Antisense-based cancer therapeutics: are we there yet?

Despite significant advances that have been made in recent years, there is still an urgent need for novel, more effective and less toxic therapeutics for human cancer. Among many new molecular therapeutics being explored for cancer therapy, antisense oligonucleotides are a promising nucleic acid-based approach, with numerous antisense agents being evaluated in preclinical studies and several anticancer antisense drugs in clinical trials. Although there are still a few problems facing the development of antisense strategies for cancer therapy, with progress made in chemical modifications, target selection and drug delivery systems, antisense oligonucleotides are emerging as a novel approach to cancer therapy used alone or in combination with conventional treatments such as chemotherapy and radiation therapy.     

Virtual screening: are we there yet?

The cost of pharmaceutical development has increased dramatically in recent years, and many assorted approaches have been developed to decrease both the time and costs associated with bringing a drug to the market. Among these methods is the use of in silico screening of compound databases for potential new lead compounds, commonly referred to as virtual screening (VS). Virtual screening has become an integral part of the early discovery process in pharmaceutical development, readily observed by the large number of methodologies that have been published to date. Other reviews have been published detailing the various types of virtual screening methods in use. This work will review some of the virtual screening approaches and strategies that have been attempted to identify compounds to launch medicinal chemistry campaigns. Understanding trends and drivers in VS should help to set expectations about how and when VS could be used and what it can and cannot deliver and how it can be integrated in a successful screening campaign and used in a complementary fashion to HTS.     

Chemotherapy in Japanese encephalitis: are we there yet?

Chemotherapy in Japanese encephalitis (JE) is at present entirely supportive and not targeted at the virus. There are no available drugs to effectively counter the viral infection, thereby making the fight against JE a daunting task. With approximately 50,000 reported cases per year, nearly 10,000 deaths and 3 billion people living in endemic regions, it is imperative that the hunt for an effective drug be expedited. Prophylactic measures are effective against JE, but the problem plaguing all is the underdevelopment and inefficiency of medical services in developing countries. Combined to that are difficulties to earn a living and illiteracy, that leaves significant proportions of the population in these countries uninformed about the magnitude of the threat and uninterested in the potential benefits of prophylactic strategies. Thus, for such countries coming under the JE endemic region, the need for developing therapeutic strategies that are cheap, easily available and with no or tolerable side effects, becomes significant. With rapid globalization and a gradual shift in global climate, JEV, like many other flaviviruses, may emerge in newer areas. This review is an effort to briefly outline the chemotherapeutic approaches adopted over the years in developing effective therapeutic countermeasures against this deadly disease and highlights the promising avenues that need to be treaded in order to win the war against JEV.     

Pharmacogenetically driven treatments for alcoholism: are we there yet?

Pharmacogenetic analyses of treatments for alcohol dependence attempt to predict treatment response and side-effect risk for specific medications. We review the literature on pharmacogenetics relevant to alcohol dependence treatment, and describe state-of-the-art methods of pharmacogenetic research in this area. Two main pharmacogenetic study designs predominate: challenge studies and treatment-trial analyses. Medications studied include US FDA-approved naltrexone and acamprosate, both indicated for treating alcohol dependence, as well as several investigational (and off-label) treatments such as sertraline, olanzapine and ondansetron. The best-studied functional genetic variant relevant to alcoholism treatment is rs1799971, a single-nucleotide polymorphism in exon 1 of the OPRM1 gene that encodes the μ-opioid receptor. Evidence from clinical trials suggests that the presence of the variant G allele of rs1799971 may predict better treatment response to opioid receptor antagonists such as naltrexone. Evidence from clinical trials also suggests that several medications interact pharmacogenetically with variation in genes that encode proteins involved in dopaminergic and serotonergic neurotransmission. Variation in the DRD4 gene, which encodes the dopamine D(4) receptor, may predict better response to naltrexone and olanzapine. A polymorphism in the serotonin transporter gene SLC6A4 promoter region appears related to differential treatment response to sertraline depending on the subject's age of onset of alcoholism. Genetic variation in SLC6A4 may also be associated with better treatment response to ondansetron. Initial pharmacogenetic efforts in alcohol research have identified functional variants with potential clinical utility, but more research is needed to further elucidate the mechanism of these pharmacogenetic interactions and their moderators in order to translate them into clinical practice.     

Treat-to-target in systemic lupus erythematosus: are we there yet?

The treat-to-target (T2T) strategy has proven benefits in several chronic medical illnesses including rheumatoid arthritis. Whether the T2T principle can be applied to SLE has become a recent topic of discussion. A European panel of rheumatologists agrees that treatment of SLE should target at multiple goals that include control of disease activity, prevention of disease flares, minimization of disease or treatment related comorbidity, and improvement of quality of life. Therapy of SLE should aim at remission or when remission cannot be achieved, the lowest possible disease activity that is assessed by a validated lupus activity index and/or organ-specific markers. However, owing to the clinical heterogeneity of SLE, there is still no consensus on the definition of remission or low disease activity state in individual organ-systems. In real life, agents readily available for therapy switching in SLE are limited. Moreover, no disease activity index is universally agreed upon for disease monitoring to make therapeutic decisions. Currently, clinical parameters for the assessment and monitoring of lupus renal disease appear to be more objective and evidence-based. A therapeutic target in terms of proteinuria and/or other renal parameters should be tested in randomized controlled trials for the proof of the T2T concept in SLE.     

Tailoring therapy for locally advanced breast cancer using molecular profiles: are we there yet?

The term 'locally advanced breast cancer' covers a range of clinical scenarios, and has the implications that surgical clearance and local control will be difficult or impossible, and long-term survival rates will be poor. Treatment selection is particularly important in this group of patients to try to obtain maximum control of disease, and potentially improve surgical options and cure rates. Currently, assessment of estrogen receptor, progesterone receptor and human epidermal receptor 2 status in tumour samples remains the gold standard for prediction of response to endocrine therapy, chemotherapy or targeted agents such as trastuzumab. Progress has been made in identifying markers that can help select treatments likely to be associated with response and avoid those associated with resistance. These potential markers include Ki67 proliferation rate, cytochrome P450 (CYP) 2D6 expression, BRCA1/2 gene status and others.     

Epigenetic screening in product safety assessment: are we there yet?

There has been a growing concern that epigenetic events, that is, heritable changes in gene expression superimposed on DNA nucleotide sequences, may be involved in chemically and/or nutritionally mediated adverse health outcomes, such as reproductive toxicity and cancer. This concern has been driven by an increasing number of studies reporting toxicant-induced alterations to the epigenome in the form of changes in DNA methylation, histone/chromatin remodeling, and altered expression of non-coding RNAs. These three major mechanisms of epigenetic modifications may have coordinated, independent, or potentially antagonistic influences on gene expression. Complicating this understanding is the incomplete understanding of the normal state and dynamic variation of the epigenome, which differs widely between cells, tissues, developmental state, age, strain, and species. This review serves as a framework to outline characteristics composing an ideal epigenetic screen(s) for hazard identification in product safety assessment. In order to implement such a screen, first there needs to be a better understanding of adaptive versus adverse changes in the epigenome, which includes identification of robust and reproducible causal links between epigenetic changes and adverse apical end points, and second development of improved reporter assay tools to monitor such changes. An ideal screen would be in vitro-based, medium- to high-throughput, and assess all three branches of epigenome control (i.e. methylation, histone modifications, non-coding RNAs), although also being quantitative, objective, portable (i.e. lab to lab), and relevant to humans.     

Epigenetic screening in product safety assessment: are we there yet?

There has been a growing concern that epigenetic events, that is, heritable changes in gene expression superimposed on DNA nucleotide sequences, may be involved in chemically and/or nutritionally mediated adverse health outcomes, such as reproductive toxicity and cancer. This concern has been driven by an increasing number of studies reporting toxicant-induced alterations to the epigenome in the form of changes in DNA methylation, histone/chromatin remodeling, and altered expression of non-coding RNAs. These three major mechanisms of epigenetic modifications may have coordinated, independent, or potentially antagonistic influences on gene expression. Complicating this understanding is the incomplete understanding of the normal state and dynamic variation of the epigenome, which differs widely between cells, tissues, developmental state, age, strain, and species. This review serves as a framework to outline characteristics composing an ideal epigenetic screen(s) for hazard identification in product safety assessment. In order to implement such a screen, first there needs to be a better understanding of adaptive versus adverse changes in the epigenome, which includes identification of robust and reproducible causal links between epigenetic changes and adverse apical end points, and second development of improved reporter assay tools to monitor such changes. An ideal screen would be in vitro-based, medium- to high-throughput, and assess all three branches of epigenome control (i.e. methylation, histone modifications, non-coding RNAs), although also being quantitative, objective, portable (i.e. lab to lab), and relevant to humans.     

Adherence: the journey of medication taking, are we there yet?

Patient adherence to medications has been an issue challenging healthcare professionals for decades. Adherence rates, causes of non-adherence, barriers and enablers to medication taking, interventions to promote adherence, and the impact of non-adherence on health outcomes, have been extensively studied. In light of this, the area of adherence research has progressed conceptually and practically. This special issue contains a range of articles which focus on different aspects of adherence, from standardising terminology and methods of measurement, to non-adherence in a broad range of patient populations, and to interventions to promote adherence.     

Alternatives to the carcinogenicity bioassay for toxicity prediction: are we there yet?

INTRODUCTION: For decades, traditional toxicology has been the ultimate source of information on the carcinogenic potential of chemicals; however, with increasing demand on regulation of chemicals and decreasing resources for testing, opportunities to accept 'alternative' approaches have dramatically expanded. The need for tools able to identify carcinogens in shorter times and at a lower cost in terms of animal lives and money is still an open issue, and the present strategies and regulations for carcinogenicity prescreening do not adequately protect human health. AREAS COVERED: This paper briefly summarizes the theories on the early steps of carcinogenesis and presents alternative detection methods for carcinogens based on genetic toxicology, structure-activity relationships and cell transformation assays. EXPERT OPINION: There is evidence that the combination of Salmonella and structural alerts for the DNA-reactive carcinogens, and in vitro cell transformation assays for nongenotoxic carcinogens, permits the identification of a very large proportion of carcinogens. If implemented, this alternative strategy could improve considerably the protection of human health.     

Investigational drugs for the management of Huntington’s disease: are we there yet?

Introduction: Huntington’s disease is a hereditary neurodegenerative disease. It is designated as a rare disease in the US, which means there are < 200,000 patients in the country who suffer from it. The drugs that are currently used to treat this disease were not designed specifically for it but developed for other diseases. Presently, two classes of drugs are being developed; those that provide symptomatic relief and those that may modify course of the disease.

Areas covered: This review is focused on seven selected drugs currently in clinical testing and describes their progress. Five of the seven drugs that are reviewed here, can be categorized as ‘symptomatic’ drugs, and, selisistat and PBT-2 are amongst the ones that would qualify as ‘disease modifying’ drugs.

Expert opinion: The authors believe that the future treatment paradigm for this disease is best met by using a disease-modifying drug that can be administered together with symptomatic drugs. Towards that end, it is important for the industry to focus on disease-modifying drugs by targeting unique pathways and targets. Furthermore, they propose that neuroprotective drugs, that is, drugs that directly work by preserving neuronal health and function is an opportunity for such disease-modifying drugs.     

Stem cell-derived hepatocytes as a predictive model for drug-induced liver injury: are we there yet?

Amongst the different types of adverse drug reactions, drug-induced liver injury is the most prominent cause of patient morbidity and mortality. However, the current available hepatic model systems developed for evaluating safety have limited utility and relevance as they do not fully recapitulate a fully functional hepatocyte, and do not sufficiently represent the genetic polymorphisms present in the population. The rapidly advancing research in stem cells raises the possibility of using human pluripotent stem cells in bridging this gap. The generation of human induced pluripotent stem cells via reprogramming of mature human somatic cells may also allow for disease modelling in vitro for the purposes of assessing drug safety and toxicology. This would also allow for better understanding of disease processes and thus facilitate in the potential identification of novel therapeutic targets. This review will focus on the current state of effort to derive hepatocytes from human pluripotent stem cells for potential use in hepatotoxicity evaluation and aims to provide an insight as to where the future of the field may lie.     

Hormone-refractory prostate cancer: where are we going?

This article addresses the current status of therapeutic options in the management of hormone-refractory prostate cancer (HRPC). Following the publication of two landmark randomised trials, docetaxel chemotherapy is now the standard of care for men with metastatic HRPC. However, the benefit of this treatment is limited. Trials are now focusing on improving the efficacy of docetaxel by combining it with novel biological agents. Several new docetaxel-based combinations are under evaluation and promising results have been found for the combination of docetaxel with angiogenesis inhibitors. Early phase III trial data for atrasentan appear interesting. New cytotoxic agents such as satraplatin and ixabepilone are being investigated in several ongoing studies in order to define their role as second-line treatments of HRPC. Vaccine therapy offers an active immunological approach for combating malignancy in a targeted manner.     

The pharmacist's guide to the future: Are we there yet?

The future of community pharmacy has always been a matter of concern for academics and practitioners alike. Recently, a paper published in this Journal brought to the discussion the importance of new technologies, such as Artificial Intelligence and Blockchain, and the emergence of market forces like Amazon or Google, to the future of the pharmacy profession. In this commentary, we offer our view about the subject, specifically focusing in the practice area of Community Pharmacy. Our choice takes into account the fact that this by far the most numerous group within the profession, and where the fear of redundancy has always been looming since the start of the Industrial Revolution. Envisioned technologies will become a reality, but by now are not mature enough to be the disrupters everyone expects. Moreover, without major shifts in the legal environment regulating the organization of health care and the provision of medicines, big players will find it difficult to substitute pharmacies. As for pharmacists, they have always adapted to the challenges presented by technological revolutions. We argue that for the coming Patient Centred era, it is more important to continue to focus on the sustainability of an enhanced role for community pharmacists, providing services that highlight pharmacists' social role, measuring outcomes, and managing populations’ health.     

Can we target the chemokine network for cancer therapeutics?

The paradigm of cancer development and metastasis has been redefined to encompass a more comprehensive interaction between the tumor and microenvironment within which the tumor cells reside. Despite the realization that this more comprehensive relationship has changed the current paradigm of cancer research, the struggle continues to more completely understand the pathogenesis of the disease and the ability to appropriately identify and design novel targets for therapy. Chemokines and chemokine receptors are being investigated for their role in tumor development and metastasis and may prove to be useful therapeutic targets. The chemokine family is a complex network of molecules that are ubiquitously expressed and perform a variety of functions most notably regulating the immune system. Here we review the importance of chemokines in the tumor-stromal interaction and discuss current concepts for targeting the chemokine network.     

Biomarkers in cancer micrometastasis: where are we at?

Despite considerable advances in the field of solid tumors, disseminated malignancy remains the cause of the vast majority of cancer-related deaths. In patients with no overt metastasis, early spread of tumor cells is usually undetected by current imaging technologies. In addition, the metastatic process is complex and depends on multiple interactions (crosstalk) of disseminating tumor cells with the individual homeostatic mechanisms, which the tumor cells can usurp. Despite these many variables, a flurry of surrogate biomarkers to detect micrometastasis has been developed in the last decade. These biomarkers open avenues for understanding cancer dormancy and metastasis, have the potential to provide novel therapeutic targets and may help predict outcome and therapeutic decisions at diagnosis and during follow-up of cancer patients. This review focuses on ongoing efforts to unravel metastasis biology, surrogate biomarkers currently investigated to monitor micrometastasis and tools used to identify, quantify and determine their capacity to efficiently establish metastasis.