Oncology Leadership Conference in Cambridge, UK, 12th May 2011

23 May 2011

One Nucleus is a networking organisation for companies and individuals working in the biotechnology and healthcare sectors in the greater London area and in the East of England. It was formed in 2010 from the merger of the London Biotechnology Network and its sister organisation for Eastern England, ERBI. As such, its members represent two "sides" of the so-called "Golden Triangle" of the UK's high-tech and knowledge-based industries, centred on Oxford, Cambridge and London.

It organises conferences including the flagship Genesis meeting, held in London every December since 2001 (see report dated 18 Jan 2011 here), and many more informal networking events. In May 2011 it launched a new series of fairly small, focused meetings, the Cambridge Life Science Leadership conferences, to bring together experts in one discipline or technology area. Oncology was an obvious choice for the first meeting in this series.

The One Nucleus Oncology Leadership Conference was held on May 12 in the Gillespie Conference Centre, part of Cambridge's beautiful Clare College. It included plenaries covering current issues in both oncology and more general drug development, and more specialist sessions featuring case studies in small molecule, biological and technology developments in the oncology area.

The opening plenary session featured two timely general talks. Firstly, Declan Jones from GSK in Stevenage introduced his company's Centre for Excellence for External Drug Discovery, which establishes and manages its alliances with biotech and academic partners, and then Steve Bates from Genzyme recommended strategies for making the most of a new product's chances of market access. The procedures for taking a drug through the complex process for registration and market approval differ not only between countries but between regions within a country, and, in general, the more data – including quality of life data – that can be provided to back up the claims made for a product, the greater its chances will be.

The priority of market access was also stressed by Jonathan Kearsey, co-founder of Leads To Development, in his introduction to the session on "small molecule" cancer drugs. He described a set of "market drivers" that influenced current cancer drug development. These included a continuing need to increase both efficacy and safety, whilst reducing drug resistance; the increasing importance of biomarkers to predict sub-populations likely to respond to a particular drug or drug combination; the growing oncology market, not only due to ageing populations but also due to new markets opening up in developing countries; and the rise of the "expert patient". Dr Kearsey's introduction was followed by an update by Gillian Gregory of consultancy Gregory Fryer Associates on regulatory issues affecting oncology drug development and several recent current case studies.

John Reader of Sareum, a biotech company specialising in oncology drug development, described his company's experience in developing specific kinase inhibitors The FLT-3 and Aurora kinases have been associated with acute myeloid leukaemia (AML). FLT-3 kinase is constitutively active in 30% of adult and 15% of paediatric cases of AML, and this activity is associated with poor prognosis. Reader and his colleagues have used a fragment-based approach with computational chemistry and X-ray crystallography to design and optimised inhibitors of both kinases; lead compounds in this series have had encouraging results in xenograft models and preparation for the first clinical trials is underway. Sareum is also investigating inhibitors of a cell cycle kinase, Chk-1, which is involved in the DNA damage response; its inhibition sensitises p53-deficient cancer cells to genotoxic chemotherapy.

Chk-1 kinase inhibitors are unlikely to have anti-cancer activity alone but may be very useful in combination with other agents. The lead molecules in this series are selective, active in animal models and orally bioavailable. Simon Cook of the BBSRC's Babraham Institute then presented a case study of how tumour cells acquire resistance to selumetinib, a novel inhibitor of the kinases MEK1 and MEK2 on the ERK pathway; this is achieved through a common mechanism in which the tumours amplify their driving oncoprotein – BRAF or KRAS – to increase signal flux down the pathway. MEK inhibitors can be extremely good drugs, but they are cytostatic, rather than cytotoxic: they trap dividing cancer cells in the G1 phase of the cell cycle. Converting this into a cytotoxic response by rational combinations with other drugs could prevent resistance from arising.

The session on novel biological products as anti-cancer drugs also featured an update on regulatory issues followed by a series of case studies. Stephen Megit from Immunocore, based near Oxford, described his company's unique T Cell Receptor based technology through which cancer cells are specifically targeted for destruction by cytotoxic T-cells of the patient's own immune system by coating them with a cancer-specific drug. Like many biological agents, however, Immunocore's bi-specific drugs only target human cells and cannot be tested in traditional, pre-clinical toxicity models. "The regulatory process for so-called "high-risk" molecules has become even more complex after the TeGenero incident in 2006", said Megit. "Nevertheless, review and approval of the Phase I protocol for our lead molecule, IMCgp100, against advanced melanoma was achieved in three months." Two parallel clinical trials of this molecule are now underway in the US and the UK.

Ching Ching Leow from MedImmune, the biologics unit of AstraZeneca,which has research bases in Maryland USA and Cambridge UK described the development of a monoclonal antibody, MED13617, to target tumour angiogenesis. Many biochemical pathways are involved in this process, any of which may theoretically be targeted by drugs. The MedImmune compound targets the protein Ang-2, which primes blood vessels for interaction with growth factors and is over-expressed in many tumour types; it is selective for Ang-2 and blocks the binding of Ang-2 to the Tie2 receptor. It has been shown to be inhibit tumour growth in pre-clinical animal models and is now in Phase I trials in adults with advanced solid tumours.

Davide Danovi, who works in Steve Pollard's group at the UCL Cancer Institute, gave an interesting talk in the section on novel technologies, describing his research into the use of glioma stem cells to screen small molecule drugs for brain tumours. Glioblastoma, the most severe form of brain cancer, forms as heterogeneous tumours that are often inoperable. Cancer stem cells form a tiny minority of the cells in these tumours but are the most important as drug targets. Danovi and his co-workers have developed lines of homogenous glioma neural stem cells (GNS cells) that are highly stable and that can be used to test the activity of potential anti-tumour compounds. They use imaging techniques to interpret the results and to distinguish between cytotoxic and cytostatic compounds.

The closing plenary address was given by Dr Austin Smith, Medical Director of Theradex, a contract research organisation that specialises in oncology services. His talk was entitled "The Hallmarks of Cancer Drug Development" in recognition of the seminal contribution of a paper by Douglas Hanahan and Robert Weinberg in 2000 that set out, for the first time, the molecular and cellular hallmarks of carcinogenesis. Ten years on, we know much more about the molecular mechanisms involved in cancer development. However, many cancers are still intractable to treatment, the WHO is predicting that global cancer cases will increase by 50% in the next ten years, and the average drug development time "from bench to bedside" is still over a dozen years.

Over a quarter of all drugs in development are for cancer indications. Smith described how the design of clinical trials, particularly early ones, was changing, but needed to change further to reduce development times. He highlighted specific challenges with researching drugs for paediatric use and the need for closer collaboration between regulatory agencies internationally. He ended with a quotation from Dr Virchow (1896) that seems remarkably apposite today: "Indeed, a great deal of industrious work is being done [on cancer]... but someone should have another bright idea". One Nucleus' first leadership conference did indeed present an impressive number of current "bright ideas" in oncology drug development, but it also highlighted the need for more.