Abstract 1670: Sabizabulin shows anti-cancer efficacy in HER2+ breast cancer and novel sabizabulin derivatives overcome paclitaxel-resistance in triple negative breast cancer

Abstract

Abstract Of the four breast cancer molecular subtypes, the HER2 overexpressing subtype (HER2+) accounts for 15% of all breast cancer cases. Preferred frontline treatment relies on anti-HER2 therapies, such as trastuzumab and pertuzumab, combined with microtubule inhibitors, such as taxanes. However, the clinical efficacy of taxanes is limited by development of chemoresistance and hematological and neurotoxicities. Other agents that target tubulin, such as colchicine-binding site inhibitors (CBSIs) are a class of promising alternatives to taxane therapy due to their ability to overcome P-gp-mediated taxane resistance. Sabizabulin (formerly known as VERU-111) is a potent CBSI that is orally bioavailable, overcomes paclitaxel resistance, and inhibits tumor growth and distant metastases in triple negative breast cancer (TNBC). Here, we demonstrate sabizabulin’s anti-cancer efficacy in HER2+ breast cancer. We report that sabizabulin inhibits proliferation of HER2+ breast cancer, maintains a low nanomolar IC50 value, inhibits colony formation, and causes apoptosis in HER2+ breast cancer cell lines. Sabizabulin inhibits the primary tumor growth in an orthotopic HER2+ in vivo model, BT474, and in a patient-derived xenograft model, HCI-12. While sabizabulin shows promising results for treatment in HER2+ breast cancer, we further optimized the structure of sabizabulin to create a new class of anti-cancer molecules: 40a, CH-2-77, and 60c. Based on in vitro data, 60c showed higher potency in HER2+ breast cancer cell lines and was chosen as the lead compound to further study in a paclitaxel-resistant triple negative breast cancer in vivo study where it was able to effectively inhibit primary tumor growth compared to the vehicle group. Citation Format: Kelli L. Hartman, Raisa I. Krutilina, Damilola Oluwalana, Deanna N. Parke, Hao Chen, Duane D. Miller, Wei Li, Tiffany N. Seagroves. Sabizabulin shows anti-cancer efficacy in HER2+ breast cancer and novel sabizabulin derivatives overcome paclitaxel-resistance in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1670.