Together we will beat cancer

Despite the doom and gloom surrounding the pharmaceutical industry and the many commentaries highlighting inefficiencies of the sectors operating model, 2011 has proven to be a near-record year for approvals of innovative new drugs. These approvals include seven new cancer treatments with two of these (Pfizer’s crizotinib, Xalkori™ and Roche’s vemurafenib, Zelboraf™) made in conjunction with companion genetic tests, reinforcing the notion that the practice of stratified medicine has truly arrived. The forthcoming special issue of Drug Discovery Today on cancer highlights innovative contributions in basic, translational and clinical research made by UK scientists and clinicians in the fight against cancer.

In the first download Carmel Pezaro, Deborah Mukher and Johann de Bono provide an overview of the discovery and development of abiraterone acetate (AA; Zytiga™). AA is a rationally designed, oral drug that inhibits the enzyme CYP-17 and blocks androgen biosynthesis in testicular, adrenal and tumour tissue. AA was approved in 2011 in both the USA and Europe for the treatment of metastatic castration-refractory prostate cancer. The approval of AA represents a notable success for academic drug discovery and development. AA was discovered at the Institute for Cancer Research (ICR) in the Cancer Research UK Centre for Cancer Therapeutics and preclinical development and Phase I clinical trials were managed by the Cancer Research UK’s Drug Development Office.

The second download authored by Jon Travers, Swee Sharp and Paul Workman reviews progress in our understanding of intracellular protein homeostasis, and the key role of the molecular chaperone heat shock protein 90 (HSP 90) in enabling the functional and structural stabilisation of a host of client oncoproteins. The authors describe a range of different HSP 90 inhibitor chemotypes that have progressed to clinical evaluation and highlight strategies to potentially improve the clinical efficacy of second generation inhibitors. Early clinical studies with first-in-class drugs have demonstrated proof-of-mechanism for this drug class and clinical responses have been observed in some patients with advanced disease. Other therapeutic applications for HSP 90 inhibitors in protein folding disorders, such as Alzheimer’s, Parkinson’s and prion diseases are also now under investigation.

The third download from Neil Jones and Almut Schultz entitled ‘targeting cancer’s sweet-spot’ discusses how targeting cancer cell metabolism has emerged as a new area for anticancer drug discovery. Although it is now nearly 100 years since Otto Warburg first demonstrated the increased demand for nutrients displayed by tumours, progress towards exploiting this axis therapeutically has been slow to take off. The authors summarise the spectrum of metabolic pathways currently under investigation as potential intervention points, including glycolysis, the tricarboxylic acid cycle, glutaminolysis, pentose phosphate pathway, lipid and co-factors synthesis. Highlighted again in this article is the importance of academic research in furthering our understanding of the interplay between activated oncogenes and these complex metabolic networks which will be essential for the identification of the most valid targets for therapeutic intervention.

Finally, on a slightly different theme, Paul Jones from Cancer Research UK and David Jones from the UK Medicines and Healthcare products Regulatory Agency (MHRA) review the new regulatory framework for cancer drug development with specific reference to the international ICH S9 guideline on nonclinical evaluation of anticancer drugs. This guideline was introduced in 2010 with the aim of facilitating and accelerating the development of anticancer drugs where initial trials are conducted in patients with advanced cancer refractory to available therapies. The authors discuss the implications of this guideline for the design of both preclinical safety and efficacy programmes and early phase clinical trials.

Outcomes for many cancer patients have improved hugely in recent years. Nevertheless, cancer remains a devastating disease for many patients and their families. Collaboration between academic scientists, industry, regulators, physicians and patients themselves is essential if we are to make further strides in conquering this hugely complex disease and fulfilling Cancer Research UK’s stated vision that ‘together we will beat cancer’.

Dr Robert Williams is Chief Drug Development Scientist and Head of Nonclinical Operations at Cancer Research UK’s Drug Development Office. A pharmacologist by training, Dr Williams received his BSc from the University of Birmingham in 1983 and a PhD from the University of Aston in 1986. Dr Williams has worked in drug discovery and development for over 20 years holding pharmaceutical industry positions in several therapeutic areas with Glaxo and Rhone-Poulenc Rorer, and spent 4 years in the biotechnology sector before joining Cancer Research UK in 2004. Dr Williams served as Chairman of the Society for Medicines Research from 2008 to 2009, is an editorial board member for Expert Opinion on Investigational Drugs and Expert Opinion on Drug Discovery and is a regular invited speaker at International Drug Discovery and Development conferences.

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