Triple-negative breast cancer (TNBC) is the most aggressive type and accounts for at least 15% of all types of breast cancer in the USA. TNBC is defined as tumors that lack the expression of estrogen receptor, progesterone receptor and human epithermal growth factor 2, and it is always characterized by poor prognosis due to the lack of molecular targets and the rapid development of resistance to many chemotherapeutic drugs. Interfering with microtubule dynamics is a validated drug target. Currently, one of the standard cares for TNBC treatment is using taxanes based chemotherapy, such as paclitaxel, which targets microtubules. However, drug resistance and neurotoxicities often limit their clinical efficacy, thus there are continuous needs to develop more effective therapies that could overcome these clinical limitations. In this study, we evaluated the preclinical efficacy of our potent tubulin inhibitor, ABI-231, in treating TNBC in mouse xenograft models. ABI-231 inhibited tubulin polymerization and effectively overcame P-gp mediated multidrug resistance, and it is orally available. ABI-231 showed remarkable anticancer activities against two TNBC cell lines at low nanomolar concentrations, and it could inhibit the cancer cell colony formation. Treatment with ABI-231 suppressed invasion and migration of TNBC cells, and significantly induced apoptosis of TNBC cells in vitro. ABI-231 inhibited TNBC tumor growth in a dose-dependent manner without acute toxicity in an orthotopic TNBC xenograft model. ABI-231 had similar efficacy to that of paclitaxel as tested in this mouse model. In addition, ABI-231 significantly reduced metastasis of TNBC in a tail vein mouse model. Collectively, these preliminary studies strongly suggest that ABI-231 is potent to inhibit the growth and metastasis of TNBC both in vitro and in vivo, and this potent tubulin inhibitor is a promising drug candidate for the more effective treatment of TNBC. Supported by NIH grant R01CA148706.
Citation Format: Shanshan Deng, Raya Krutilina, Qinghui Wang, Tiffany N. Seagroves, Duane D. Miller, Wei Li. A potent and orally available tubulin inhibitor ABI-231 suppresses triple negative breast cancer tumor growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2154.