Poly(ADP-ribose) polymerase inhibitor development: are we in the right direction?
- R Plummer1
© Plummer. 2011
Published: 16 November 2011
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear DNA-binding enzyme activated by DNA strand breaks and has a key role in the signalling of DNA single-strand breaks as part of the repair process. In anti-cancer therapy, many agents cause DNA damage as their mechanism of cytotoxicity, and repair of damage is a cause of tumour resistance. Additionally in tumours where double-strand break repair is defective (for example in BRCA-related cancers) PARP inhibitors have potential single-agent activity. Thus, PARP-1 was identified as a potential therapeutic target for cancer treatment and PARP inhibitors have entered the clinic both in combination with cytotoxic chemotherapy, as single agents in DNA repair deficient tumours, and more recently in combination with radiotherapy.
The first PARP inhibitor to be given to cancer patients in 2003 was AG014699 (rucaparib), a tricyclic indole, which is a potent intravenous inhibitor of PARP. This phase I study had a pharmacodynamic endpoint of PARP inhibition in PBMCs, demonstrating for the first time proof of mechanism of the class. Subsequently AZD2281 (olaparib) entered clinical trials as a single agent (2005), and demonstrated the proof of concept of synthetic lethality in BRCA defective tumours in two small phase II studies. Over the last 5 years seven further inhibitors have entered cancer clinical trials either as a single agent (MK4827) or in combination with various cytotoxic regiments (ABT888, veliparib; BSI-201, iniparib; CEP-9722; INO-1001; E7016, BMN 673) in late preclinical development.
Initial exciting data suggesting that iniparib improved outcome in patients with triple-negative breast cancer in combination with chemotherapy have not been confirmed in phase III studies, although there are clearly patients who benefit from this agent. In terms of mechanism of action, iniparib differs from all the other compounds in the class that are competitive inhibitors at the NAD+ binding site of PARP. Iniparib is postulated to have a different mechanism of action and may not be a bona fide PARP inhibitor.
It has been a period of rapid clinical development of a new class of agents with exciting evidence of improved response rates in some tumour areas. This class of agents also presents some interesting challenges in clinical trial design, and mechanistic understanding. This presentation will overview the current clinical status of PARP inhibitors and will discuss these challenges and potential biomarker strategies.