Abstract 4293: In vivo imaging and tracking of a PARP inhibitor at single-cell resolution

Abstract

Abstract PARP is an enzyme involved in sensing single-stranded DNA breaks and plays a critical role in the organization of DNA damage repair. Several PARP inhibitors have been developed for clinical use, particularly in breast and ovarian cancers with BRCA mutations. Despite the scientific rationale and promising early clinical results with PARP inhibitors, more advanced clinical trials in breast cancer have been disappointing. One of the questions arising from these trials is to better understand why the PARP inhibitors failed. We used a window-chamber system in mice to image the distribution and function of model PARP inhibitors such as AZD2281-Bodipy. Specifically, we measured the kinetics of vascular, cellular, and subcellular uptake and distribution of AZD2281-Bodipy in breast (MDA-MB-231, MDA-MB-436) and ovarian (OVCAR429, A2780) tumors over time. Additionally, using the fluorescently-labeled inhibitor, we were able to examine the heterogeneity of AZD2281 localization in single cancer cells in vivo. Our data provide the first example of single-cell distribution of fluorescent small molecule inhibitors. When coupled with reporter cell lines (e.g. for apoptosis, DNA damage, autophagy, and senescence), this approach will be a powerful tool to understand drug action in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4293. doi:1538-7445.AM2012-4293