Networking drug development in oncology

28 Oct 2011

The life sciences and healthcare networking organisation One Nucleus was formed in 2010 from the merger of two similar bodies which were centred on London and the East of England respectively. It aims to increase the global competitiveness of its member companies, in part by organising meetings ranging from the international Genesis conference held in London every December to small, informal evening events in Cambridge and London. During 2011 it has launched a series of day-long "leadership seminars" in specialist areas of biotechnology and drug discovery, with oncology the first topic to be covered.

The success of the first Oncology Leadership Seminar, held in Cambridge last May (see previous post) led One Nucleus laying on a follow-up meeting. This was held on October 12 in the City of London, at the headquarters of the prestigious law firm Charles Russell. The wide-ranging meeting, termed an Oncology Networking Seminar, included three contrasting plenary lectures; two sessions of short scientific presentations; and a short session on financing drug development in oncology. And as at all One Nucleus events, there were also plenty of opportunities for networking.

Chas Bountra, a Chief Scientist and Professor of Translational Medicine at the University of Oxford, gave the first plenary lecture, representing the Structural Genomics Consortium (SGC). Structural genomics is the name given to any project to determine protein structures on an "industrial scale". The SGC, which includes the University of Toronto and the Karolinska Institute in Sweden as well as Oxford, focuses on structures of therapeutically relevant human proteins. It has so far contributed more than 1300 structures to the public Protein Data Bank, including fifty-six human kinases, many of which will be potential drug targets for cancer. Bountra's interesting thesis was that models of open innovation, far from threatening commercial drug discovery, are actually essential if productivity is to return to the industry.

Currently 90% of candidate drugs that reach Phase II clinical trials for novel ("pioneer") targets fail to reach the clinic, and the proprietary work of many companies in developing similar molecules in parallel to this point is wasted. Bountra proposed that a public-private partnership model be used to develop the best candidate molecules for these targets to Phase II (proof of clinical mechanism, or POCM) with intellectual property only being generated on those targets that pass this important hurdle. Working in this way would also enable the rapid publication of negative results, preventing further wasted effort and, importantly, unnecessary exposure of patients to molecules destined for failure. Such a model should deliver more clinically validated and therefore de-risked targets, which pharmaceutical companies can then exploit to produce novel medicines. Patient groups and regulatory agencies will be able to play a more active role in this endeavour.

This thought-provoking lecture was followed by one by Dr. Madhuri Warren, a medical pathologist and CEO of Pathology Diagnostics, based in Cambridge. Warren described the technologies used by her company in analysing tissue samples of human tumours, preparing and imaging them, and validating accurate high throughput tissue-based assays for use throughout the drug development process. The challenges encountered by Pathology Diagnostics' scientists are not only technical: the use of human tissue is dictated by consent and ethical issues and governed by national and international law.

The main focus of Warren's talk, however, was the use of immunohistochemistry (IHC) in discovering and validating biomarkers for pre-clinical and clinical drug development in oncology. This technique generates a visible signal whenever an antibody binds to its target antigen, for example a cell surface receptor tyrosine kinase such as EGFR that is dysregulated in cancer. Although the automatic methods that Pathology Diagnostics and its competitors are developing to analyse the resulting image data are now quite sophisticated, there is still an important role for manual and semi-automated methods. Pathology Diagnostics is committed to continuing its advances in automated image analysis, as well as contributing to the development of quality standards.

The third plenary was very different again. Jennifer Pierce, a biotechnology IP expert based at hosts Charles Russell, gave a "snapshot" of the current climate of deals, mergers and acquisitions in the pharma and biotech industries with an emphasis on how companies can "future-proof" their business plans and promote themselves in what she described as a "deal-making food chain". There are many aspects to consider when planning and negotiating a successful deal. Thinking ahead on a timescale of at least 5-10 years is essential; the limitations of the proposed agreement, the territory or territories over which it will hold and its overall structure must be taken into account, and – although this may go against a company's instincts – it is important to plan for the end of an agreement before it is even signed.

The next session featured five short talks on the overall theme of systems biology and biomarkers. The session chair, Davidson Ateh, CEO of London-based start-up BioMoti, introduced the topic as addressing the importance of delivering "the right combination of drugs to the right patient at the right time". Niall Martin of MISSION Therapeutics, based in Cambridge, kicked off with a discussion of how his company is targeting DNA damage responses and repair in cancer. He described MISSION, founded by Steve Jackson of Cancer Research UK, a world expert on DNA repair proteins, as a "phoenix rising from the ashes" of KuDOS, the company bought and then relinquished by AstraZeneca. MISSION is developing drugs to inhibit proteins involved in the ubiquitin pathway that control aspects of the DNA damage response, in similar fashion to inhibitors of PARP, a protein involved in the repair of single-strand breaks in DNA. These show a selective killing called synthetic lethality in BRCA-deficient cells. MISSION intends to identify protein targets in the ubiquitin pathway that can lead to selective killing of tumour cells through the same synthetic lethality.

Malcolm Young, founder and CEO of e-Therapeutics, and named by the Sunday Times as one of eighteen "brains behind the 21st century", was the next to speak. He described the thinking behind the development of the company's lead compound, ETS2101, as a "selective apoptotic" drug that would, colloquially, "remind cancer cells to undergo apoptosis". Theirs is a network-based approach, seeking compounds that disrupt not a single protein but the network of proteins and protein-protein interactions that protect a cell from apoptosis. The compound selected, which previously failed in clinical trials for a neurology indication, was found to selectively kill cancer cells including cancer stem cells, in a number of cell lines and tumour types. Its first Phase I clinical trials are due to start early in 2012. This session also featured talks by Mark Chadwick, CEO of Physiomics, the first company to commercialise the "virtual tumour" systems biology approach; Bill Blair, founder of Scottish start-up UB Pharma, which is targeting the ubiquitin pathway; and Scott Cuthill of Chroma Therapeutics, which uses a novel technology to target cell accumulation in haematological cancers.

It is well known that many of the most promising and innovative anti-cancer therapies in development harness the power of the immune system to selectively target cancer cells. Monoclonal antibodies have been the fastest-growing sector of the pharmaceutical industry since 2006, with cancer one of their most important indications. Immune-based cancer therapies were the focus of the second session of short talks. Firstly, Tom Shepherd from Kymab described a novel technology for generating transgenic mice to produce fully human monoclonal antibodies, known as the Kymouse™. Uniquely, these mice can produce antibodies utilising the functional diversity of the entire human immunoglobulin gene repertoire, while retaining the B-cell biology of normal mice. A bank of stem cells re-derived from these mice will also be used to rapidly generate new, customised mouse strains, particularly knock-outs to eliminate "self-tolerance" to highly conserved drug targets.

No technology for generating monoclonal antibodies will be of any use unless suitable targets for those antibodies are available, and the number of proteins targeted by antibodies in the clinic or in development is still relatively small. This problem was well addressed by Ralph Minter from MedImmune. This company, a US-based wholly-owned subsidiary of AstraZeneca with its European base in Cambridge, is using phage display and tissue microarrays to screen cancer cells for targets based on their phenotypes, focusing initially on non-small cell lung cancer and triple-negative ((ER-, PR-, HER2-) breast cancer, both of which respond poorly to current therapeutic options. Other talks in this session were given by representatives from Oxford BioTherapeutics, Cytune Pharma, and BLiNK Therapeutics, a recent spin-out from Cancer Research Technology and the "youngest" company on the programme. The day ended with an interesting short session on investment opportunities, including a presentation by Tobby Simon, CEO of Synergia Bio Sciences, a biopharmaceutical company based in Bangalore, about financing research and pharmaceutical developments in India. All in all, it was an excellent day with a varied programme with something to offer anyone interested in drug development for cancer. One Nucleus' specialist oncology programme is becoming a useful one to watch.