From Genes to Drugs

The UK’s Institute of Cancer Research is celebrating its centenary in 2009, under the slogan “Help make our first centenary our last”.

Pre-eminent among events held to celebrate this anniversary was a three-day conference held in June 2009 at the prestigious Queen Elizabeth II conference centre in Westminster.

Scarcely more than a century after William Bateson first coined the word “genetics”, the conference theme, Cancer Genes: Discovery and Exploitation, illustrated our understanding of cancer as a genetic disease. The programme featured about thirty talks by world-class researchers and well over 250 posters. The first two days concentrated on the discovery and understanding of genes associated with cancer. This short report presents highlights of the session held on the third day, Wednesday 10 June, which moved genetic research towards the clinic with the sub-theme “From Genes to Drugs”.

This third conference day could have been spoiled by London Underground staff, who chose that day to strike. Cancer researchers are a hardy bunch, however, and when I arrived – admittedly, not quite at the start of the first presentation – the large lecture hall was already almost full.

The first speaker was Stephen Jackson, from the Gurdon Institute, Cambridge UK, and scientific founder of KuDOS Pharmaceuticals, Cambridge, UK. He described the role of defects in the normal DNA repair response in cancer development, focusing particularly on the repair of highly cytotoxic double-strand DNA breaks. Cancer cells with mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 are hugely sensitive to inhibitors of one class of DNA repair proteins, the poly(ADP-ribose) polymerases (PARP). Inhibiting these proteins slows down DNA repair leading to the death of cancer cells. Jackson presented positive results of early clinical trials of PARP inhibitors in BRCA-deficient breast and ovarian cancers, describing them as “the most important slides I have ever shown”.

The second speaker, Stephen Fesik, has recently moved to the Vanderbilt University School of Medicine in Tennessee from a long career at Abbott Laboratories. Fesik described the use of SAR by NMR, a technique he pioneered for fragment-based drug discovery using structure-based design, and other methods to discover inhibitors of the anti-apoptotic members of the Bcl-2 family of proteins. One of these, ABT-263, regresses tumours in mice and is showing promise in early stage clinical trials in chronic lymphocytic leukaemia. Despite its large size, it is orally bioavailable.

The first 'home team' speaker in this session was Richard Marais, professor of molecular oncology at the ICR. His work focuses on melanoma, the most deadly form of skin cancer. In 2002, the Cancer Genome Project highlighted one protein, BRAF, as being mutated in about 70% of human melanomas. The most common BRAF mutation, V600E, is also often found in benign human naevi (birthmarks and moles). Marais and his group have synthesised novel inhibitors that block BRAF signalling and inhibit proliferation in melanoma cells, some of which are orally available.

Further talks on signalling pathways in cancer development, and drugs being developed to target them, were given by Jose Baselga from the Val d’Hebron University Hospital in Barcelona, Spain, and by two speakers from the Memorial Sloan-Kettering Cancer Center in New York, Neal Rosen and Charles Sawyers. Baselga described drugs that target phosphatidyl inositol 3-kinase (PI3K), a signalling protein in the growth factor receptor pathway, and Sawyers described novel developments in anti-androgen therapy for men with recurrent prostate cancer known as “castrate resistant” disease. Rosen discussed how oncogene activation can lead to constitutive negative feedback, attenuating or terminating the signalling pathway involved, and how further mutations can inactivate this feedback apparatus. The BRAF mutation V600E described by Marais is an example of a mutation that is relatively insensitive to feedback mechanisms.

The importance of clinical trial design in the development of targeted anti-cancer drugs was discussed by Johann de Bono of the ICR and the Royal Marsden NHS Trust. Drug development is complex and extremely expensive, with the cost of developing a single drug “from concept to clinic” currently estimated at upwards of a billion dollars. He proposed some principles of good practice in designing early stage clinical trials for cancer, illustrating his talk with examples from the ICR’s own drug discovery programmes, including PARP inhibitors for breast cancer, and abiraterone, currently in Phase III trials for prostate cancer.

Ian Tannock from the University of Toronto, Canada, described the role of drug distribution in driving drug resistance. Although molecular changes to cancer cells dominate the drug resistance literature, changes in the micro-environment that lead to decreasing drug concentration in tumours may be just as important. Often, drugs penetrate normal tissue more easily than tumour tissue, leading to decreases in effective drug concentration. Tannock’s group is testing whether co-prescribing doxorubicin with the proton pump inhibitor pantoprazole, which inhibits the sequestration of drug in endosomes, can potentiate doxorubicin activity.

The day was summed up in a final presentation by Paul Workman, head of the Cancer Research UK Centre for Cancer Therapeutics at ICR. He presented “good and bad views” from the cancer genome using examples from Centre projects – particularly inhibitors of molecular chaperones, which are necessary for the folding and stability of oncogenic proteins, and of PI3 kinase – and looked forward into a future of “personalised molecular medicine”. Less than a decade after the completion of the Human Genome Project, we are now beginning to understand many of the mutations underlying the “genetic chaos” that is cancer, and to intervene in the hijacked biochemical pathways in a rational way. Significant challenges remain, however, and many of these mirror themes discussed by earlier speakers: combating drug resistance, selecting optimal combination therapies, discovering biomarkers and designing clinical trials. Workman showed how HSP90 molecular chaperone inhibitors, including the ICR’s NVP-AUY922, have the advantage of hitting multiple cancer-activated signalling pathways simultaneously and show promise in breast cancer and melanoma, amongst other malignancies. He also showed promising results with the ICR’s PI3 kinase inhibitor GDC-0941. In both cases biomarkers indicate inhibition of the molecular target in the clinic.

Jonathan Kipling, Secretary of the ICR, said of the whole meeting: "The ICR Centenary Conference has been a great success with nearly 800 people coming from across the country and around the globe. Over a hundred students were part of our audience and it was inspiring to see world-renowned leaders in their field discussing research at the very cutting-edge with scientists at every stage of their careers." It is impossible to guess whether the ultimate challenge of beating cancer completely in the next hundred years will be possible. But the range of basic and applied research discussed here indicates that this second century shared by the ICR and by genetics and drug development has made an extremely promising start.