Introduction and Background: Breast cancer afflicts 1 in 8 women in the United States and is the second leading cause of cancer death in women. An estimated 232,340 new cases of invasive breast cancer will be diagnosed in 2013 with 39,620 deaths. Triple-negative breast cancer (TNBC) lacks estrogen (ER), progesterone receptors (PR), and human epidermal growth factor 2 (HER2) and accounts for ∼15% of breast cancers. TNBC is associated with an overall poor prognosis due to an aggressive and early pattern of metastasis and a relative lack of therapeutic targets. Chemotherapy remains the cornerstone of treatment albeit with a dismal response rate (∼ 25%) to monotherapy. It is critical to improve therapeutics in this disease. A key to improving treatment is identification of synergism between drugs which enhances effectiveness, decreases resistance and reduces toxicities. With TNBC being highly proliferative, we sought to exploit potential utility of agents targeting specific aspects of proliferation and could exhibit synergy.
Experimental Methods: We assembled a library of agents, each with unique intracellular mechanisms and targets that have subtly different effects on cell division. We constructed detailed dose response curves (DRC) for these agents in MDA-MB-231, a TNBC cell line. Subsequently, we performed a novel synergy screen testing 105 unique two-drug combinations in TNBC. Our screen was especially designed to distinguish between synergism and additivity through presence of an internal control and performed in sufficient replicates to distinguish changes in viability exceeding 5%.
Results: We have discovered a promising synergistic combination of 5-iodo 2-deoxypyrimidinone 2′-deoxyribose (IPdR) with Aurora kinase inhibitors, MLN 8237 and ZM 447439. IPdR is a pro-drug of 5-iodo-2′-deoxyuridine (IUdR), a potent radiosensitizer. MLN 8237 is a selective inhibitor of Aurora A kinase which activates the spindle assembly checkpoint leading to mitotic arrest while ZM 447439 disrupts activity of Aurora B kinase and results in accelerated mitotic slippage, failed cytokinesis, and ultimate apoptotic cell death. This is the first time that synergy between IPdR and anti-mitotic agents has been demonstrated and moreover, the first discovery of cytotoxic effect of IPdR without requiring hepatic metabolism to IUdR.
Conclusions and Future Directions: The discovery of synergy between IPdR and Aurora kinase inhibitors is a significant finding with potential clinical implications. We are pursuing further studies understanding the underlying biology behind this synergy and validation in pre-clinical models of TNBC. We plan to pursue these synergistic combinations in early phase clinical trials through the NCI CTEP or other mechanisms.
Citation Format: Murtuza M. Rampurwala, Alka Choudhary, Mark E. Burkard. Novel synergy of radiosensitizer prodrug IPdR with Aurora kinase inhibitors in triple-negative breast cancer. [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 2638. doi:10.1158/1538-7445.AM2014-2638