Biomarkers for parp inhibitors

Dearman, C; Sharma, RA; Curtin, NJ

doi:10.1007/978-3-319-14151-0_24

Biomarkers for parp inhibitors

Lookup NU author(s): Professor Nicola Curtin ORCiD

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Abstract

© Springer International Publishing Switzerland 2015.There is considerable excitement about the clinical potential of PARP inhibitors (PARPi), based on highly publicised results from several clinical trials. In this chapter, we will demonstrate that PARP inhibition is not a generic strategy for treating cancer in non-selected patients and that the most promising results involve accurate patient selection using predictive biomarkers. Laboratory studies have indicated that PARPi can induce synthetic lethality in cells with homologous recombination repair (HRR) defects. HRR is a multifactorial process with many gene products involved in the signalling and repair of DNA damage by HRR, a defect in any one of the components of HRR can compromise the entire pathway and confer PARPi sensitivity. The challenge now is to identify the multiple contributors to HRR defects in cancer tissue that may sensitise cancers to PARPi therapy, mutations in other genes of the DNA damage response (DDR) and post-transcriptional modifications. In this chapter, we will review the fundamental concepts underpinning the identification and validation of predictive and pharmacodynamic biomarkers. In this chapter, we place particular emphasis on biomarkers that have the capacity for validation in the clinic and promising future avenues for patient-centred research in this field. Finally, challenges in selecting, developing and validating clinical biomarkers will be discussed.