Abstract B42: Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer
Authors: Belz Jodi , Liby Karen , Baldwin Paige , Kumar Rajiv , van de Ven Anne L. , Cormack Robert , Makrigiorgos Mike , Sridhar Srinivas 
Published: May 2016

Abstract
The breast cancer-associated gene 1 (Brca1) is the most frequently mutated tumor suppressor gene found in familial breast cancers. Mutations of the gene modulate many cellular functions including DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy can produce cell death in cancers with genetic predispositions for impaired DNA repair or transcription pathways such as Brca1 mutants. Here we report a novel biodegradable implant for the local delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib in contrast to low bioavailability and toxicity associated with oral delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ∼50μg Talazoparib. The implants were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50 was determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− mice. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: In vitro studies
The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses. Breast cancer cell lines W0069 and W780, derived from Brca1 Co/Co; MMTV-Cre; p53+/− mice were highly sensitive to Talazoparib, most likely due to Brca1 mutation. PARP expression was examined via western blot analysis.
In vivo studies
In vivo studies using sustained drug release implants loaded with Talazoparib were also carried out in Brca1Co/Co;MMTV-Cre;p53+/- genetically engineered mice with 1 or more spontaneous breast tumors. Following a one-time implantation, tumors reduced in size by an average of 50%, while untreated tumors increased ∼5X in size. Talazoparib dosing appeared to be well tolerated by the mice. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib was observed in vitro and in vivo. The Talazoparib-loaded implants represent a novel delivery route that was well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition and is a promising new route for the treatment of highly aggressive breast cancer models.
We would like to acknowledge the Breast Cancer Research Foundation. This work was supported by the Army- W81XWH-14-1-0092 and Northeastern University – Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Karen Liby, Paige Baldwin, Rajiv Kumar, Anne L. van de Ven, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B42.