Section of Cancer Therapeutics (including the Cancer Research UK Cancer Therapeutics Unit)

Scientific Overview 

The Cancer Research UK Cancer Therapeutics Unit is a unique academic drug discovery and development group. Its mission is to discover and develop novel and effective therapeutics for the treatment of cancer. Our aims are:

• To identify and validate novel genes and pathways as targets for therapeutic intervention in cancer
• To implement innovative technologies for drug discovery and development
• By these means, to discover novel mechanism-based drugs and to develop these as rapidly as possible from the laboratory bench through to hypothesis-testing early clinical trials
• To develop novel gene-directed enzyme prodrug therapies
• As a result, to contribute to the improved treatment of human cancers

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Our research strategy is to target the molecular and microenvironmental differences between cancer and normal tissues, in the expectation that this will deliver more effective and less toxic therapies than those currently available. To do this we employ a range of modern technologies to increase the efficiency and speed of drug development, including high-throughput screening, fragment-based hit discovery, virtual screening, in silico medicinal chemistry, gene expression microarrays and high-throughput pharmacokinetic analysis (cassette dosing). Simultaneous development of new therapeutic agents and molecular biomarkers, and their combined use in the discovery and implementation of personalised diagnosis and treatments, is critical for rational drug development. In Addition to in-house projects, we also have a range of established academic and commercial collaborations to help develop new therapies quickly and effectively for patient benefit.

Cancer drug development is a multidisciplinary process involving close collaboration between cell and molecular biologists, tumour biologists, pharmacologists, medicinal chemists, structural biologists and clinicians. Individual research projects are grouped in the form of ‘clusters’. These are: chaperones, signalling, chromatin modulation, cell cycle, angiogenesis and invasion, and directed enzyme prodrug therapies. The clusters represent natural groupings according to the biological effects and processes in which the target is involved.

The identification, validation and selection of new targets is facilitated by our three molecular biology teams that have interests in cell cycle control, angiogenesis and apoptosis. New drug leads are identified by high-throughput screening, fragment-based hit discovery and virtual screening. This work is complemented by x-ray crystallography and biophysical methods to characterise protein-ligand interactions. Drug discovery is in close collaboration with teams that specialise in molecular pharmacology, pharmacokinetics, biomarkers  and tumour biology. Finally, novel agents, from within our own Centre and elsewhere, are taken into early evaluation in patients by our clinical team, in association with the Section of Medicine and The Royal Marsden Hospital. A wide range of drug discovery and development projects are underway. As elsewhere in ICR, results are reported according to the work carried out by discipline-based laboratory Teams. In practice, the drug discovery and development work is carried out by multidisciplinary Project Teams made up of members of several different laboratory Teams. The work is therefore highly integrated and collaborative.

Recent Highlights

• The opening of the Oak Foundation Centre for Phase I clinical trials represents a major landmark for new drug development at the Royal Marsden/Institute of Cancer Research
• Our pioneering PK-PD driven Phase I clinical trial with the first-in-class inhibitor of the HSP90 molecular chaperone 17-AAG provided the first demonstration of molecular target inhibition in the tumour and of prolonged stable disease in 2 patients with metastatic melanoma, leading to a Phase II trial in this disease. Subsequent work in collaboration with Richard Marais showed that mutant BRAF was unusually dependent on HSP90 and that the responses in melanoma patients may be associated with BRAF and RAS mutations.
• Discovery of the pyrazole resorcinol series of HSP90 inhibitors. In collaboration with Vernalis this was optimised to the development candidate NYP-AUY922 which has been taken into the clinic by Novartis. A second, oral development candidate from a different series has also been selected.
• In collaboration with Yamanouchi/Astellas we identified multiple series of PI3 kinase inhibitors, including PI-103. In collaboration with Piramed we optimised the lead compound into a development candidate, now taken into the clinic by Genentech as GDC-0941.
• Discovery of nanomolar inhibitors of PKB, in collaboration with Astex Technology Ltd, and demonstration of activity in human tumour xenograft models.
• The discovery of nanomolar, selective inhibitors of CHK1 in collaboration with Sareum Ltd. We have used structure-based methods to identify and optimise inhibitors of the cell cycle regulatory kinase CHK1 to provide potent and highly selective compounds which potentiate the efficacy of DNA-damaging agents in vivo in colorectal carcinoma models.
• Based on promising preclinical results, a proposal for a GDEPT Phase I clinical trial has been accepted by Cancer Research UK New Agents Committee.
• Four series of 1nM inhibitors of mutant B-RAF have been identified, in collaboration with Professors Richard Marais and David Barford.
• We have identified novel inhibitors that show differential effects on HIF-1 activity in response to growth factors and hypoxia.
• We have identified an average two preclinical development candidates each year over the last 5 years.
• Our 17-hydroxylase/lyase inhibitor abiraterone has shown early promise in the clinic against hormone refractory prostate cancer.

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