Treating systemic prostate cancer: emerging drug targets and therapies

Prostate cancer is the most common cancer among men and is the second most common cause of cancer death. Although more patients are now diagnosed with localised prostate cancer since the advent of prostate specific antigen (PSA) screening, 30 - 40% will develop recurrent disease even following definitive therapy with either surgery or radiation. Patients who develop recurrent disease may be treated with androgen deprivation strategies, however within 1 - 2 years, most patients will develop androgen independent prostate cancer (AIPC). While chemotherapy has been shown to have palliative benefit in this situation, there is no evidence of prolonged survival. Given the shear numbers of patients with this disease and its inexorable progression to AIPC for which no life prolonging therapy exists, there clearly is a need for improved treatment strategies for systemic prostate cancer. Research in this area includes testing combinations of previously studied chemotherapeutic agents as well as the identification and testing of novel agents. It is these drugs that are designed to target strategic pathways to improve survival and increase quality of life in these patients. In this paper, we will not review traditional chemotherapeutic agents but discuss several key potential areas of targeted therapy for prostate cancer.     

Human genomics and obesity: finding appropriate drug targets

The increasing prevalence of obesity worldwide has prompted the World Health Organization (WHO) to classify it as a global epidemic. Around the globe, more than a half billion people are overweight, and the chronic disease of obesity represents a major threat to health care systems in developed and developing countries. The major health hazards associated with obesity are the risks of developing diabetes, cardiovascular disease, stroke, osteoarthritis and some forms of cancer. In this paper, we review the prevalence of obesity and its cost to health care systems and present the relative contribution of environmental conditions and genetic makeup to the development of obesity in people. We also discuss the concept of “essential” obesity in an “obesigenic” environment. Though weight gain results from a sustained imbalance between energy intake and energy expenditure, it is only recently that studies have identified important new mechanisms involved in the regulation of body weight. The etiology of the disease is presented as a feedback model in which afferent signals inform the central controllers in the brain as to the state of the external and internal environment and elicit responses related to the regulation of food intake and energy metabolism. Pharmaceutical agents may intervene at different levels of this feedback model, i.e., reinforce the afferent signals from the periphery, target the central pathways involved in the regulation of food intake and energy expenditure, and increase peripheral energy expenditure and fat oxidation directly. Since obesity results from genetic predisposition, combined with the proactive environmental situation, we discuss new potential targets for generation of drugs that may assist people in gaining control over appetite as well as increasing total energy expenditure and fat oxidation.     

Novel targets in prostate cancer

Despite recent advances in the understanding of the cellular and molecular biology of prostate cancer, new options for the treatment of prostate cancer remain elusive. Targeted therapies have shown promising activities in many solid tumours and the growing number of targets and targeted agents is creating numerous opportunities for clinical research in advanced prostate cancer. At ASCO 2006 in Atlanta, a clinical science symposium on novel targets in prostate cancer was presented. It consisted of three abstracts, each of which was followed by a discussant who reviewed the work and placed it in the overall context of current approaches to treating prostate cancer. The three abstracts were a discussion of a new method for quantification of the androgen receptor; the impact of high-dose vitamin D plus chemotherapy on hormone refractory disease and on the risk of thromboembolic disease; and the paradoxical effects seen with the raf-kinase and vascular endothelial growth factor inhibitor sorafenib, which produced improvement in bone scans in the absence of any prostate-specific antigen responses.     

Androgen receptor: structure,role in prostate cancer and drug discovery

Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein.     

Blood-brain barrier genomics and proteomics: elucidating phenotype, identifying disease targets and enabling brain drug delivery

The blood-brain barrier (BBB) regulates the passage of material between the bloodstream and the brain. Recent genomic and proteomic studies of the BBB have identified some of the unique molecular characteristics of this vascular bed, and have reinforced the concept that the BBB is heavily involved in brain function. Genomic and proteomic techniques have also been used to analyze the molecular events underlying diseases that have BBB involvement, such as multiple sclerosis, Alzheimer's disease, stroke and HIV-1 infection. It is expected that a better understanding of the complex mechanisms that link the BBB to neurological disease will ultimately lead to the development of innovative treatments.     

Chemical genomics and emerging DNA technologies in the identification of drug mechanisms and drug targets

Chemical genomics combines chemistry with molecular biology as a means of exploring the function of unknown proteins or identifying the proteins responsible for a particular phenotype induced by a small cell-permeable bioactive molecule. Chemical genomics therefore has the potential to identify and validate therapeutic targets and to discover drug candidates for rapidly and effectively generating new interventions for human diseases. The recent emergence of genomic technologies and their application on genetically tractable model organisms like Drosophila melanogaster, Caenorhabditis elegans and Saccharomyces cerevisiae have provided momentum to cell biological and biomedical research, particularly in the functional characterization of gene functions and the identification of novel drug targets. We therefore anticipate that chemical genomics and the vast development of genomic technologies will play critical roles in the genomic age of biological research and drug discovery. In the present review we discuss how simple biological model organisms can be used as screening platforms in combination with emerging genomic technologies to advance the identification of potential drugs and their molecular mechanisms of action.     

The impact of molecular targets in cancer drug development: major hurdles and future strategies

The last decades were characterized by enormous technological advances resulting in a better understanding of disease pathologies and improvement of treatment strategies. The development of targeted drugs, whose beginning can be traced back to Paul Ehrlich’s theory of the ‘magic bullet’ approximately 100 years ago, is today widely appraised as a promising strategy to combat benign, as well as malignant, diseases. Over 40 years after US President Nixon declared the ‘war on cancer’, treatment outcome, especially of solid tumors in the advanced stages of disease, still lies far behind expectations. In this perspective article, the authors discuss the recent development of targeted cancer drugs and identify major hurdles. The authors further highlight future strategies that might improve and accelerate the drug-development process.     

Small interfering RNA therapy in cancer: mechanism,potential targets,and clinical applications

Background: Small interfering RNA (siRNA) has become a powerful tool in knocking down or silencing gene expression in most cells. siRNA-based therapy has shown great promise for many diseases such as cancer. Major targets for siRNA therapy include oncogenes and genes that are involved in angiogenesis, metastasis, survival, antiapoptosis and resistance to chemotherapy. Objectives: This review briefly summarizes current advances in siRNA therapy and clinical applications in cancers, especially in pancreatic cancer. Methods: This review article covers several aspects of siRNA therapy in cancer, which include the types of siRNA, the delivery systems for siRNA, and the major targets for siRNA therapy. Specific attention is given to siRNA in pancreatic cancer, which is our main research focus. Results/conclusion: siRNA can be introduced into the cells by using either chemically synthesized siRNA oligonucleotides (oligos), or vector-based siRNA (shRNA), which allows long lasting and more stable gene silencing. Nanoparticles and liposomes are commonly used carriers, delivering the siRNA with better transfection efficiency and protecting it from degradation. In combination with standard chemotherapy, siRNA therapy can also reduce the chemoresistance of certain cancers, demonstrating the potential of siRNA therapy for treating many malignant diseases. This review will provide valuable information for clinicians and researchers who want to recognize the newest endeavors within this field and identify possible lines of investigation in cancer.     

Functional genomics approaches for the identification and validation of antifungal drug targets

So far, antifungal drug discovery seems to have benefited little from the enormous advances in the field of genomics in the last decade. Although it has become clear that traditional drug screening is not delivering the long-awaited novel potent antifungals, little has been reported on efforts to use novel genome-based methodologies in the quest for new drugs acting on human pathogenic fungi. Although the market for a novel systemic and even topical broad-spectrum antifungal appears considerable, many large pharmaceutical companies have decided to scale back their activities in antifungal drug discovery. Here we report on some of the recent advances in genomics-based technologies that will allow us not only to identify and validate novel drug targets but hopefully also to discover active therapeutic agents. Novel drug targets have already been found by 'en masse' gene inactivation strategies (e.g. using antisense RNA inhibition). In addition, genome expression profiling using DNA microarrays helps to assign gene function but also to understand better the mechanism of action of known drugs (e.g. itraconazole) and to elucidate how new drug candidates work. No doubt, we have a long way to go just to catch up with the advances made in other therapeutic areas, but all tools are at hand to derive practical benefits from the genomics revolution. The next few years should prove a very exciting time in the history of antifungal drug discovery.     

Current and potential targets for drug design in the androgen receptor pathway for prostate cancer

Introduction: Modulating the androgen axis by different agents has been one of the most successful therapeutic interventions in the field of prostate cancer therapy. Newer agents such as abiraterone and enzalutamide have been widely adapted and have contributed to an increase in the overall survival of prostate cancer patients. However, most of these patients will develop resistance to these agents and will need chemotherapy.

Areas covered: In this review, this author discusses current agents which modulate the androgen axis, the mechanisms of resistance to these agents and investigative agents which are designed to bypass these mechanisms of resistance. Potential targets in the androgen axis and related biochemical pathways are, furthermore, identified.

Expert opinion: Understanding the mechanism of resistance to these agents is crucial in developing third generation anti-androgen agents which can potentially contribute to the longevity of prostate cancer patients to a greater extent. Besides developing more potent agents, it is also important to formulate new strategies to resensitize patients to current anti-androgen agents by carefully sequencing chemotherapy regimens and abrogating genetic changes which are known to cause resistance to anti-androgens. Combinatorial approach with immunotherapy offers prospects which may yield better results and need to be thoroughly explored.     

Pharmacotherapy for prostate cancer,with emphasis on hormonal treatments

For more than half a century, hormonal therapy has been one of the cornerstones of prostate cancer therapy. However, the position and timing of androgen deprivation therapy is continuously challenged. Nowadays, it is often combined with other types of treatment in a multi-modal approach, especially with radiation therapy. Besides the well-known luteinising hormone-releasing hormone agonists, several developments have been introduced (e.g., luteinising hormone-releasing hormone antagonists or improved depot formulations achieving a better pharmacokinetic slope and lower testosterone levels). Research developments include a better understanding of the different gonadotropin-releasing hormone isoforms, the ligand-independent transformation of the androgen receptor and androgen receptor overexpression in hormone-insensitive disease. Prostate cancer, previously thought to be chemotherapy insensitive, is now treated at the metastatic stage by taxane-based chemotherapies. The combination of hormonal therapy and chemotherapy is currently studied at various stages of the disease, as early as localised or locally advanced prostate cancer. It is very likely that, in the future, pharmacological treatment for prostate cancer will include combination therapies rather than monotherapies. The authors suggest an in-depth re-evaluation of the place of androgen deprivation therapy in prostate cancer.