Abstract 4483: Preclinical study of Dbait, an inhibitor of three DNA repair pathways, in breast cancer treatment.
Authors: Marie Dutreix, Youlia M. Kirova, Amelie Croset, Flavien Devun, Jian-Sheng Sun
Journal: Cancer Research (2013)

Abstract Background: Five main types of therapies are available for the treatment of Breast Cancer (BC): surgery, radiation therapy, chemotherapy, hormone therapy, and most recently, targeted therapy. Most patients are treated with surgery in combination with one or more additional therapies for optimal cancer management. The limit of targeted therapy is that they are usually directed at specific targets in the body (extracellular receptors, kinases and enzymes) and therefore apply for limited number of patients. Herceptin and more recently trastuzumab have been shown to increase survival of patients over-expressing the HER2/neu receptor (20-30% of BC). PARP inhibitors that act as synthetic lethal with BRCA deficiency have shown promising results. These inhibitors that target the PARP-dependent DNA repair pathway seem however less efficient in patient with active homologous recombination repair. We have recently developed a new strategy (DNA repair bait, Dbait in short) that inhibits three central repair pathways (Homologous Recombination, Non Homologous End Joining and Single Strand Break Repair). DT01 is the 1st drug candidate of this family of DNA repair inhibitor already in a phase 1 trial in local metastatic melanoma. This study demonstrates the efficiency of DT01 in BC treatment. Materials and methods: Twelve BC cell lines were characterized for DNA repair gene expression and activation of the DNA damage response DDR (pH2AX and PAR detection) by western blot analysis of the proteins and classified according to their BRCA status. Clonal survival to Dbait (the DT01 in vitro variant) was analyzed 10 days after treatment. Four xenografted models derived from cell lines or patient samples were assayed for sensitivity to DT01. DT01 (5mg) was subcutaneousely administered every day for a week (5 sessions) or four days per week for three weeks (12 sessions of 2mg). In parallel, the PARP inhibitor ABT-888 was orally administered at the dose of 25 mg/day/kg during one week to compare efficiencies. Tumor growth and survival of untreated and treated animals were monitored during 150 days. Tumors were analyzed for different repair and stress markers by immunocytology. Results: This study provides the evidences that: i) Dbait induces death in vitro in BRCA-/- cells but also in BRCA+/+ cells having a high level of spontaneous DDR; ii) DT01 controls tumor growth in all the model tested with or without BRCA mutation; iii) DT01 cured 30% BRCA-/- tumors; iv) DT01 was more efficient that ABT-888 which did not allow any cure and showed a 73% increase of survival. At the end of the study 80% of the animals treated by DT01 were still alive. Conclusion: DT01 is a promising investigational medicinal product to treat Breast Cancer. Its association with radiotherapy is under investigation. Citation Format: Marie Dutreix, Youlia M. Kirova, Amelie Croset, Flavien Devun, Jian-Sheng Sun. Preclinical study of Dbait, an inhibitor of three DNA repair pathways, in breast cancer treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4483. doi:10.1158/1538-7445.AM2013-4483