Preclinical drug development for childhood cancer

Importance of the field: More effective drugs are needed to treat poor prognosis paediatric malignancies. Development of anticancer agents for childhood cancers faces several unique challenges compared with their adult counterparts.

Areas covered in this review: We demonstrate how recent advances in preclinical drug development may overcome these difficulties and challenges. We explain the role of academia, regulators and industry in this field, address issues with preclinical models and illustrate several examples of biology-driven drug development in childhood cancers.

What the reader will gain: Increased knowledge about preclinical drug development in paediatric oncology including different preclinical models, established preclinical research networks, and relationships among academia, industry and regulators, as illustrated by several examples of targeted agents in childhood solid malignancies.

Take home message: It is anticipated that emerging advanced preclinical models and testing platforms will provide a more efficient, biologically-driven rationale to support the use of targeted therapies in several malignancies such as neuroblastoma, medulloblastoma or high grade glioma which account for the majority of deaths related to childhood cancer.     

Ligand-directed profiling: applications to target drug discovery in cancer

Background: Generation of targeted therapy remains a major challenge in medicine. The development of drugs that can discriminate between tumor cells and non-malignant cells would improve efficacy and reduce general side effects. Phage display allows identification of specific supramolecular complexes that can target therapeutic compounds or imaging agents, both in vitro and in vivo. The use of phage display to identify molecules expressed on the surface of human cancer cells without bias, as well as to provide initial steps toward identification of a ligand/receptor-based map of the human microvasculature, has broad implications for drug discovery in general, especially for cancer therapy. Objective/method: In this review, we discuss the use of phage display technology as a ligand-directed targeting strategy and its applications to drug discovery. Conclusion: Compared to other existing drug discovery platforms, phage display technology has the advantage to provide valuable clues pointing to target proteins in an unbiased biological context. The result from various display library screenings indicates that in many cases the selected peptide motifs mimic biological ligands. Analysis of peptide motifs targeting a receptor provides a basis for rational drug design of targeted peptidomimetics.     

Optimizing drug development of anti-cancer drugs in children using modelling and simulation

Modelling and simulation (M&S)-based approaches have been proposed to support paediatric drug development in order to design and analyze clinical studies efficiently. Development of anti-cancer drugs in the paediatric population is particularly challenging due to ethical and practical constraints. We aimed to review the application of M&S in the development of anti-cancer drugs in the paediatric population, and to identify where M&S-based approaches could provide additional support in paediatric drug development of anti-cancer drugs. A structured literature search on PubMed was performed. The majority of identified M&S-based studies aimed to use population PK modelling approaches to identify determinants of inter-individual variability, in order to optimize dosing regimens and to develop therapeutic drug monitoring strategies. Prospective applications of M&S approaches for PK-bridging studies have scarcely been reported for paediatric oncology. Based on recent developments of M&S in drug development there are several opportunities where M&S could support more informative bridging between children and adults, and increase efficiency of the design and analysis of paediatric clinical trials, which should ultimately lead to further optimization of drug treatment strategies in this population.     

Targeted cancer drug delivery with aptamer-functionalized polymeric nanoparticles

Abstract

Based on exceptional advantages of aptamers, increasing attention has been presented in the utilise of them as targeted ligands for cancer drug delivery. Recently, the progress of aptamer-targeted nanoparticles has presented new therapeutic systems for several types of cancer with decreased toxicity and improved efficacy. We highlight some of the promising formulations of aptamer-conjugated polymeric nanoparticles for specific targeted drug delivery to cancer cells. This review paper focuses on the current progresses in the use of the novel strategies to aptamer-targeted drug delivery for chemotherapy. An extensive literature review was performed using internet database, mainly PubMed based on MeSH keywords. The searches included full-text publications written in English without any limitation in date. The abstracts, reviews, books as well as studies without obvious relating of aptamers as targeted ligands for cancer drug delivery were excluded from the study. The reviewed literature revealed that aptamers with ability to modify and conjugate to various molecules can be used as targeted cancer therapy agents. However, development of aptamers unique to each individual’s tumour to the development of personalised medicine seems to be needed.     

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.     

The clinical pharmacologist in drug discovery and development

1 Clinical pharmacology is a key activity in drug discovery and drug development with much to contribute to drug innovation.
2 However, very few clinical pharmacologists choose the pharmaceutical industry as their ultimate career.
3 Medical alumni of the RPMS clinical pharmacology department illustrate this; only four industrial careers vs thirty professors of clinical pharmacology or medicine.     

Novel approaches to anticonvulsant drug discovery

Introduction: The history of epilepsy dates back to 2000 BC. Yet, it was not until 1912 that the activity of the first antiepileptic, phenobarbital was discovered by accident. After this discovery, the next antiepileptic drugs to be discovered (phenytoin and primidone) were based on the phenobarbital's structure. Then, in 1960, carbamazepine was developed empirically, while in 1962, valproate demonstrated anticonvulsant activity against experimental seizures. The next antiepileptic drugs synthesized were either modifications of the existing drugs (such as oxcarbazepine and pregabalin) or completely novel chemical structures (lacosamide, perampanel and retigabine).

Areas covered: The present paper briefly refers to the history of epilepsy and development of antiepileptic drugs. Further, the paper provides a discussion on the antiepileptogenic effects of antiepileptic drugs in terms of the constant percentage of epileptic patients with refractory seizures. The authors also review the likely factors involved in the false refractoriness (such as through the use of caffeine-containing beverages and smoking). Finally, the authors consider future directions in the search of novel antiepileptic drugs.

Expert opinion: In spite of the considerable number of newer antiepileptic drugs, the number of drug-resistant epileptic patients remains unchanged. This may be rather an indication of the suitability of the currently available discovery procedures for effective antiepileptic drugs in the whole population of epileptic patients. The authors, however, believe that it is likely that models of mimic chronic epilepsy will help bridge the gaps and aid in the discovery of novel antiepileptic drugs – ones that can effectively modify the course of the disease.     

iPSCs and small molecules: a reciprocal effort towards better approaches for drug discovery

The revolutionary induced pluripotent stem cell (iPSC) technology provides a new path for cell replacement therapies and drug screening. Patient-specific iPSCs and subsequent differentiated cells manifesting disease phenotypes will finally position human disease pathology at the core of drug discovery. Cells used to test the toxic effects of drugs can also be generated from normal iPSCs and provide a much more accurate and cost-effective system than many animal models. Here, we highlight the recent progress in iPSC-based cell therapy, disease modeling and drug evaluations. In addition, we discuss the use of small molecule drugs to improve the generation of iPSCs and understand the reprogramming mechanism. It is foreseeable that the interplay between iPSC technology and small molecule compounds will push forward the applications of iPSC-based therapy and screening systems in the real world and eventually revolutionize the methods used to treat diseases.     

Current mathematical models for cancer drug discovery

Introduction: Pharmacometric models represent the most comprehensive approaches for extracting, summarizing and integrating information obtained in the often sparse, limited, and less-than-optimally designed experiments performed in the early phases of oncology drug discovery. Whilst empirical methodologies may be enough for screening and ranking candidate drugs, modeling approaches are needed for optimizing and making economically viable the learn-confirm cycles within an oncology research program and anticipating the dose regimens to be investigated in the subsequent clinical development.

Areas covered: Papers appearing in the literature of approximately the last decade reporting modeling approaches applicable to anticancer drug discovery have been listed and commented. Papers were selected based on the interest in the proposed methodology or in its application.

Expert opinion: The number of modeling approaches used in the discovery of anticancer drugs is consistently increasing and new models are developed based on the current directions of research of new candidate drugs. These approaches have contributed to a better understanding of new oncological targets and have allowed for the exploitation of the relatively sparse information generated by preclinical experiments. In addition, they are used in translational approaches for guiding and supporting the choice of dosing regimens in early clinical development.     

Found in translation: integrated approaches to drug development

Anidulafungin is the most recently approved compound of the echinocandin antifungal class. Its mode of action is the noncompetitive inhibition of β–(1,3)-D-glucan synthesis. Potent fungicidal activity has been demonstrated against many Candida spp., including non-albicansCandida spp. and fluconazole-resistant strains, as well as fungistatic activity against Aspergillus spp. Owing to low oral bioavailability, it can only be administered intravenously. Anidulafungin is not metabolized by the liver and renal clearance is negligible, thus rendering dosage adjustments in patients with impaired hepatic or renal function unnecessary. Due to lack of interference with the cytochrome P450 pathway, it displays minimal drug–drug interaction. Anidulafungin has been approved by the US FDA for the treatment of esophageal and invasive candidiasis after clinical trials demonstrated its noninferiority to fluconazole. In September 2007, anidulafungin gained EMEA approval for the treatment of invasive candidiasis in adult non-neutropenic patients. For those with invasive or noninvasive candidiasis with resistance or intolerance to fluconazole in particular, as well as those requiring antifungal medication, that anidulafungin does not interact with concomitant medication means it may be regarded as a safe and efficacious treatment option. Promising results from animal models and experience with the other echinocandins indicate several potential lines of investigation: invasive aspergillosis, prophylaxis and treatment of transplant patients, and empirical treatment in patients with febrile neutropenia. Significant differences in clinical efficacy or safety favoring anidulafungin over the other echinocandins are yet to be discovered.     

Drug discovery and development: lessons from an undeveloped drug

In this article, drug discovery and preclinical development paradigms, as employed in today’s pharmaceutical companies, are discussed. The antimalarial drug, artemisinin, is given as an example of a compound that is unlikely to be developed by a modern pharmaceutical company, yet is a safe and effective drug for the treatment of a deadly disease. It is argued that the use of prespecified charts, listing undesired properties to deselect molecules may lead to missed opportunities in bringing best-in-class medications to patients. Implementation of systems pharmacology, disease progression and pharmacokinetic/pharmacodynamic models are proposed. These models offer a superior approach in selecting the best drug candidates with the highest chance of success of entry into the market.     

Positron emission tomography (PET): Expanding the horizons of oncology drug development

Positron emission tomography (PET) allows three-dimensional quantitative determination of the distribution of radioactivity permitting measurement of physiological, biochemical, and pharmacological functions at the molecular level. Until recently, no method existed to directly and noninvasively assess transport and metabolism of neoplastic agents as a function of time in various organs as well as in the tumor. Standard preclinical evaluation of potential anticancer agents entails radiolabeling the agent, usually with tritium or ¹⁴C, sacrifice experiments, and high-performance liquid chromatography (HPLC) analysis to determine the biodistribution and metabolism in animals. Radiolabeling agents with positron-emitting radionuclides allows the same information to be obtained as well as in vivo pharmacokinetic (PK) data by animal tissue and plasma sampling in combination with PET scanning. In phase I/II human studies, classic PK measurements can be coupled with imaging measurements to define an optimal dosing schedule and help formulate the design of phase III studies that are essential for drug licensure [1]. Many of the novel agents currently in development are cytostatic rather than cytotoxic and therefore, the traditional standard endpoints in phase I and II studies may no longer be relevant. The use of a specialized imaging modality that allows PK and pharmacodynamic (PD) evaluation of a drug of interest has been proposed to permit rapid and sensitive assessment of the biological effects of novel anticancer agents. The progress to date and the challenges of incorporating PET technology into oncology drug development from the preclinical to clinical setting are reviewed in this article.     

Advances in preclinical approaches to Chagas disease drug discovery

ABSTRACT

Introduction: Chagas disease affects 8–10 million people worldwide, mainly in Latin America. The current therapy for Chagas disease is limited to nifurtimox and benznidazole, which are effective in treating only the acute phase of the disease but with severe side effects. Therefore, there is an unmet need for new drugs and for the exploration of innovative approaches which may lead to the discovery of new effective and safe drugs for its treatment.

Areas covered: The authors report and discuss recent approaches including structure-based design that have led to the discovery of new promising small molecule candidates for Chagas disease which affect prime targets that intervene in the sterol pathway of T. cruzi. Other trypanosome targets, phenotypic screening, the use of artificial intelligence and the challenges with Chagas disease drug discovery are also discussed.

Expert opinion: The application of recent scientific innovations to the field of Chagas disease have led to the discovery of new promising drug candidates for Chagas disease. Phenotypic screening brought new hits and opportunities for drug discovery. Artificial intelligence also has the potential to accelerate drug discovery in Chagas disease and further research into this is warranted.     

Reducing QT liability and proarrhythmic risk in drug discovery and development

Drug-induced torsades de pointes (TdP), a rare, life-threatening, polymorphic, ventricular tachycardia associated with prolongation of the QT interval, has been the main safety reason for the withdrawal of medicines from clinical use over the last decade. Most often, drugs that prolong the action potential and delay ventricular repolarization do so through blockade of outward (repolarizing) currents, predominantly the rapid delayed rectifying potassium current, I_Kr. While QT interval prolongation is not a safety concern per se, in a small percentage of people, it has been associated with TdP, which either spontaneously terminates or degenerates into ventricular fibrillation. Furthermore, recent data suggest that shortening of the QT interval may also be a new safety issue waiting to surface. This review article summarizes the presentations given at a symposium entitled ‘Reducing QT liability and proarrhythmic risk in drug discovery and development’, which was part of the Federation of the European Pharmacological Societies congress, Manchester, UK, 13–17 July 2008. The objective of this symposium was to assess the effects of implementing the latest regulatory guidance documents (International Conference on Harmonization S7A/B and E14), as well as new scientific and technical trends on the ability of the pharmaceutical industry to reduce and manage the QT liability and associated potential proarrhythmic risk, and contribute to the discovery and development of safer medicines. This review outlines the key messages from communications presented at this symposium and attempts to highlight some of the key challenges that remain to be addressed.This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010     

放疗联合靶向药物治疗食管癌的研究进展

在我国,食道癌是癌症死亡的第四大最常见的原因,严重威胁人类的健康。手术是食管癌治疗的重要方式,但对于不可手术的进展期食管癌患者,放化疗是其标准的治疗方式。然而目前的治疗方式预后仍然欠佳。因此,有必要开发更有效的新药融入该综合治疗模式中。靶向药物联合放疗在头颈部肿瘤治疗中已被证实能使患者获益。本综述集中阐述了在食管癌治疗中靶向药物的安全性及有效性,同时指出靶向药物与放射治疗相结合显示了良好的耐受性及令人满意的近期疗效,值得更深入的临床试验进一步研究。     

Challenges for drug discovery and development in China

Introduction: The drug development industry is restructuring worldwide in terms of the research and development process. As with pharmaceuticals in the west, China faces major challenges for drug discovery and development.

Areas covered: In this review, the authors discuss anti-cancer, anti-allergy, anti-infectious, and proprietary Chinese Medicines (pCM) for various chronic diseases (such as the allergic diseases: eczema, asthma and allergic rhinitis), which remain the contemporary therapeutic strategies that are being explored and developed. Drug transporters, disease specific biomarkers, pharmacophores, bioactive natural products and pharmacogenetics are some aspects of research technologies. Proprietary Chinese medicine remains one of the most popular strategies. There is however the issue of good research documentation of efficacy versus adverse effects. China has a complex healthcare system involving a large patient pool.

Expert opinion: Various factors can impact drug development in China including the concurrent use of both western and Chinese medicines, pharmacogenetic variances, lack of multidisciplinary team impact on disease management and drug safety. China may adopt the current development of big data analysis in other countries such as UK and US to build and centralize a nationwide database for better monitoring and clinical evaluation to provide more efficient care at a lower cost.     

Structural biology approaches to antibacterial drug discovery

Antibacterial drug discovery has undertaken a major experiment in the 12 years since the first bacterial genomes were sequenced. Genome mining has identified hundreds of potential targets that have been distilled to a relatively small number of broad-spectrum targets (‘low-hanging fruit’) using the genetics tools of modern microbiology. Prosecuting these targets with high-throughput screens has led to a disappointingly small number of lead series that have mostly evaporated under closer scrutiny. In the meantime, multi-drug resistant pathogens are becoming a serious challenge in the clinic and the community and the number of pharmaceutical firms pursuing antibacterial discovery has declined. Filling the antibacterial development pipeline with novel chemical series is a significant challenge that will require the collaboration of scientists from many disciplines. Fortunately, advancements in the tools of structural biology and of in silico modeling are opening up new avenues of research that may help deal with the problems associated with discovering novel antibiotics.