Abstract 1753: A novel FOXM1 inhibitor inhibits FOXM1 cell proliferation, migration, and invasion tumor growth in triple negative breast cancer

Abstract Triple-negative breast cancer (TNBC) accounts for ∼15-20% of breast cancer cases (52, 000 women in the US only), is characterized by lack of estrogen, progesterone, and HER2 receptor expression; aggressive phenotype, high rates of early relapse and metastasis and the worst mortality rates among all breast cancer subtypes. TNBC is insensitive to the available targeted therapies, including anti-estrogens (i.e, tamoxifen, aromatase inhibitors), anti-HER2 and EGFR antibodies due to lack of actionable targets. Unfortunately, about 50-70% of the patients cannot achieve complete pathological remission in response to chemotherapy and die within the first 5 years after diagnosis. Therefore, there is a critical need for the development of highly effective and novel therapies to improve patient survival. We previously validated for the first time FOXM1 protooncogenic transcription factor as a potential molecular target in TNBC through genetic knockdown studies and demonstrated that genetic inhibition of FOXM1 completely blocks TNBC tumor growth in multiple tumor models in mice with no detected toxicity. We also found that FOXM1 expression is associated with dramatically shorter patient survival and identified it as a poor prognostic marker. We demonstrated that FOXM1 drives tumorigenesis, progression by inducing cell proliferation, invasion/metastasis, drug resistance by transactivating expression of multiple oncogenes. We found that FOXM1 is broadly overexpressed in TNBC tumors due to widespread p53 mutations which are detected in about 84% of TNBC patients, suggesting that TP53 mutations are the major driver of FOXM1 overexpression. Overall data suggest that FOXM1 is an excellent potential molecular target for TNBC. However, currently, there is no FDA approved inhibitor of FOXM1. To identify potential inhibitors, utilizing silico docking and molecular dynamics studies we screened the chemical libraries and found identified a novel which interacted with FOXM1 protein based on in silico molecular dynamics studies and demonstrated that this inhibitor suppresses FOXM1 expression and cell proliferation, migration, invasion, and induces apoptosis in TNBC cells and more potent that well known FOXM1 inhibitor (FDI-6). In vivo treatment mice bearing MDA-MB-231 tumors with novel FOXM1 inhibitor (20mg/kg, twice a week) incorporated in single-lipid nanoparticles suppressed growth of TNBC tumor xenografts in mice with no toxicity. In conclusion, the findings indicate that the novel FOXM1 inhibitor represents a potent and safe therapeutic agent with significant potential for the treatment of TNBC and other FOXM1-driven cancers. This discovery offers new hope for improving outcomes in a disease that currently has limited treatment options. Citation Format: Sayra Dilmac, Nermin Kahraman, Ogun Ali Gul, Ferah Comert Onder, Bulent Ozpolat. A novel FOXM1 inhibitor inhibits FOXM1 cell proliferation, migration, and invasion tumor growth in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1753.