Progress of molecular targeted therapies for prostate cancers

Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients.     

Progress of molecular targeted therapies for prostate cancers

Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients.     

Prostate cancer outcome: epidemiology and biostatistics

Substantial gaps exist in our ability to accurately predict prognosis, and these gaps limit our understanding of the complex mechanisms that contribute to the greatest cancer epidemic of our time, prostate cancer. This review addresses contemporary epidemiologic and biostatistical issues in prostate cancer. It covers the science of outcome prediction and biomarker evaluation, recognition of the need to combine biomarkers to improve the accuracy of our outcome estimates and an analysis of current outcome assessment methods, including the TNM staging system and multivariate regression models. The simplicity and intuitive ease of the current TNM staging system must be balanced against its serious limitations in predictive accuracy and its loss of clinical utility. Statistical regression methods are required as we move to the new era of personalized medicine. We must implement statistical approaches that integrate the new molecular biomarkers with existing prognostic biomarkers to accurately predict which patients require treatment and to determine the optimal therapy.     

Meta-analysis of microRNA-183 family expression in human cancer studies comparing cancer tissues with noncancerous tissues

MicroRNA-183 (miR-183) family is proposed as promising biomarkers for early cancer detection and accurate prognosis as well as targets for more efficient treatment. The results of their expression feature in cancer tissues are inconsistent and controversy still exists in identifying them as new biomarkers of cancers. Therefore, to systemically evaluate the most frequently reported cancers in which miR-183 family members were up- or down-regulated is critical for further investigation on physiological impact of its aberrant regulation in specific cancers. The published studies that compared the level of miR-183 family expression in cancer tissues with those in noncancerous tissues were reviewed by the meta-analysis with a vote-counting strategy. Among the 49 included studies, a total of 18 cancers were reported, with 11 cancers reported in at least two studies. In the panel of miR-183 family members' expression analysis, colorectal cancer and prostate cancer ranked at the top among consistently reported cancer types with up-regulated feature. Bladder cancer, lung cancer and hepatocellular carcinoma were the third most frequently reported cancer types with significant over-expression of miR-96, miR-182 and miR-183 respectively. Breast cancer and gastric cancer were presented with inconsistent regulations and the members of this family had their own distinct regulated features in other different cancers. MiR-183 family, either individually or as a cluster, may be useful prognostic markers and/or therapeutic targets in several cancers. Further studies and repeat efforts are still required to determine the role of miR-183 family in various cancer progressions.     

Toll‐like receptors in prostate infection and cancer between bench and bedside

Toll‐Like receptors (TLRs) are a family of evolutionary conserved transmembrane proteins that recognize highly conserved molecules in pathogens. TLR‐expressing cells represent the first line of defence sensing pathogen invasion, triggering innate immune responses and subsequently priming antigen‐specific adaptive immunity. In vitro and in vivo studies on experimental cancer models have shown both anti‐ and pro‐tumoural activity of different TLRs in prostate cancer, indicating these receptors as potential targets for cancer therapy. In this review, we highlight the intriguing duplicity of TLR stimulation by pathogens: their protective role in cases of acute infections, and conversely their negative role in favouring hyperplasia and/or cancer onset, in cases of chronic infections. This review focuses on the role of TLRs in the pathophysiology of prostate infection and cancer by exploring the biological bases of the strict relation between TLRs and prostate cancer. In particular, we highlight the debated question of how reliable mutations or deregulated expression of TLRs are as novel diagnostic or prognostic tools for prostate cancer. So far, the anticancer activity of numerous TLR ligands has been evaluated in clinical trials only in organs other than the prostate. Here we review recent clinical trials based on the most promising TLR agonists in oncology, envisaging a potential application also in prostate cancer therapy.     

An Outlook on Ovarian Cancer and Borderline Ovarian Tumors: Focus on Genomic and Proteomic Findings

Among the gynaecological malignancies, ovarian cancer is one of the neoplastic forms with the poorest prognosis and with the bad overall and disease-free survival rates than other gynaecological cancers. Ovarian tumors can be classified on the basis of the cells of origin in epithelial, stromal and germ cell tumors. Epithelial ovarian tumors display great histological heterogeneity and can be further subdivided into benign, intermediate or borderline, and invasive tumors. Several studies on ovarian tumors, have focused on the identification of both diagnostic and prognostic markers for applications in clinical practice. High-throughput technologies have accelerated the process of biomolecular study and genomic discovery; unfortunately, validity of these should be still demonstrated by extensive researches on sensibility and sensitivity of ovarian cancer novel biomarkers, determining whether gene profiling and proteomics could help differentiate between patients with metastatic ovarian cancer and primary ovarian carcinomas, and their potential impact on management. Therefore, considerable interest lies in identifying molecular and protein biomarkers and indicators to guide treatment decisions and clinical follow up. In this review, the current state of knowledge about the genoproteomic and potential clinical value of gene expression profiling in ovarian cancer and ovarian borderline tumors is discussed, focusing on three main areas: distinguishing normal ovarian tissue from ovarian cancers and borderline tumors, identifying different genotypes of ovarian tissue and identifying proteins linked to cancer or tumor development. By these targets, authors focus on the use of novel molecules, developed on the proteomics and genomics researches, as potential protein biomarkers in the management of ovarian cancer or borderline tumor, overlooking on current state of the art and on future perspectives of researches.Key Words: Ovarian cancer, borderline ovarian tumors, markers, genomics, proteomics, oncogenes.     

The Use of Biomarker Expression to Characterize Neoplastic Processes

Biomarkers have been used by pathologists to aid the diagnosis of tumors for almost three decades. Their use has resulted in the re-evaluation and reclassification of several types of tumors. Currently, biomarkers are required to differentiate certain specific tumors with similar histologic patterns. Additional uses of biomarkers in the characterization of neoplastic processes are discussed including their use in prognosis, detecting early neoplastic processes, identifying tumor recurrence, measuring the effectiveness of various therapies (surrogate end point biomarkers), and identifying targets for novel therapies including immunotherapy and gene therapy. We propose that these newer uses of biomarkers will be just as important to pathology in the future as the uses of biomarkers in diagnosis have been over the past two decades.     

Apoptosis in prostate carcinogenesis

Development of effective therapeutic modalities for the treatment of human cancer relies heavily upon understanding the molecular alterations that result in initiation and progression of the tumorigenic process. Many of the molecular changes identified in human prostate tumorigenesis so far play key roles in apoptosis regulation. Apoptosis represents a universal and exquisitely efficient cellular suicide pathway. Since the therapeutic goal is to trigger tumor-selective apoptotic cell death (without clinically significant effects on the host), elucidation of the mechanisms underlying apoptosis deregulation will lead to the identification of specific cellular components for targeting therapeutic interventions. As our understanding of its vital role in the development and growth of the prostate gland has expanded, numerous genes that encode apoptotic regulators have been identified that are severely impaired in prostate cancer cells. In addition, the expression of apoptotic modulators within prostatic tumors appears to correlate with tumor sensitivity to traditional therapies such as hormonal ablation and radiotherapy. No strict correlation between apoptosis induction and a patient's long-term prognosis has emerged, perhaps due to the fact that the ability to achieve initial remission alone does not adequately predict long-term outcome. This review will encompass the known molecular changes intimately involved in the apoptotic pathway which have potential prognostic value in disease progression, as well as therapeutic significance in the enhancement of the apoptotic response to novel and established treatment strategies for the treatment of androgen-dependent and androgen-independent prostatic tumors. The main focus will be on the role of the transforming growth factor-beta (TGF-beta) signaling pathway, bcl-2 and the bcl-2 family members, the caspase cascade (apoptosis executioners), and the Fas pathway in induction and regulation of apoptosis following therapeutic stimuli for the management of advanced prostate cancer.     

Functional relationship and gene ontology classification of breast cancer biomarkers

Breast cancer is a complex disease that still imposes a significant healthcare burden on women worldwide. The etiology of breast cancer is not known but significant advances have been made in the area of early detection and treatment. The advent of advanced molecular biology techniques, mapping of the human genome and availability of high throughput genomic and proteomic strategies opens up new opportunities and will potentially lead to the discovery of novel biomarkers for early detection and prognostication of breast cancer. Currently, many biomarkers, particularly the hormonal and epidermal growth factor receptors, are being utilized for breast cancer prognosis. Unfortunately, none of the biomarkers in use have sufficient diagnostic, prognostic and/or predictive power across all categories and stages of breast cancer. It is recognized that more useful information can be generated if tumors are interrogated with multiple markers. But choosing the right combination of biomarkers is challenging, because 1) multiple pathways are involved, 2) up to 62 genes and their protein products are potentially involved in breast cancer-related mechanisms and 3) the more markers evaluated, the more the time and cost involved. This review summarizes the current literature on selected biomarkers for breast cancer, discusses the functional relationships, and groups the selected genes based on a Gene Ontology classification.     

Exploration of DNA methylation markers for diagnosis and prognosis of patients with endometrial cancer

The accurate diagnosis of endometrial cancer (EC) holds great promise for improving its treatment choice and prognosis prediction. This work aimed to identify diagnostic biomarkers for differentiating EC tumors from tumors in other tissues, as well as prognostic signatures for predicting survival in EC patients. We identified 48 tissue-specific markers using a cohort of genome-wide methylation data from three common gynecological tumors and their corresponding normal tissues. A diagnostic classifier was constructed based on these 48 CpG markers that could predict cancerous versus normal tissue with an overall correct rate of 98.3% in the entire repository. Fifteen CpG markers associated with the overall survival (OS) and development of EC were also identified based on the methylation patterns of the EC samples. A prognostic model that aggregated these prognostic CpG markers was established and shown to have a higher discriminative ability to distinguish EC patients with an elevated risk of mortality than the FIGO staging system and several other clinical prognostic variables. This study presents the utility of DNA methylation in identifying biomarkers for the diagnosis and prognosis of EC and will help improve our understanding of the underlying mechanisms involved in the development of EC.     

Genomic signatures associated with the development, progression, and outcome of prostate cancer

Prostate cancer remains a common cause of cancer death in men. Applications of new genomic technologies to the recent development of high-quality prostate cancer models in multiple contexts have added great molecular insight into the development of and progression to metastasis. Genomic analysis of DNA, RNA, and protein alterations allows for the global assessment of this disease and provides the molecular framework to improve risk classification, outcome prediction, and development of targeted therapies. The creation of expression profiles and signatures will allow the evaluation of cancer phenotypes and give insight into determining those with increased risk of cancer, identification of critical pathways involved in the development of cancer, prediction of disease outcome, and assessment of the response of cancer to established and novel therapies.This review focuses on highlighting recent work in genomics and on its role in evaluating potential genetic modifiers of prostate cancer and novel biomarkers that may help with prostate cancer diagnosis, its potential to provide a better understanding of prostate cancer behavior and transition to metastatic disease, and its role in current and new therapies in prostate cancer. This framework has the exciting potential to be predictive and provide personalized and individual treatment to the large number of men diagnosed with prostate cancer each year.     

Serum-based protein biomarkers for detection of lung cancer

Lung cancer is one of the most common cancers in terms of both incidence and mortality.The major reasons for the increasing number of deaths from lung cancer are late detection and lack of effective therapies. To improve our understanding of lung cancer biology, there is urgent need for blood-based, non-invasive molecular tests to assist in its detection in a cost-effective manner at an early stage when curative interventions are still possible. Recent advances in proteomic technology have provided extensive, high throughput analytical tools for identification, characterization and functional studies of proteomes. Changes in protein expression patterns in response to stimuli can serve as indicators or biomarkers of biological and pathological processes as well as physiological and pharmacological responses to drug treatment, thus aiding in early diagnosis and prognosis of disease. However, only a few biomarkers have been approved by the FDA to date for screening and diagnostic purposes. This review provides a brief overview of currently available proteomic techniques, their applications and limitations and the current state of knowledge about important serum biomarkers in lung cancer and their potential value as prognostic and diagnostic tools.     

STEAP proteins: from structure to applications in cancer therapy

The human 6-transmembrane epithelial antigen of prostate (STEAP) family comprises STEAP1, STEAP2, STEAP3, and STEAP4. All of these proteins are unique to mammals and share an innate activity as metalloreductases, indicating their importance in metal metabolism. Overall, they participate in a wide range of biologic processes, such as molecular trafficking in the endocytic and exocytic pathways and control of cell proliferation and apoptosis. STEAP1 and STEAP2 are overexpressed in several types of human cancers, namely prostate, bladder, colon, pancreas, ovary, testis, breast, cervix, and Ewing sarcoma, but their clinical significance and role in cancer cells are not clear. Still, their localization in the cell membrane and differential expression in normal and cancer tissues make STEAP proteins potential candidates as biomarkers of several cancers, as well as potential targets for new immunotherapeutic strategies for disease attenuation or treatment. This review brings together the current knowledge about each STEAP protein, giving an overview of the roles of this family of proteins in human physiology and disease, and analyzes their potential as immunotherapeutic agents in cancer research.     

The Roles of IAPs with Ubiquitin Ligase Activity in the Occurrence and Development of Malignant Tumors

The inhibitors of apoptosis proteins (IAPs) are a family of highly conserved proteins involved in apoptosis. Recent studies indicate that IAPs with RING domains act as ubiquitin E3 ligases and play an important role in the occurrence and development of malignant tumors through inhibiting the caspases and regulating MAPKs (mitogen-activated protein kinases) and NF-κB (nuclear factor kappa-B) signaling. The mechanisms of IAPs in malignant tumors are complex and diverse, including resistance to cell death, inflammatory response, invasion and metastasis. IAPs inhibit apoptosis through both intrinsic and extrinsic pathways. They promote inflammatory response and regulate immune response. Besides, they both promote and inhibit tumor cell migration. Recent studies indicated that IAPs are positively correlated with poor prognosis in most malignant tumors, and negatively correlated with poor prognosis in some other few malignant tumors. The conclusions above show that it will be particularly necessary to further explore the relationship among IAPs, the occurrence and development of malignant tumors and the prognosis of patients. This review summarizes the latest research of IAPs that serve as E3s, in particular XIAP (X-chromosome linked IAP), c-IAP1 (cellular IAP1), c-IAP2 (cellular IAP2) and ML-IAP (melanoma IAP), covering the structures, functions in the malignant tumors, the signaling pathways and their correlation with the development and prognosis of malignant tumors, as well as the progress of anti-tumor drugs and therapies for IAPs. Furthermore, this review explores the problems and challenges in the current studies, which may provide new directions and strategies for future research.     

Extracellular heat shock proteins and cancer: New perspectives

Heat shock proteins (HSPs) are a large family of molecular chaperones aberrantly expressed in cancer. The expression of HSPs in tumor cells has been shown to be implicated in the regulation of apoptosis, immune responses, angiogenesis and metastasis. Given that extracellular vesicles (EVs) can serve as potential source for the discovery of clinically useful biomarkers and therapeutic targets, it is of particular interest to study proteomic profiling of HSPs in EVs derived from various biological fluids of cancer patients. Furthermore, a divergent expression of circulating microRNAs (miRNAs) in patient samples has opened new opportunities in exploiting miRNAs as diagnostic tools. Herein, we address the current literature on the expression of extracellular HSPs with particular interest in HSPs in EVs derived from various biological fluids of cancer patients and different types of immune cells as promising targets for identification of clinical biomarkers of cancer. We also discuss the emerging role of miRNAs in HSP regulation for the discovery of blood-based biomarkers of cancer. We outline the importance of understanding relationships between various HSP networks and co-chaperones and propose the model for identification of HSP signatures in cancer. Elucidating the role of HSPs in EVs from the proteomic and miRNAs perspectives may provide new opportunities for the discovery of novel biomarkers of cancer.     

Chronic inflammation and cancer: suppressing the suppressors

Chronic inflammation typical to various chronic diseases is associated with immunosuppression, mediated primarily by immature myeloid-derived suppressor cells (MDSCs). A variety of factors induce MDSC differentiation arrest, thus manipulating the host’s immune function and suppressing the innate and adaptive immune systems, as reflected by their impaired status associated with down-regulated expression of the CD247 molecule. Such chronic inflammation-induced immunosuppressive features are also found in many tumors, generating tumor micro- and macro-environments that act as critical barriers to effective anti-tumor responses and therapies. This knowledge offers new and novel candidate immune targets for therapeutic interventions, in combination with more conventional approaches as chemotherapy, radiotherapy, and cancer cell targeted therapy. Therapeutic manipulation of chronic inflammation during cancer development is likely to enhance efficacy of treatments such as vaccinations, and adoptive T cell transfer, thus switching the chronic pro-cancer inflammatory environments into an anti-cancer milieu. Based on the functional relevance of immune networking in tumors, it is advantageous to merge monitoring immune biomarkers into the traditional patient’s categorization and treatment regiments, which will provide new prognostic and/or predictive tools to clinical practice. A better identification of environmental and tumor-specific inflammatory mechanisms will allow directing the clinical management of cancer toward a more personalized medicine.     

Detecting microRNAs of high influence on protein functional interaction networks: a prostate cancer case study

ABSTRACT: BACKGROUND: The use of biological molecular network information for diagnostic and prognostic purposes and elucidation of molecular disease mechanism is a key objective in systems biomedicine. The network of regulatory miRNA-target and functional protein interactions is a rich source of information to elucidate the function and the prognostic value of miRNAs in cancer. The objective of this study is to identify miRNAs that have high influence on target protein complexes in prostate cancer as a case study. This could provide biomarkers or therapeutic targets relevant for prostate cancer treatment. RESULTS: Our findings demonstrate that a miRNA's functional role can be explained by its target protein connectivity within a physical and functional interaction network. To detect miRNAs with high influence on target protein modules, we integrated miRNA and mRNA expression profiles with a sequence based miRNA-target network and human functional and physical protein interactions (FPI). miRNAs with high influence on target protein complexes play a role in prostate cancer progression and are promising diagnostic or prognostic biomarkers. We uncovered several miRNA-regulated protein modules which were enriched in focal adhesion and prostate cancer genes. Several miRNAs such as miR-96, miR-182, and miR-143 demonstrated high influence on their target protein complexes and could explain most of the gene expression changes in our analyzed prostate cancer data set. CONCLUSIONS: We describe a novel method to identify active miRNA-target modules relevant to prostate cancer progression and outcome. miRNAs with high influence on protein networks are valuable biomarkers that can be used in clinical investigations for prostate cancer treatment.     

Search for potential markers for prostate cancer diagnosis, prognosis and treatment in clinical tissue specimens using amine-specific isobaric tagging (iTRAQ) with two-dimensional liquid chromatography and tandem mass spectrometry

This study aimed to identify candidate new diagnosis and prognosis markers and medicinal targets of prostate cancer (PCa), using state of the art proteomics. A total of 20 prostate tissue specimens from 10 patients with benign prostatic hyperplasia (BPH) and 10 with PCa (Tumour Node Metastasis [TNM] stage T1-T3) were analyzed by isobaric stable isotope labeling (iTRAQ) and two-dimensional liquid chromatography-tandem mass spectrometry (2DLC-MS/MS) approaches using a hybrid quadrupole time-of-flight system (QqTOF). The study resulted in the reproducible identification of 825 nonredundant gene products (p < or = 0.05) of which 30 exhibited up-regulation (> or =2-fold) and another 35 exhibited down-regulation (< or =0.5-fold) between the BPH and PCa specimens constituting a major contribution toward their global proteomic assessment. Selected findings were confirmed by immunohistochemical analysis of prostate tissue specimens. The proteins determined support existing knowledge and uncover novel and promising PCa biomarkers. The PCa proteome found can serve as a useful aid for the identification of improved diagnostic and prognostic markers and ultimately novel chemopreventive and therapeutic targets.