CNS drug development - lost in translation?

CNS drug development is characterized by an especially high attrition rate, despite clear unmet medical needs in the field of neuro-pharmacology and significant investment in R of novel CNS drug treatments. Here, we overview the issues underlying the intrinsic difficulty of CNS drugs development, including obstacles of pharmacokinetic nature and lack of predictivity of preclinical tests. We highlight current efforts to overcome these limitations, with an emphasis on modeling opportunities towards early recognition of CNS candidates (stressing the possibilities of multi-target directed ligands or "magic shotguns") and different approaches to improve CNS bioavailability.     

Animal models to guide clinical drug development in ADHD: lost in translation?

We review strategies for developing animal models for examining and selecting compounds with potential therapeutic benefit in attention-deficit hyperactivity disorder (ADHD). ADHD is a behavioural disorder of unknown aetiology and pathophysiology. Current understanding suggests that genetic factors play an important role in the aetiology of ADHD. The involvement of dopaminergic and noradrenergic systems in the pathophysiology of ADHD is probable. We review the clinical features of ADHD including inattention, hyperactivity and impulsivity and how these are operationalized for laboratory study. Measures of temporal discounting (but not premature responding) appear to predict known drug effects well (treatment validity). Open-field measures of overactivity commonly used do not have treatment validity in human populations. A number of animal models have been proposed that simulate the symptoms of ADHD. The most commonly used are the spontaneously hypertensive rat (SHR) and the 6-hydroxydopamine-lesioned (6-OHDA) animals. To date, however, the SHR lacks treatment validity, and the effects of drugs on symptoms of impulsivity and inattention have not been studied extensively in 6-OHDA-lesioned animals. At the present stage of development, there are no in vivo models of proven effectiveness for examining and selecting compounds with potential therapeutic benefit in ADHD. However, temporal discounting is an emerging theme in theories of ADHD, and there is good evidence of increased value of delayed reward following treatment with stimulant drugs. Therefore, operant behaviour paradigms that measure the effects of drugs in situations of delayed reinforcement, whether in normal rats or selected models, show promise for the future.     

Erlotinib and pantoprazole: a relevant interaction or not?

AIMS

There is increasing evidence that erlotinib exposure correlates well with treatment outcome. In this report we present a case of therapeutic drug monitoring of erlotinib in a patient with a gastric ulcer, treated with the proton pump inhibitor pantoprazole. This agent may cause an unwanted, but not always unavoidable, interaction since absorption of erlotinib is pH dependent.

METHODS

Erlotinib trough concentrations were monitored in a patient during treatment with orally and intravenously administered pantoprazole.

RESULTS

Erlotinib trough concentrations were diminished during high dose intravenously administered pantoprazole, but returned to normal when the dose was reduced and pantoprazole was administered orally.

CONCLUSIONS

More studies are needed to assess the dose dependency of the interaction between pantoprazole and erlotinib. Furthermore, we advise to monitor closely erlotinib plasma concentrations and adjust the erlotinib dose accordingly when a clinically relevant interaction is suspected and no proper dosing guidelines are available.     

Is there a world beyond bevacizumab in targeting angiogenesis in glioblastoma?

INTRODUCTION: Antiangiogenic approaches are currently the dominating experimental therapeutic strategy in glioblastoma. First enthusiasm was provoked by promising radiological response rates and an apparent clinical benefit with some of these agents. Major limitations include the modest number of durable responses, the lack of cytotoxic antitumor activity, of synergy when combined with chemotherapy and of an overall survival benefit. AREAS COVERED: We review the rationale as well as preclinical and clinical evidence for the future development of antiangiogenic agents in glioblastoma. The most prominent approach targets VEGF and includes agents such as the VEGF antibody bevacizumab, the VEGF receptor fusion protein aflibercept or the tyrosine kinase inhibitors cediranib and XL-184. Inhibition of angiogenic pathways by small molecules, for example, enzastaurin, or anti-integrin-based approaches, for example, cilengitide, represent alternative strategies. EXPERT OPINION: Enzastaurin and cediranib failed in randomized Phase III trials in recurrent glioblastoma, aflibercept in Phase II. By contrast, bevacizumab was conditionally approved in many countries. Recently completed Phase III trials for bevacizumab and cilengitide in the first-line setting will define the future role of these agents. This intense clinical trial activity reflects the hope that antiangiogenic agents will become part of the limited therapeutic options for glioblastoma.     

ASCO 2013: bevacizumab and glioblastoma – a marriage dissolution?

The prognosis of patients affected by glioblastoma (GBM) is grim albeit the integrated therapeutic approaches now available. Standard surgery followed by chemoradiation median overall survival (OS) reaches 15 months in clinical trials. Despite primary treatment, recurrence is the rule in patients with GBM and for them OS ranges from 6 to 9 months. In recent years, the therapeutic scenario has been profoundly changed in view of the promising results obtained by bevacizumab (Avastin ), the most promising anti-angiogenesis agent, in two clinical trials. The results of both trials were presented at the last ASCO meeting in Chicago. Progression free survival was significantly improved with an acceptable safety and tolerability profile but surprisingly quality of life was preserved only in the AVAGlio trial. However, both studies showed that overall survival was not improved adding bevacizumab to temozolomide and radiotherapy.     

Found in translation? Commentary on a BJP themed issue about animal models in neuropsychiatry research

This themed issue of Br J Pharmacol is dedicated to the utility and needs of animal models in psychiatry research. The following articles document strengths and weaknesses, indicate areas where better models are sorely needed and provide examples where pharmacological studies may result in mechanistic breakthrough and aid in drug development. In addition, complicating factors both in disease and treatment strategies are canvassed, such as sex differences, genetic and environmental influences. While not exhaustive, the intention was to use a number of exemplars to stimulate discussion around how animal models can aid in improving our understanding and treatment of many devastating conditions.

Linked Articles

This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-20Karl Menninger once said ‘unrest of spirit is a mark of life’, acknowledging the widespread occurrence of psychiatric disorders. According to the World Health Organisation 2014 Global Health Estimates, ‘mental and behavioural disorders’ make up 7.3% of all disability adjusted life years (DALYs) while ‘neurological conditions’ add an additional 2.9% of all DALYs. Tellingly, unipolar depression sits within the top 10 of all causes (see http://www.who.int/healthinfo/global_burden_disease/estimates/en/index2.html). As stated in the 2013 World Health Report ‘The creativity and skills of researchers should be used to strengthen investigations not only in academic centres but also in public health programmes, close to the supply of and demand for health services’(WHO, 2013). The ever-growing incidence rates for psychiatric disorders and the need for better therapeutic approaches make this somewhat generalized statement a sobering reality check. Accordingly, we have dedicated a special issue of the British Journal of Pharmacology to scrutinize animal models in the psychiatry domain and to provide some direction for the field. Better models with better validity will undoubtedly assist in knowledge advances that may facilitate drug development. One should however recognise that modelling psychiatric disorders with constellations of symptomology and comorbidity is a difficult, often impossible, task. Nevertheless, advances in modeling aspects of disorders are happening and will continue to be refined going forwards.Parenthood is a time of immense change. In addition to obvious lifestyle changes (and lack of sleep!), there is substantial physiological and behavioural plasticity. The opening review of this issue details numerous manipulations that have been used in an attempt to model aspects of post-partum mood and anxiety disorders (Perani and Slattery, 2014). For example, stress, diet, deliberate hormone fluctuation with phantom pregnancy, separation and selective breeding have all been examined in this regard. As indicated by Perani and Slattery, a major drawback in many of the studies has been a relative lack of end-point readouts and therefore a need going forward is to more broadly characterise the consequences of an individual manipulation. In addition, developing models that incorporate findings from genetic association studies is also clearly warranted.There is a recent appreciation that adolescence maybe a particularly vulnerable time for the onset of certain psychiatric diseases (O’Connor and Cryan, 2014). As highlighted by Ganella and Kim, anxiety disorders often present in childhood and early adolescence (Ganella and Kim, 2014), suggesting that early diagnosis and intervention may have long-lasting benefit. Indeed fear learning has clear developmental modulation, as has the ‘therapeutic’ process of extinction. Interestingly, in juvenile subjects it is suggested that extinction may not involve new learning but rather may be a form of erasure. This would then argue for behavioural therapies in children as soon as possible after diagnosis of an anxiety disorder (Ganella and Kim, 2014). In older subjects, extinction is well-established as an active learning process and is widely studied as a translational behavioural intervention for anxiety. Thus, there is a considerable literature detailing conditioned fear and the extinction of conditioned fear. Here, Bukalo and colleagues provide a review of the pertinent circuitry for extinction of conditioned fear and a wide range of pharmacological intervention strategies (Bukalo et al., 2014). Indeed, they conclude that despite the obvious major challenges that beset all CNS drug development, systems neuroscience advances should ultimately identify molecular targets for new therapeutics. Nevertheless, this should be paralleled by deeper investigation of behavioural approaches which would likely reach patients sooner than a new chemical entity. As with anxiety, depression also presents with cognitive impairment. The issue of cognitive affective biases in depression, and the ability to model these in animals is detailed along with pharmacological validation studies (Hales et al., 2014). While these approaches to depression are in relatively early days, studies to date suggest this as a worthy line of enquiry, potentially enabling causal mechanistic studies as well as playing a part in drug development.In addition to anxiety disorders, extinction has also been used in the context of addiction research and treatment. Perry and colleagues present a discussion of how cues and contextual stimuli regulate drug use and also relapse (Perry et al., 2014). Indeed, in the case of relapse prevention, they argue how the cues themselves can become treatment targets via active extinction training in a relevant contextual environment. This opens an arena for small molecule drugs to be employed to facilitate the learning process behind cue extinction procedures and thereby strengthen the ongoing protection against relapse. Addiction is a complex, multi-faceted disorder and often shares comorbidity with other psychiatric disorders. The relationship between impulsivity and addiction is addressed by Jupp and Dalley (2014), and examines whether treating impulsivity can also impact upon drug-seeking. Aberrant eating patterns are increasingly likened to addiction disorders due to common psychological and anatomical systems being implicated in both disorders. There are a number of models that recapitulate facets of both binge eating and anorexia nervosa (van Gestel et al., 2014). In both cases, drugs targeting monoamine systems are a major focus of preclinical and clinical investigations.In 2009, the incidence of eating disorders in the UK was 164.5 per 100,000 girls aged 15–19, almost 10-fold the number for boys of the same age (Micali et al., 2013). This exemplar highlights the need to consider sex when modeling disorders in animals. Indeed the National Institutes of Health in the US have recently unveiled policies to ensure that preclinical research they fund considers females and males in all animal studies (Clayton and Collins 2014). Two reviews address this issue and highlight how sex can interact with genetic, environmental and pharmacological mechanisms in affective disorders (Kokras and Dalla, 2014; Joel and Yankelevitch-Yahav, 2014). Indeed, it is argued that ‘sexual dimorphism’ should be abandoned and further that ‘sex differences’ are reconsidered as ‘sex interactions’ (Joel and Yankelevitch-Yahav, 2014). In a similar manner, McOmish and colleagues address critical issues of face, construct and predictive validity in animal models with the complicating factors of gene x environment interactions that are a feature of our life (McOmish et al., 2014).As mentioned above, modeling of complex behavioural disorders in animals is fraught with danger. Even if the aetiology of the human condition is known, making a robust animal model can be difficult. Consider then the task of modeling a human condition for which the aetiology is unknown! Migraine is an example of a chronic disorder for which the pathophysiology in humans is still equivocal, yet there are a number of models that have helped our understanding of specific aspects of headache and migraine (Erdener and Dalkara, 2014). Indeed, this demonstrates the need for forward and reverse translation in all animal modelling, where advances in human studies (such as imaging) can be applied to the pertinent models and findings in such models can be tested in human studies.This special issue began with post-partum disorders and wraps up with a discussion of post-stroke depression (Kronenberg et al 2014). Depression is common after stroke, and those who succumb typically show worse outcomes. Evidence is presented to show how in rodent models, fluoxetine and citalopram have shown efficacy not only to reduce post-stroke ‘depression’ but have also improved other outcomes, such as lesion size and extrafocal degeneration. This is complemented by positive trials of fluoxetine in human stroke patients, irrespective of depression status (Kronenberg et al 2014).This Special Issue therefore provides food for thought regarding conceptualizing and putting into practice animal models that have relevance in psychiatric research and drug development strategies. The purpose was not to cover every disorder, but rather highlight some examples that will hopefully stimulate debate within the field. Research areas that have been relatively neglected to date are particularly focused on. Readers are also referred to a previous Special Issue in the Journal (Green et al., 2011) that focused on other disorders such as schizophrenia, anxiety and Alzheimer’s Disease (Jones et al., 2011; Cryan & Sweeney, 2011, Van Dam and De Deyn, 2011). A major challenge going forwards is to not only incorporate new technologies and methodologies, but to constantly update and back/forward translate when appropriate. Insodoing, this approach may help us to further identify the cause(s) and possible treatments of many debilitating conditions.     

NEPA,EPA and risk assessment: Has EPA lost its way?

The EPA risk assessment practice denies the inclusion of beneficial responses in the evaluation process. This practice represents a marked deviation from the original guidelines set forth within NEPA, which required the integrated goal of environmental protection as including both a reduction in risk as well as an enhancement of health benefit. It is time for regulatory agencies such as EPA to incorporate both harm and benefit within its risk assessment process.     

Targeting βIII-tubulin in glioblastoma multiforme: from cell biology and histopathology to cancer therapeutics

Glioblastoma multiforme (GBM) is the most common, aggressive, and chemorefractory brain tumor in human adults. Notwithstanding significant discoveries in the elucidation of pathways of molecular signaling and genetics of GBM during the past 20 years there has been no breakthrough in the pharmacological treatment of this high-grade malignancy. We, and others, have previously demonstrated increased expression of βIII-tubulin in GBM asserting a link between aberrant expression of this β-tubulin isotype and a disruption of microtubule dynamics associated either with malignant tumor development de novo, or with progression and malignant transformation of a low-grade glioma into GBM. This article reviews βIII-tubulin as a promising target in the experimental treatment of GBM and examines the potential use of epothilones, a new family of anticancer agents shown to be active in βIII-tubulin-expressing tumor cells, as well as the "double hit" therapeutic concept of tumor cell sensitization to tubulin binding agents (TBAs) by βIII-tubulin silencing. The latest progress regarding the function and potential role of βIII-tubulin in aggressive tumor behavior, cancer stem cells, tumor cell hypoxia, and resistance to taxane-related compounds, is also critically appraised.     

Lost in translation? Ten years of development of histone deacetylase inhibitors in acute myeloid leukemia and myelodysplastic syndromes

Introduction: Epigenetic changes and mutations in epigenetic modifiers characterize and likely drive many cases of acute myeloid leukemia and myelodysplastic syndrome. Development of DNA methyltransferase inhibitors has been most successful in these diseases. While many epigenetic marks are potential targets of cancer therapies, histone deacetylase inhibitors (HDACi) have undergone the most advanced development to date.

Area Covered: In this review, the authors describe and discuss the biology and the clinical results of HDAC inhibitors in the settings of myeloid malignancies.

Expert opinion: While significant results have been achieved in lymphoma and myeloma, efficacy remains limited in myeloid malignancies for both single agent and HDACi based combination regimens. The redundancy and the pleiotropic activity of HDACi (on both histone and non-histone proteins) are key factors that have limited to date the selection of patients and the design of robust biomarkers. Recent advances in biology (mechanisms of resistance, immunology) and the design of a more specific third generation of HDACi are two important features that will drive the future clinical development of HDACi in myeloid malignancies.     

Targeting translation for treatment of cancer--a novel role for IRES?

Protein synthesis plays an important role in the regulation of cell proliferation. While the role of cap-dependent translation in cell transformation has been studied extensively another translation initiation mechanism, internal initiation of cellular mRNAs, emerged recently and is relatively unappreciated and poorly understood. Internal initiation is mediated by IRES elements that are found in the 5' untranslated region (5' UTR) of mRNA. Curiously, several oncogenes, growth factors and proteins involved in the regulation of programmed cell death contain IRES elements in their 5' UTRs. Internal initiation escapes many control mechanisms that regulate cap-dependent translation. In this review I will discuss the data supporting the hypothesis that selective translation of these factors may contribute to the survival of cancer cells under stressful situations, such as lack of nutrients, hypoxia, or therapy-induced DNA damage and contributes to the development and progression of cancer and to the establishment of cancer cells that are resistant to conventional therapies.