Abstract PS3-02-15: L024, a promising candidate for the prevention and interception of triple negative breast cancer and its metastasis to the brain

Abstract L024, a promising candidate for the prevention and interception of triple negative breast cancer and its metastasis to the brainIntroduction: Estrogen receptor negative (ER-neg) breast cancer (BC) disproportionately affects younger women, women of African descent, and socioeconomically disadvantaged populations. Excluding high-risk groups, e.g. BRCA1 carriers, for whom there are surgical risk reduction strategies, no approved preventive agents exist for this subtype. ER-neg BCs, including triple-negative (TNBC) and HER2+ tumors, often metastasize to the brain at early stages, yet remain clinically undetected until neurologic symptoms appear, by which time prognosis is poor. Current therapies, including adjuvant drugs for ER-neg BC, offer limited efficacy against brain metastases due to poor brain penetration. Radio-surgical approaches to treat brain metastases carry significantly debilitating side effects with no significant enhancement in survival. There is an urgent need for safe, non-hormonal risk-reducing medications that can prevent both ER-neg BC and its dissemination to the brain.We have identified L024, a promising first-in-its-class, non-endocrine agent which shows strong efficacy against ER-neg BC. Mechanistic studies demonstrate that L024 acts through inhibition of SREBP1-driven lipogenesis, suppression of the PI3K-AKT axis, and downregulation of NF-κB-mediated inflammation, key pathways in ER-neg BC progression and metastasis. However, its potential to intercept or prevent metastatic dissemination, particularly to the brain, remains unexplored. We hypothesize that L024 suppresses ER-neg tumor growth and hinders early metastatic spread to the brain, representing a novel preventive and interceptive approach. Methods: We evaluated the antiproliferative effects of L024 across five ER-neg BC cell lines: MDA-MB-231 (human TNBC), HCC-1937 and HCC-3153 (BRCA1-mutant TNBC), 4T1 (mouse TNBC with high metastasis potential), and MDA-MB-231-Br (human brain-tropic TNBC) using IncuCyte under single and repeated dosing. We developed xenograft tumors of MDA-MB-231 cells in nude mice and treated the animals with daily doses of 80 mg/kg of L024 when the tumors reached a threshold size. We monitored changes in tumor size over 28 days and conducted RNA sequencing on the tumors upon the completion of the studies. Invasion and migration were assessed using Transwell assays with or without extracellular matrix following sublethal L024 treatment (5 μM, 2.5 μM). In silico ADME studies were conducted using ADC Lab software. Pharmacokinetics (PK) were evaluated in female CD-1 mice dosed with L024 (50 mg/kg). Drug levels in plasma, mammary, and brain tissue were measured and modeled using SAAM II. Results: L024 significantly inhibited malignant cell proliferation at concentrations dose-dependently, with effects sustained up to six days post-treatment. It also significantly reduced tumor growth and epithelial to mesenchymal transition in xenograft tumors, suggesting anticancer and antimetastatic effects. Sublethal doses reduced invasion and migration of 4T1 and MDA-MB-231-Br cells, suggesting further validating anti-metastatic potential. In silico profiling indicated favorable CNS penetration: low molecular weight (<400 Da), optimal lipophilicity (LogP = 3.9), low topological polar surface area (66.76 Å2), and no P-gp/BCRP efflux liability. In vivo PK confirmed high brain exposure, with brain-to-plasma (Kp) ratios >1 between 1–8 h post-dosing and clearance by 24 hours, indicating suitability for prevention and therapy. Conclusions: L024 reprograms metabolic and inflammatory pathways essential for ER-neg BC progression and early brain metastasis. CNS pharmacokinetics support further evaluation in immunocompetent models of TNBC with brain metastatic potential. Citation Format: A. Hajirahimkhan, E. T. Bartom, S. M. Roy, A. M. Eremin, R. Chen, D. M. Watterson, S. E. Clare, S. A. Khan. L024, a promising candidate for the prevention and interception of triple negative breast cancer and its metastasis to the brain [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 PS3-02-15.