Abstract AS29: PARP inhibitor nano-therapy in ovarian cancer models

Abstract

Abstract Introduction: Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Olaparib is a potent PARP inhibitors that is currently indicated for oral inhibitor therapy in several clinical trials for a variety of cancers. Oral administration of these inhibitors in general results in poor bioavailability and tumor accumulation. Here we report the first novel nanoformulations customized for olaparib (NanoOlaparib), thus enabling a platform which provides a safe vehicle for intravenous delivery specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity. Methods: Two nanoparticle (120nm size) formulations NanoOlaparib and NanoOlaparibPt have been successfully formulated and tested in vitro on several cancer cell lines. Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines PA-1, KURAMOCHI, OVSAHO, SKOV3, and 4306, were generated using MTS assay and EC50's were determined using Prism. The synergism due to chemosensitization using cisplatin was studied for both therapies using isobolograms developed from delayed viability assay. Results: In vitro studies Cell viability studies were carried out with NanoOlaparib and NanoOlaparibPt in OvCa cell lines. The highly Pt-sensitive cell line PA-1 is strongly responsive to NanoOlaparib (blue) and NanoOlaparibPt (grey) although it is not known to carry a germline BrCa mutation. The multi-drug resistant cell line SKOV-3 is also more responsive to NanoOlaparib and combination NanoOlaparibPt. In vivo studies A pilot study was carried out in an endometrial OvCa murine model with KRaS-PTEN deletion to test the nanoformulations for biocompatibility and therapeutic efficacy. Bioluminescence images (Fig. 2) show tumor suppression of more than a nearly a factor of 3. All formulations were well tolerated. Conclusions: A robust nanoparticle formulation of the PARP inhibitor, Olaparib, has been successfully demonstrated. Both chemo sensitization and radio sensitization were studied in PC3, VCaP cell lines. Combinatorial administration of Nano (Olaparib+Cisplatin) showed greater cell death than Cisplatin alone or Cisplatin+ Olaparib/DMSO. We observed a significant enhancement in the cell killing ability (both immediate and delayed) with NanoOlaparib when compared to olaparib alone. Increased tumor accumulation and therapeutic efficacy were observed in prostate and breast cancer GEM models. These results show that NanoOlaparib amplifies the therapeutic efficacy of PARP inhibition and imply a very promising role for the nano-olaparib formulation in ovarian and other cancers. Figure 1:(a) TEM of Nanolaparib. The scale bar is 100nm long. (b) Cell viability studies with PA-1 and SKOV-3 cell lines and several formulations. (c) In vivo studies of NanoOlaparibPt in endometrial Kras/Pten models. Bioluminescence images before (T0) and after 3 (T3) and 6 (T6) NanoOlaparibPt administrations.Figure 1:. (a) TEM of Nanolaparib. The scale bar is 100nm long. (b) Cell viability studies with PA-1 and SKOV-3 cell lines and several formulations. (c) In vivo studies of NanoOlaparibPt in endometrial Kras/Pten models. Bioluminescence images before (T0) and after 3 (T3) and 6 (T6) NanoOlaparibPt administrations. Citation Format: Shifalika Tangutoori, Paige Baldwin, Jamie Medina, Anders Ohman, Daniela Dinulescu, Srinivas Sridhar. PARP inhibitor nano-therapy in ovarian cancer models [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS29.