Development of PARP inhibitors in oncology

Abstract

Poly (ADP-ribose) polymerase (PARP) plays a key role in DNA repair mechanisms by detecting and initiating repair after DNA strand breaks. Inhibition of PARP in DNA repair-defective tumors (like those with BRCA1 or BRCA2 mutations) can lead to gross genomic instability and cell death. Likewise, combining PARP inhibition with cytotoxic agents such as chemotherapy or radiation therapy is synergistic in many preclinical models. Several drugs designed to inhibit PARP are currently in clinical development, many following a development path different from that of typical anticancer agents. In this review we will focus on the early clinical data from PARP inhibitors that are entering clinical trials, the potential tumors they might target, their combination with other drugs and the different biomarkers that are being explored. Concepts such as ‘BRCAness’, synthetic lethality, Phase 0 trials and pharmacodynamic markers will be discussed in the context of the development of PARP inhibitors.

Keywords::

• BRCA1
• BRCA2
• BRCAness
• PARP inhibitor
• pharmacodynamics
• poly (ADP-ribose) polymerase

Acknowledgements

M Iniesta is supported by a grant from Alfonso Martin Escudero Foundation, Madrid, Spain. We would like to thank Anthony Tolcher for the opportunity of conducting several trials with PARP inhibitors and for sharing his experience. We would also like to thank Judit Balmaña for critically reviewing this manuscript.

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