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Targeting the DNA damage response in oncology: past, presen... : Current Opinion in Oncology
Current Opinion in Oncology:
May 2012 - Volume 24 - Issue 3 - p 316–324
doi: 10.1097/CCO.0b013e32835280c6
INNOVATIVE EARLY CLINICAL TRIALS METHODOLOGY AND NEW THERAPEUTICS IN CANCER: Edited by Ahmad Awada
Targeting the DNA damage response in oncology: past, present and future perspectives
Abstract
Purpose of review:
The success of poly(ADP-ribose)
polymerase inhibition in BRCA1 or BRCA2 deficient tumors as an
anticancer strategy provided proof-of-concept for a synthetic lethality
approach in oncology. There is therefore now active interest in
expanding this approach to include other agents targeting the DNA damage
response (DDR). We review lessons learnt from the development of
inhibitors against DNA damage response mechanisms and envision the
future of DNA repair inhibition in oncology.
Recent findings:
Preclinical synthetic lethality
screens may potentially identify the best combinations of DNA-damaging
drugs with inhibitors of DNA repair and the DDR or two agents acting
within the DDR. Efforts are currently being made to establish robust and
cost-effective assays that may be implemented within appropriate
time-scales in parallel with future clinical studies. Detection of
relevant mutations in a high-throughput manner, such as with
next-generation sequencing for genes implicated in homologous
recombination, including BRCA1, BRCA2, and ataxia telangiectasia mutated
is anticipated. Novel approaches targeting the DDR are currently being
evaluated and inhibitors of ATM, RAD51 and DNA-dependent protein kinase
are now in early drug discovery and development.
Summary:
There remains great enthusiasm in oncology
practice for pursuing the strategy of synthetic lethality. The future
development of antitumor agents targeting the DDR should include
detailed correlative biomarker work within early phase clinical studies
wherever possible, with clear attempts to identify doses at which robust
target modulation is observed.
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