Abstract 2397: Nanoformulations of PARP inhibtors for cancer therapy

Abstract

Abstract Introduction: Poly ADP Ribose Polymerase inhibitor therapy (PARPi) exploits a synthetic lethality strategy in cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Olaparib and BMN-673 are potent PARP inhibitors that are currently indicated for oral PARPi in several clinical trials for a variety of cancers. Oral administration in general results in poor bioavailability and tumor accumulation. Here we report novel and well characterized nanoformulations customized for olaparib (NanoOlaparib) and BMN-673 (NanoBMN) , 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. Our nanoplatform is also tailored for the combinatorial chemotherapy and radio-sensitization in several cancers including prostate, ovarian and breast cancer cell lines with and without the BRCA mutations. Methods: Two nanoparticle formulations NanoOlaparib and NanoBMN have been successfully formulated and tested in vitro on several cancer cell lines. The initial combination studies were performed with Cisplatin and PARPi nanoformulations defined by ∼163 nm diameter, zeta potential ∼ +10mV, and loaded with olaparib (2.3mM) or BMN-673 (200µM) and cisplatin (∼3.3mM). Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines were generated using MTS assay and EC50's were determined using Prism. The synergism due to radiosensitization using 220 keV beam was studied for both therapies using isobolograms developed from clonogenic assays on prostate and breast cancer cells. The efficacy of combination PARPi and Pt therapy with nanoparticle platform was determined on ovarian cancer cell lines including PA-1, KURAMOCHI etc. The functionality of nanoPARPi/combination formulations on all the cancers, reflected by inhibition of PARylation, γ-H2AX and RAD-51 was determined by immunoflourescence assays. Results: Radiosensitization showed strong radiosensitization, achieving long-term cell kill of more than 90% with NanOlaparib and 4 Gy radiation in prostate cancer PC3, VCaP and LNCaP cell lines. VCaP which carries a TMPRSS2: ERG fusion was more responsive than PC3 for monotherapy using NanoOlaparib alone, and had better radiation sensitization compared to the other cell lines tested so far. In all studies NanoOlaparib showed better efficacy in combination with radiation than free Olaparib. Similar studies with nanoBMN are underway. Conclusions: Robust nanoparticle formulations NanoOlaparib and NanoOlaparibPt have been successfully demonstrated. We observed a significant enhancement in the efficacy with both nanoformulations. Strong radiosensitization was observed after several days. These results imply an important role for the nanoOlaparib and nanoBMN formulations as chemo and radio-sensitizers enabling several therapeutic approaches. Citation Format: Shifalika Tangutoori, Paige Baldwin, Houari Korideck, Robert Cormack, Mike G. Makrigiorgos, Srinivas Sridhar. Nanoformulations of PARP inhibtors for cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2397. doi:10.1158/1538-7445.AM2014-2397