Generating Preclinical Models To Assess Bone Marrow Toxicity Induced By The Parp Inhibitor Olaparib In Combination With Chemotherapy.

Inhibitors of the DNA damage response (DDR) provide an exciting opportunity as new anti-cancer therapies. A prominent example is olaparib, an inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1), that has shown potential as a monotherapy for tumours bearing BRCA1/2 defects in clinical trials. Apart from monotherapy based on the concept of synthetic lethality, PARP inhibitors also have the potential to provide additional benefit when used in combination with DNA damage-inducing chemotherapies. In the clinic, however, this approach has been challenging due to enhanced bone marrow toxicity. Our aim is to generate preclinical models to provide a better understanding of the mechanisms for this limiting bone marrow toxicity. We characterized in vitro responses to DNA damage induced by IR and chemotherapy in human hematopoietic multipotent progenitors and mesenchymal stem cells, both components of bone marrow. In parallel, we modelled the effects of a platinum chemotherapy (carboplatin) in combination with olaparib in wild type rats with the aim of reproducing the clinical combination-induced bone marrow toxicity. We will present data that provide initial insights into the suitability of the rat pre-clinical model to guide combination dose and schedules with olaparib and an assessment of the ability of different bone marrow and peripheral blood cell populations to act as useful biomarkers to guide better tolerated combination schedules. Citation Format: Mark J. O9Connor, Helen Mason, Steve Horner, Ian Slater, Alan Lau, Elaine Cadogan, Lenka Oplustilova. Generating preclinical models to assess bone marrow toxicity induced by the PARP inhibitor olaparib in combination with chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4420. doi:10.1158/1538-7445.AM2013-4420