Abstract 3670: NanoPARPi inhibitors for ovarian and prostate cancer therapy
Authors: Tangutoori Shifalika , Bladwin Paige , Ohman Anders , Korideck Houari , Cormack Robert , Dinulescu Daniela , Makrigiorgos Mike , Sridhar Srinivas 
Published: August 2015

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 and BMN-673 are potent PARP inhibitors that are currently indicated for chronic therapy in several clinical trials for a variety of cancers. Here we report novel and well characterized nanoformulations customized for olaparib (NanoOlaparib) and BMN-673 (NanoBMN-673), 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-673 have been successfully formulated and tested invitro on several cancer cell lines. The initial combination studies were performed with Cisplatin and each of the PARP inhibitors and the nanoformulation is defined by nanoparticles ∼120 nm diameter, zeta potential ∼ +30mV, and loaded with Olaparib (18mM) 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 various customized assays and EC50's were determined. The synergism due to radiosensitization was studied for both therapies using isobolograms. The efficacy of combination PARPi and Pt therapy with nanoparticle platform was determined on GEMM models of endometrial cancers. The functionality of nanoPARPi formulations, reflected by inhibition of PARylation, and cleaved PARP was determined by immunoflourescence assays.

Results: NanoPARPi inhibitors were assayed on atleast 8 ovarian cancer cells using various cell based assays. NanoBMN was the most potent PARP inhibitor which is not functionally dependent on BRCA sensitive cells lines whereas nanoOlaparib, seems to be sensitive towards triple negative GEMM derived Ovarian cells (403, 404). PTEN deficient prostate cancer cells were more susceptible to radiosensitization with both nanoPARPi inhibitors (Olaparib, BMN-673), achieving significant long-term cell kill. In all studies NanoBMN-673 showed better efficacy in combination with radiation than NanoOlaparib. In vivo studies with irradiation are underway.

Conclusions: Robust nanoformulations, NanoOlaparib and nanoBMN-673 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-673 as chemo and radio-sensitizers enabling several combination therapeutic approaches.

Citation Format: Shifalika Tangutoori, Paige Bladwin, Anders Ohman, Houari Korideck, Robert Cormack, Daniela Dinulescu, Mike Makrigiorgos, Srinivas Sridhar. NanoPARPi inhibitors for ovarian and prostate cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3670. doi:10.1158/1538-7445.AM2015-3670