Abstract 1687: A BRCA2-targeting antisense oligodeoxynucleotide enhances cisplatin effectiveness by decreasing human tumor cell proliferation, metastatic frequency, and metabolic response

BRCA2 is involved in homologous recombination repair of double-stranded DNA breaks in human cells. Inactivating mutations in BRCA2 predispose to early onset cancer of the breast, ovary and other tissues. However, patients with tumors that harbor BRCA2 mutations respond better to cancer therapy. Therefore, reducing BRCA2 in cancer cells capable of homologous recombination repair may sensitize otherwise resistant tumors to DNA-damaging anti-cancer treatment. We developed a second generation antisense oligodeoxynucleotide (BR-1) that specifically targets BRCA2. BR-1 decreased BRCA2 mRNA and protein and inhibited BRCA2-mediated RAD51 repair focus formation. BR-1 potently sensitized A549 (lung), SKOV-3 (ovarian), and MDA-MB-231 (breast) cells to cisplatin as evidenced by decreased cell proliferation. However, non-cancerous HK-2 kidney cells were not sensitized to cisplatin by BR-1. In A549 cells BR-1 enhanced cisplatin or ionizing radiation-induced inhibition of in vitro colony formation. Cisplatin-resistant head and neck squamous cancer cells (HN-15a) were rendered as sensitive to cisplatin following BR-1 treatment as the parent population. In addition, BR-1 plus cisplatin treatment decreased A549 cell metastatic frequency in an in vivo chicken chorio-allantoic membrane (CAM) model by over 70% when compared with drug treatment alone. Treatment with BR-1 and cisplatin decreased cellular respiration (decreased oxygen consumption) compared to control oligonucleotide plus cisplatin treatment, suggesting that downregulation of BRCA2 in the context of platinating drug treatment alters cellular metabolism. This change in respiration occurred independently of changes in mitochondrial number. We are continuing to develop and test BR-1 with the aim of applying it in an adjuvant setting with cisplatin in human clinical trials in the future. Supported by grants from the Ontario Centres of Excellence (OCE) Citation Format: Mateusz Rytelewski, Jessica Tong, Adrian Buensuceso, Hon Leong, Peter Ferguson, Saman Maleki Vareki, Christine Di Cresce, Larissa Romanow, Trevor Shepherd, Bonnie Deroo, Ann Chambers, Mark Vincent, James Koropatnick. A BRCA2-targeting antisense oligodeoxynucleotide enhances cisplatin effectiveness by decreasing human tumor cell proliferation, metastatic frequency, and metabolic response. [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 1687. doi:10.1158/1538-7445.AM2014-1687