PEBC Report - Programa de Epigenética y Biología del Cáncer

Alan Ashworth
Professor Alan Ashworth FRS, is
Professor of Molecular Biology
and Director of The Breakthrough
Breast Cancer Research Centre
at The Institute of Cancer
Research, London. The Centre
contains around 120 scientists and
researchers working on aspects of
breast cancer ranging from basic
molecular and cellular biology
through to translational research and clinical trials.
Ashworth contributed to the discovery of the BRCA2 gene
in 1995 and ten years later, Prof. Ashworth’s team identified
the synthetic lethal relationship between BRCA mutations
and PARP inhibitors. The exquisite sensitivity of BRCA1 or
BRCA2 mutant cells to PARP inhibitors forms the rationale
behind clinical trials that are now assessing the potential of
these agents. Ashworth’s other research interests are wide
ranging and include high-throughput genomic and functional
approaches to the study of cancer.
Ashworth is an elected member of EMBO and the Academy
of Medical Sciences. In 2008, he was elected a Fellow of the
Royal Society for his contributions to mammalian genetics
and the developments of new therapeutic approaches for
cancer.
Breakthrough Breast Cancer Research Centre
The Institute of Cancer Research
London, UK
Synthetic Lethal Approaches to the
Development of New Therapies Targeting DNA
Repair Deficiencies in Cancer
Many tumours harbour defects in their ability to maintain
genomic integrity. This contributes to the mutational burden
and likely fosters pathogenesis. We have been exploring
therapeutic strategies to exploit these defects. We
have used a synthetic lethal approach to target the defect
in DNA repair by homologous recombination in tumours
with a BRCA1 or BRCA2 mutation. This strategy using
PARP inhibitors is showing considerable promise in the
clinic. Here, I will describe the approach as well recent
work defining determinants of sensitivity and resistance to
PARP inhibitors. The application of the synthetic lethal
approach to other cancer types will also be discussed.
Selected publications
Turner N, Tutt A, Ashworth, A (2004) Hallmarks of 'BRCAness'
in sporadic cancers. Nat Rev Cancer 4: 814-819
Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA,
Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C,
Martin NM, Jackson SP, Smith GC, Ashworth, A (2005)
Targeting the DNA repair defect in BRCA mutant cells as a
therapeutic strategy. Nature 434: 917-921
Iorns, E., Lord, C.J., Turner, N. and Ashworth, A (2007) Utilizing
RNA interference to enhance cancer drug development. Nat
Rev Drug Disc, 6, 556-568.
Edwards, S., Brough, R., Lord, C.J., Natrajan, R., Vatcheva, R.,
Levine, D.A., Boyd, J., Reis-Filho, J.S. and Ashworth, A.
(2007) Resistance to Therapy caused by Intragenic Deletion
in BRCA2. Nature, 451 (7182): 1111-5
Ashworth A (2008) A synthetic lethal therapeutic approach:
poly(ADP) ribose polymerase inhibitors for the treatment of
cancers deficient in DNA double-strand break repair. J Clin
Oncol, 26: 3785-3790
Cancer Epigenetics and Biology Symposium
14 28, 29 May 2009, Barcelona