Stem cells and cancer drug discovery

2 Feb 2010

Stem cells are defined as those "generalist" cells that are uniquely capable both of self-replicating through mitotic division and of differentiating into a wide variety of functional cell types, and thus they share some of the key characteristics of tumour cells. Thus, almost self-evidently, cancer can be thought of a stem cell disease. Yet the media focus of the undoubted medical potential of stem cells tends to focus on other applications, particularly on degenerative disease, and on "blue skies" approaches that are unlikely to bear practical fruit for decades. However, a recent meeting focused on stem cells in drug discovery highlighted a number of applications of these of immediate interest to the cancer research community. This meeting, held under the auspices of the UK’s Biochemical Society, took place at GlaxoSmithKline’s impressive research headquarters in Stevenage, UK. It was extremely popular; there were a number of overseas delegates and the pharmaceutical industry was particularly well represented.

Conference delegates discussed a wide range of issues concerning stem cell research and its applications. Although only one paper – an elegant study of the use of glioblastoma stem cells to screen for drugs against this disease – was specific to cancer, two more general issues that were discussed extensively have direct applications to oncology. These were the use of stem cells in in vitro assays for drug toxicity and the development of three-dimensional tissue culture systems.

Several speakers highlighted the often quoted difficulties faced by the pharmaceutical industry with blockbuster drugs coming off patent and few in the pipelines to replace them. Despite record investment, the hope (some would say hype) offered by the Human Genome Project and allied efforts, and a few notable successes such as kinase inhibitors, the number of new drug registrations is declining and the percentage of failures in late clinical trials is increasing. Toxicity, particularly cardiotoxicity and hepatotoxicity, must bear a large part of the blame for these failures. This is, of course, not a new problem in drug discovery; a useful discussion session led by a panel of industry experts tackled the question of how stem cell research could lead to new solutions to this and other "old problems". Panellists and audience members discussed how cultures derived from either human embryonic or induced pluripotent (adult) stem cells would be expected to be more relevant and reproducible, and therefore safer, than the cell cultures currently used for testing a wide range of drugs. One panellist, Julie Holder from hosts GlaxoSmithKline, stressed the potential for stem cell cultures to aid the "three R’s": replacing, refining and reducing the use of animals in drug screening.

Frank Bonner, chief executive of the public-private collaboration Stem Cells for Safer Medicine (SC4SM) described how this was enabling the creation of stable, homogenous populations of cardiomyocytes and hepatocytes from human stem cells for use in early predictive toxicity screens. Several academic speakers, including David Hay from the MRC Centre for Regenerative Medicine in Edinburgh, and Chris Denning from the University of Nottingham made reference to the value of this work.

Two speakers – Lars Sundstrom, from the University of Bristol and spinout company Capsant Ltd., and Dan Maltman from Durham University and spinout Reinnervate Ltd – described developments in cell culture technology in which cells grow, not on flat plates, but on three-dimensional "scaffolds". The additional interactions that arise between cells cultured in three dimensions allow them to differentiate further and develop a wider range of "normal" cell functions. Reinnervate’s porous polystyrene scaffold material, Alvetex™, allows hepatocytes to form characteristic liver structures such as microvilli and tight junctions, and to show enhanced metabolic activity when compared to standard liver cell cultures. This approach may have particular application to screening drugs against cancer, as Sundstrom explains: "Tumour cells cultured in three-dimensional systems or 'micro-tumours' behave differently and more typically of the in vivo environment than they do in standard tissue cultures, so they are more realistic models".

Davide Danovi, who works with keynote speaker Austin Smith at the Wellcome Trust Centre for Stem Cell Research at the University of Cambridge, UK, presented an elegant study of the use of stem cells from glioblastoma in screening. Glioblastoma – the most common and most devastating form of adult brain tumour – is inadequately modelled by current cell lines, as these do not include the small percentage of proliferating tumour cells, termed Glioma Neural Stem Cells (GNS), which are now known to be responsible for maintaining the tumour cell mass. Danovi and his co-workers have developed a live image-based system of screening drugs against GNS cells cultured from patients with tumours with different genetic profiles1. These were tested with libraries of drugs in clinical use and new chemical entities (NCEs) and with a panel of kinase inhibitors, and compounds active against all tumour lines and against a subset were identified.

Paul Duffy from AstraZeneca, a member of the discussion panel, is unlikely to be the only participant to identify this targeting of cancer stem cells (or tumour progenitor cells) as the topic within stem cell biology of most pressing importance in oncology. It is, however, by no means the only relevant topic in this area, as the breadth of innovative work presented at this one meeting showed.


1. S.M Pollard, et al: Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens. Cell Stem Cell 4(6), 568-80 (2009)