Abstract 1116: Targeting replication stress by carbazole blue- A novel strategy to treat triple negative breast cancers

Abstract

Abstract Background: Triple-negative breast cancers (TNBC) are the most aggressive forms of breast cancer and almost 60% of patients with TNBCs develop chemo-resistance, leading to recurrence, poor prognosis and poor survival. TNBCs have been reported to have high levels of replication stress, which plays pivotal role in genomic instability, and therapy resistance. Targeting replication stress is an emerging approach for better TNBC treatment. Here, we evaluated the anticancer efficacy of carbazole blue (CB), a synthetic analogue of carbazole that we recently synthesized on TNBC cells growth and progression. Experimental Design: The effect of CB on breast cancer growth was assessed in vitro as well as in orthotopic mouse xenograft and PDX-models of breast cancer. In addition, the therapeutic efficacy and safety of CB was determined in long term toxicity studies in mice and also in ex-vivo explants from breast cancer patients. The mechanism of action of CB was evaluated by performing gene expression, cell cycle, apoptosis and DNA repair studies as well as proteins involved in the above mentioned mechanisms. Results: Our results demonstrated that CB inhibits short and long term viability of TNBC cells in a dose dependent manner without affecting normal mammary epithelial cells. We show that the systemic delivery of CB using nanoparticle-based delivery approach suppressed breast cancer growth without inducing toxicity in preclinical and PDX mouse models of triple negative breast cancer. Our long term toxicity studies reveled that CB treatment did not induce any toxicity in Balb/c mice. Using ex-vivo explants from breast cancer patients, we demonstrated that CB modulated breast cancer growth. Consistent with that, our results revealed that CB treatment induced G1/S cell cycle arrest and apoptosis in TNBCs. Interestingly, our gene expression analysis revealed that CB modulates expression and activity of several genes known to be involved in DNA replication and DNA repair machinery. Conclusions: Our results for the first time showed the CB can serve as a novel and potent therapeutic agent for treating breast cancer in general and TNBC in particular. These findings highlight the potential of CB to be applied as a safe regimen for treating breast cancer patients. As exploiting replication stress to treat cancer is gaining major interest, compound/s that may induce replication stress and inhibit DNA repair ability of cancer cells, has immense translational potential. Citation Format: Subapriya Rajamanickam, Kaitlyn Bates, Santosh Timilsina, JunHyoung Park, Benjamin Onyeagucha, Panneerdoss Subbarayalu, Nourhan Abdelfattah, Kwang Hwa Jung, Edward Favours, Tabrez A. Mohammad, Hung-I Harry Chen, Benny A. Kaipparettu, Yidong Chen, Jack L. Arbiser, Manjeet K Rao. Targeting replication stress by carbazole blue- A novel strategy to treat triple negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1116. doi:10.1158/1538-7445.AM2017-1116