Cancer Research UK and its commercial subsidiary, Cancer Research Technology (CRT) have established a consortium led by four world-class scientists to research the prevalence, characteristics of cancer stem cells, to discover novel biomarkers and protein drug targets in these cells and, in time, to collaborate with industry to develop and test novel stem-cell directed therapeutics. The lead researchers bring to the consortium expertise in different techniques and cancer types. Three are very closely linked to the clinic. Fiona Watt, deputy director of the new Cancer Research UK Cambridge Institute, studies squamous epithelial tumours of the skin, head and neck; Rob Clarke, of the Paterson Institute for Cancer Research at the University of Manchester, focuses on breast cancer, and Norman Maitland of the University of York researches prostate cancer. The fourth consortium member, Alan Clarke from Cardiff University, develops genetically engineered mouse models of human cancers. 

Cancer Research Technology marked the launch of the consortium on January 18, 2011 with a seminar explaining the nature of cancer stem cells and their promise as drug targets to the UK media and, through them, to the general public. “The issue of stem cells in general can be an emotive one, and people need to understand a little of what cancer stem cells are if they are to appreciate their usefulness in drug development”, said Clive Stanway, Chief Scientific Officer at CRT in introducing the seminar.

Stanway began with a brief personal overview of progress in developing cancer therapeutics, as “good… but still not good enough”. Molecularly-targeted drugs such as Glivec® and Sutent® have proven successful in several cancers, and there are many more candidate molecules in clinical development, one of the most promising being Plexxicon’s B-Raf kinase inhibitor PLX4032 for melanoma. However, none of these have completely overcome the problem of resistance. Often a cancer thought to be cured by chemo- or radio-therapy, or surgery, recurs in a more aggressive form months, years or even decades later. The cancer stem cell hypothesis states that tumours, like normal tissues, contain small populations of cells that are capable of renewing that tissue alone. These stem cells are “young”, non-differentiated cells that divide to form daughter cells that can differentiate into all the cells of that tissue. Importantly, they are adult stem cells, so cancer stem cell research would not involve techniques such as the use of “spare” IVF embryos that have proved so controversial with some sections of the public.

Cancer stem cells, like other adult stem cells, are usually quiescent, dividing only when necessary. Many scientists now believe that most cancer drugs, in targeting rapidly dividing cells, leave cancer stem cells unaffected, and that this small cell population is responsible for the re-growth of tumours thought to have been removed. Cancer stem cells are now fairly well understood and characterised in haematological malignancies, but there is still some controversy in the cancer community over the role – or even the existence – of stem cells in solid tumours. “There is more evidence for stem cells in some solid tumour types than others, and it is possible that their role is tumour type dependent”, said Stanway. “In cases where cancer stem cells have been characterised, it should eventually be possible to design a wholly effective cancer treatment as a combination of drugs that target both the stem cells and the proliferating cells of the tumour.”

The second speaker was one of the lead scientists from the consortium, Fiona Watt from Cambridge. Taking squamous cell carcinomas of the skin –her own research area – as an example, she described cancer stem cells or “cancer-initiating cells” as the least differentiated cells in a heterogeneous tumour. In order to target this population of self-renewing cells it is important to determine which signal transduction pathways are dysregulated, and which genes and proteins are differentially expressed, in these cells. Watt described three high throughput assays – one in vitro and two in vivo – which the consortium will be developing using frozen samples of well-characterised tumour cells obtained directly from consortium members’ institutions.

Several signal transduction pathways have already been highlighted as being potentially involved in cancer stem cell function, including the Notch and WNT pathways. Watt briefly described the likely role of the complex Notch pathway, which is conserved in most multi-cellular organisms. It is one of the main controls of cell differentiation, which it can either stimulate or inhibit; too much or too little Notch signalling can also stimulate inflammation. The consortium has identified a panel of eight proteins, many from this pathway and each thought to be a potential marker of cancer stem cells in at least one of the tumour types studied. The consortium aims to validate and select some of these as markers of stem cell activity in the relevant tumour types.

Julian Blagg, head of chemistry at the Cancer Research UK Cancer Therapeutics Unit at the Institute of Cancer Research spoke next, and he focused on signalling in the WNT pathway as a target for drugs that might be applicable to cancer stem cells. The Cancer Therapeutics Unit aims to understand many different molecular mechanisms involved in cancer and develop specific small molecule drugs to target them. Targeting cancer stem cells and the pathways that are dysregulated in them is an important part of this stratified approach. About 80% of colon cancers have defects in one or more of the genes involved in the WNT pathway, and these are also thought to lead to increased cancer stem cell proliferation. This pathway controls gene transcription through the protein beta-catenin. Mutations arising at different points on it increase the level of beta-catenin mediated signalling in the nucleus and therefore increase gene expression. Several proteins regulated by the WNT pathway are known to be stem cell biomarkers, and may also be useful targets for stem-cell directed cancer therapeutics. Researchers on the WNT project, a collaboration between the Cancer Therapeutics Unit, Cardiff University and END Merck Serono, have developed cell lines to discover small molecule inhibitors that act at different points on the WNT pathway. They will assess the prioritised chemicals further in in vitro culture using the epithelial cells of the intestinal crypt, which is the most rapidly proliferating tissue in normal adult mammals.

The final speaker, Helen Sabzevari, Global Head of Oncology-Immunology at EMD Serono in Billerica, Massachusetts, USA, gave a pharmaceutical industry perspective on stem cells as a target for cancer drug development. “We are not looking for a single ‘magic bullet’ against cancer”, she said. “Instead, our aim is to de-bulk tumours and stabilize the disease, turning cancer into a chronic illness that patients can live with long term, similar to diabetes or HIV.” Therapies that can target and kill the residual tumour cells remaining in stable disease would be a definitive final step in the war against cancer. EMD Serono, the US-based pharmaceutical division of Merck KGaA, a German pharmaceutical-chemical giant, is searching for drugs that act on signalling pathways known to be dysregulated in cancer stem cells; the mechanisms that these cells use to evade the human immune system are also potential targets. “Our approach is multi-faceted and multi-disciplinary, and we rely on collaboration with external groups including Cancer Research UK”, said Sabzevari. The meeting ended with a lively discussion session.

The Cancer Stem Cell Consortium is not the first to be established by CRT. Senectus Therapeutics Ltd. was established in 2008 as a company within CRT to research cellular senescence and immortality in cancer, with telomerase the key drug target, and has already secured translational funding worth $1M (€740K). Both consortia should stand a good chance of adding to CRT’s already impressive pipeline of candidate anti-cancer drugs in the years to come.