Targeting the DNA damage response in oncology: past, present and future perspectives : Current Opinion in Oncology

Secondary Logo

Journal Logo

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

Basu, Bristia,b; Yap, Timothy A.a,c; Molife, L. Rhodaa,c; de Bono, Johann S.a,c

Author Information
Current Opinion in Oncology 24(3):p 316-324, May 2012. | DOI: 10.1097/CCO.0b013e32835280c6

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.

© 2012 Lippincott Williams & Wilkins, Inc.

You can read the full text of this article if you:

Access through Ovid