Abstract PS4-12-10: A novel therapeutic targeting triple negative breast cancer brain metastases

Abstract A novel therapeutic targeting triple negative breast cancer brain metastasesStacey J. Baker, Adrienne Boire, E.Premkumar Reddy, Hanna Y. IrieBackground/Rationale: Patients diagnosed with triple negative breast cancer (TNBC) have the lowest five-year survival rates compared to those diagnosed with other subtypes. Many patients develop metastatic recurrences soon after their initial diagnosis. Particularly problematic are central nervous system (CNS) metastases including brain and leptomeningeal metastases, for which patients with TNBC are at higher risk. Even after initial multimodality treatment, recurrent disease is common and contributes to the poor prognosis of patients with CNS disease. Cancer stem cells (CSC) defined as CD44 high/CD24 low-EpCAM+, and/or positive for high levels of aldehyde dehydrogenase-1 (ALDH1hi), play a critical role in treatment resistance of many cancers. CSCs are resistant to chemo/immunotherapy, as well as radiotherapy, and evade immune responses. Many TNBC’s are enriched for CSCs, and CSCs have been identified or isolated from brain metastases of multiple tumor types. Therefore, to achieve more durable remission and improve survival, CNS-targeted treatments need to eradicate CSCs in addition to bulk tumor cells. Although several CSC-inhibiting therapeutics have been proposed, the efficacy of most have been limited by single pathway-targeting. We recently discovered and reported on a novel compound, 108600, that potently and simultaneously targets multiple pathways activated in TNBC CSCs.108600, an inhibitor of CK2/Dyrk1/TNIK kinases, induces apoptosis of CSCs, as well as bulk tumor cells CK2/Dyrk1/TNIK expression is significantly higher in brain metastases vs. the paired primary breast tumors (GSE184869). Our studies investigated 108600 as a potential novel therapeutic for TNBC brain metastases. Methods: TNBC cell lines that spontaneously metastasize to the brain (BrM) were treated in vitro with 108600. Cell viability and apoptosis of bulk culture, as well as the CSC subpopulation, were assessed using Cell TiterGlo assays and flow cytometry. Pharmacokinetic studies were performed to assess bioavailability of 108600 in the brain. In vivo efficacy studies were initiated with human TNBC tumors in the brain generated by intracranial injection. Progression of tumor growth in the brains of mice treated with vehicle or 108600 were monitored by serial IVIS Imaging. Results: MDA-MB231, E0771 or 4T-1 cell line variants that spontaneously metastasize to the brain (BrM) were treated with vehicle or 108600 in vitro. 108600 potently inhibited viability of bulk culture BrM cells. There is significant enrichment of CD44hi/CD24low CSCs in MDA-MB231 BrM cells (∼60%).108600 treatment decreased viability of the CSC subpopulation and induced their apoptosis, as assessed by flow cytometry (Annexin V staining). In pharmacokinetic studies, levels of 108600 in the brain after a single intraperitoneal (IP) injection (50mg/kg) were significantly higher than the in vitro IC50 values for growth inhibition using BrM cells. In vivo efficacy studies were initiated using tumor models generated by direct intracranial injection of MDA-MB231/Luciferase cells for maximal consistency of intracranial tumor formation. Treatment with 108600 (IP) significantly inhibited growth of TNBC tumors in the brain. Ongoing and future studies aim to assess the efficacy of 108600 treatment against tumors formed by spontaneous metastases and effects on survival. Citation Format: S. J. Baker, A. Boire, E. Reddy, H. Y. Irie. A novel therapeutic targeting triple negative breast cancer brain metastases abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-12-10.