australia; however, brain metastases are exceedingly rare.

Materials and methods

We review four cases of biopsy-proven brain metastases from prostate cancer and review the relevant literature.

Results

Three of four patients had acinar adenocarcinoma of prostate with one patient having ductal adenocarcinoma variant on histopathology. Three patients had the brain as the only site of metastatic disease. All patients underwent surgery, and three of four patients underwent adjuvant palliative radiotherapy to the brain.

Conclusion

Brain metastases from prostate cancer are rare, but brain metastases without other sites of metastatic disease are exceedingly rare and may be more common with ductal adenocarcinoma variant.     

Considerations for the use of gonadotropin-releasing hormone agonists and antagonists in patients with prostate cancer

Prostate cancer is the second most common cause of cancer-related deaths in men, representing a major source of morbidity and mortality. Androgen deprivation therapy is the primary treatment for patients with advanced prostate cancer at disease presentation, which can be achieved either with surgical or chemical castration. The development of gonadotropin-releasing hormone agonists revolutionized the treatment of advanced prostate cancer, replacing the need for surgical castration. Agonists downregulate gonadotropin-releasing hormone agonist receptors in the pituitary gland, and thus decrease the release of luteinizing hormone and testosterone. Although agonists are a common therapeutic option to date, their use is associated with testosterone surges, metabolic dysfunction and an increase in the risk of cardiovascular disease; they might contribute to tumor flares and potentially an increase in non-cancer mortality. More recently, gonadotropin-releasing hormone antagonists have entered the prostate cancer treatment landscape. Unlike agonists, antagonists directly inhibit the androgen receptor in the pituitary gland, and thus do not cause initial testosterone surges. In this article, we provide a concise review of the mechanism of actions, safety and efficacy of the approved agonists and antagonists for prostate cancer treatment.     

Androgen receptor aberrations in the era of abiraterone and enzalutamide

Prostate cancer is the most prevalent non-skin cancer and the second leading cause of cancer death in men of the western world. As growth and differentiation of prostate cancer largely depend on androgens, inhibition of the androgen/androgen receptor signaling axis is the main treatment for locally advanced and/or metastatic tumors. Although first-line androgen deprivation therapies like chemical/surgical castration and/or administration of anti-androgens are able to control the disease for several years, prostate cancer almost invariably recurs as castration-resistant prostate cancer. This stage of the disease is characterized by a sustained AR-signaling despite castrate levels of circulating androgens. Various molecular mechanisms were shown to induce castration resistance. This review will discuss the most recent and relevant experimental findings on AR-signaling in castration-resistant prostate cancer in order to provide a comprehensive interpretation of the clinical behavior of this tumor entity following treatments with abiraterone, enzalutamide, ARN-509 or taxanes.     

慢性前列腺炎在前列腺癌发生发展中作用研究进展

前列腺癌是泌尿外科常见的恶性肿瘤,越来越受到人们的广泛关注。其具体发病机制不详,近年来研究发现慢性前列腺炎症与前列腺癌的发生密切相关。本文主要针对慢性前列腺炎和前列腺癌的相关性及其可能存在的机制途径作一综述。     

Genetic analysis of the principal genes related to prostate cancer: A review

Prostate cancer is one of the most common leading causes of cancer death in men. Attributable to many genetic linkage and genome-wide association studies (GWAS) around the world, several high-penetrance genetic variants have been identified. Many polymorphisms in genes, such as ELAC2 (locus HPC2), RNase L (locus hereditary prostate cancer 1 gene [HPC1]), and MSR1 have been recognized as important genetic factors that confer an increased risk of developing prostate cancer in many populations. A review of the literature was then performed analyzing the roles of these and other genes in prostate cancer. Our main challenge is optimizing the role of these genes in prostate cancer development, even trying to use these genes as general biomarkers. The principal aim of this review is to determine the most important variants in the principal genes related to prostate cancer and examine the differences among populations. The concept of individualized or personalized targeted cancer therapy has gained significant attention throughout oncology. In prostate cancer, the creation of a personalized panel of single-nucleotide polymorphisms (SNP) biomarkers may be important for the early and accurate detection of this cancer. As a result, the need for a good biomarker is required to detect prostate cancer earlier and to provide tools to follow patients during the early stages of the cancer. At present, prostate cancer continues to have an unclear etiology, which is a combination of genetic and numerous environmental factors. Among genetic factors, no variants of the RNase L, ELAC2, or MSR1 genes have been detected with similar expression patterns in different populations all around the world.     

Multidrug resistance gene (MDR1) expression in human brain tumors.

Multidrug resistance for many types of cancer outside the central nervous system (CNS) has been found to be due to the overexpression of the multidrug resistance gene MDR1, of which the gene-product P-glycoprotein acts as a membrane-bound efflux pump for many anticancer drugs. To examine whether brain tumors overexpress the MDR1 gene, 25 brain-tumor specimens were subjected to Northern blot analysis: 10 gliomas, eight meningiomas, three schwannomas, one malignant lymphoma, and three tumors metastatic to the brain. Ten fresh-frozen autopsy specimens of various parts of normal brain were also analyzed. Blots were hybridized with 32P-labeled Chinese hamster complementary deoxyribonucleic acid (cDNA) and 32P-labeled human MDR1 cDNA. The MDR1 gene messenger ribonucleic acid (mRNA) was detected in two tumors using the Chinese hamster probe (one sphenoid wing meningioma and one metastatic prostate tumor) and in one CNS lymphoma using the human probe. Intact mRNA could not be extracted from the fresh-frozen autopsy specimens of normal brain. Seventeen tumors were examined for P-glycoprotein by immunohistochemical staining using murine monoclonal antibody C219: eight gliomas, eight meningiomas, and one craniopharyngioma. The neoplastic cells from two gliomas and three meningiomas and the blood vessels within six gliomas and two meningiomas stained positively for P-glycoprotein. Seven of 10 normal brain specimens stained positively for P-glycoprotein in blood vessels but no specimen demonstrated staining of parenchymal cells. This study demonstrates that the MDR1 gene can be detected in normal brain, and in malignant, benign, and metastatic lesions. P-glycoprotein can be present in tumor blood vessels even when it is not seen in neoplastic cells. Although the role of P-glycoprotein in tumor blood vessels needs to be further examined and more clearly defined, drug resistance in malignant primary brain tumors may result from characteristics not solely of neoplastic cells but also tumor vasculature.     

Association between ABCB1 (MDR1) gene 3435 C>T polymorphism and colchicine unresponsiveness of FMF patients

The multidrug resistance gene-1 (MDR1, adenosine triphosphate-binding cassette transporter: ABCB1, P-glycoprotein) encodes membrane proteins that play a crucial role in protecting cells from xenobiotics, chemicals, and drugs. The TT genotype of 3435 codon in exon 26 of MDR1 gene causes overexpression of gene activity and effluxes many chemically diverse compounds across the plasma membrane. We studied the association between C3435T polymorphisms (single nucleotide polymorphism) of MDR1 gene and colchicine-resistant familial Mediterranean fever (FMF) patients. Total genomic DNA samples from 52 FMF patients of colchicine unresponsiveness were used for FMF (MEFV) and MDR1 genes profile analyses. Target genes were genotyped by multiplex PCR-based reverse-hybridization Strip Assay method. The preliminary current results showed increased T allele frequency (0.596) in colchicine unresponsiveness of FMF patients. The distributions of the CC, CT, and TT genotypes in colchicine nonresponder FMF patients were 17%, 46%, and 37%, respectively. Our results indicate that C3435T polymorphism in exon 26 of MDR1 gene is associated with colchicine resistance in nonresponder FMF patients during the common therapy protocol.     

A computational bioinformatics analysis of gene expression identifies candidate agents for prostate cancer

Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males worldwide. Although great progress has been made, the molecular mechanisms of prostate cancer are far from being fully understood and treatment of this disease remains palliative. In this study, we sought to explore the molecular mechanism of prostate cancer and then identify biologically active small molecules capable of targeting prostate cancer using a computational bioinformatics analysis of gene expression. A total of 3068 genes, involved in cell communication, development, localisation and cell proliferation, were differentially expressed in prostate cancer samples compared with normal controls. Pathways associated with signal transduction, immune response and tumorigenesis were dysfunctional. Further, we identified a group of small molecules capable of reversing prostate cancer. These candidate agents may provide the groundwork for a combination therapy approach for prostate cancer. However, further evaluation for their potential use in the treatment of prostate cancer is still needed.