Opinion

Vessel normalization strategies aim to increase tumour perfusion and oxygenation, and have the potential to reduce metastasis and improve responses to conventional anticancer therapies. Here, Carmeliet and Jain discuss the benefits and limitations of this emerging new treatment paradigm for cancer and other angiogenic disorders.

G-quadruplexes are four-stranded DNA structures that appear to be over-represented in the promoter region of various genes, including oncogenes such asMYC and KRAS. This article discusses evidence indicating the possibility of therapeutically modulating the transcription of such genes through the targeting of G-quadruplexes with small molecules, and considers challenges and opportunities for the development of such molecules as anticancer drugs.

The reduction in attrition rates of cancer therapeutics in the clinic requires robust translational strategies. In their Perspective, Caponigro and Sellers review historical and current uses of preclinical model systems, and discuss how these systems can be optimized for rationally predicting the therapeutic benefit of drug candidates.

Has high-throughput screening (HTS) been unfairly blamed one factor responsible for the decline in productivity in the pharmaceutical industry? This article discusses some common misconceptions about the nature and value of HTS, and argues in support of its importance as a key tool in the discovery of novel chemotypes in drug discovery and chemical biology.

The Fc (crystallizable fragment) region of therapeutic antibodies can have an important role in their safety and efficacy. This article summarizes the current knowledge of antibody Fc functionality, provides a strategy for assessing the effector functions of different classes of therapeutic antibodies and proposes a path for routine testing and controls for manufacturers of antibody products.

Data on the fraction of protein-bound drug are frequently used to guide chemical structure design and to prioritize compounds forin vivostudies. Here, the authors highlight how these practices are misleading and could result in the wrong compounds being progressed through discovery programmes.

Regulatory and economic incentives to develop drugs for rare diseases, known as orphan drugs, have resulted in substantial improvements in the treatment for patients with some such diseases. However, the advent of orphan drug development has also raised several questions, from the definition of rarity, to the pricing of orphan drugs and their impact on health-care systems. Tambuyzer considers such questions and related misconceptions with the aim of aiding future progress in the field.

Developing optimal combination strategies for molecularly targeted anticancer drugs is substantially more complex than for traditional chemotherapies. Here, Doroshow and colleagues discuss the lessons learned from the evaluation of combinations of molecularly targeted anticancer agents by the US National Cancer Institute (NCI), and highlight several new approaches that the NCI has initiated to improve the effectiveness of such combinations.

Currently, drug development is based on a consecutive phase model and Phase I clinical trials often have tolerability as their primary objective. Here, Cohen advocates new concepts for drug development that are based on pharmacological knowledge about the effects of the drug and an adaptive, cyclical development process.

The development of new protease inhibitors has proved challenging in recent years. In their Perspective, Drag and Salvesen discuss the underlying reasons for this, and how lessons learned from failures can inform future research directions in the field.

The permeation of a drug across a biological membrane is one of the most important determinants of the pharmacokinetics of a drug. Here, the authors discuss the contribution of passive transport and carrier-mediated transport to the total permeation of a drug, focusing onin vitro and in vivoresults, as well as highlighting the implications for drug discovery.

Efforts to repeat the success of pioneering molecularly targeted cancer drugs, such as trastuzumab, for particular patient populations have been hampered by factors such as a lack of correlation between the molecular markers used to select patients for treatment and the drug response. This article highlights lessons learned from the development of drugs targeting members of the epidermal growth factor receptor family, and discusses strategies to decrease the risk of failure in clinical trials by more effectively integrating molecular diagnostics into anticancer drug discovery and development.

Biomarker strategies are increasingly being applied in drug development to address the challenges posed by heterogeneity in the underlying mechanisms of disease processes and inter-patient variability in drug responses. With the aim of enhancing understanding of the regulatory significance of such biomarker data by regulators and sponsors, the US FDA initiated a programme in 2004 to allow sponsors to submit exploratory data voluntarily, without immediate regulatory impact. This article discusses a selection of case studies from the first 5 years of this programme, highlighting lessons learned.

This article explores some of the challenges and opportunities in developing personalized treatment for patients with cancer, which could improve outcomes, reduce toxicity, improve efficiency in drug development and help control the rising costs of cancer care.

Computational chemistry — in particular, virtual screening — can provide valuable contributions in hit and lead discovery. However, it seems that there are relatively few examples so far of drug discovery projects in which virtual screening has been the key contributor. This article discusses aspects that could be limiting the potential of virtual screening, and proposes key directions in which significant progress could be made.

Advanced therapy medicinal products (ATMPs) offer hope for the treatment of diseases for which therapeutic options are currently lacking. This article discusses the regulatory role of the Committee for Advanced Therapies at the European Medicines Agency, highlighting issues and challenges observed in ATMP development.

Long-term therapeutic options for the treatment of obesity are limited. In his Perspective, Cao discusses the functions of the vasculature within adipose tissue — particularly its role in tissue growth and development, and the potential of targeting adipose tissue angiogenesis as a novel anti-obesity therapy.

Proteomics techniques can be applied in drug target identification and validation, but data interpretation can be complicated by the identification of proteins in unexpected cellular locations. Here, Butler and Overall discuss the importance of recognizing that many intracellular proteins may have physiological functions in the extracellular compartment, and its implications for drug discovery.

The emerging resistance to current antimalarial drugs calls for new strategies to control the disease. This article highlights the potential of targeting the obligate short-lived hepatic forms of the malaria parasite and ways to overcome the challenges of developing drugs that will achieve this.

Orloff and colleagues describe how moving from the traditional approach to clinical trials based on sequential, distinct phases towards a more integrated strategy that increases flexibility and maximizes the use of accumulated knowledge could have a key role in improving the efficiency and cost-effectiveness of drug development. Using examples in which novel trial designs have been successfully applied, they also illustrate the use of the tools involved, such as Bayesian methodologies, and discuss the advantages and challenges for their more widespread implementation.