Abstract 3040: FOXM1 as a drug target in NF1-associated malignant peripheral nerve sheath tumors

Abstract Purpose: Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas that arise spontaneously or via transformation of benign tumors, called plexiform neurofibromas (PNFs) and atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBPs), in patients with Neurofibromatosis Type 1 (NF1). Understanding molecular events that cooperate to promote malignancy is a priority in the field. One putative driver, FOXM1, is a powerful transcription factor that heightens the activities of kinases, MEK and CDK4/6, known to drive MPNST growth. We sought to understand the role of FOXM1 in these deadly sarcomas and hypothesized it is a new druggable target that is essential for MPNST pathogenesis. Methods: FOXM1 mRNA and protein expression were evaluated in patient-matched PNFs, ANNUBPs, and MPNSTs via RNA-Seq and IHC. For in vitro studies, knockdown (KD) of FOXM1 was performed in MPNST cell lines (S462, sNF96.2, JH2-002). Proliferation, survival, and cell cycle progression were measured in response to FOXM1 inhibitors, including newly developed NB-55, NB-73 and NB-115 drugs. To directly test the in vivo role of FOXM1 in MPNST initiation and progression, de novo MPNSTs were initiated by Nf1/Ink4a/Arf editing in the sciatic nerve of Nf1+/-, DhhCre, Foxm1 floxed mice relative to Nf1+/-;DhhCre controls. Results: In patient-matched tumor sets, FOXM1 mRNA was significantly elevated in MPNSTs relative to PNF/ANNUBP precursor lesions. FOXM1 protein expression rose dramatically in a stepwise manner from normal nerve to PNFs, ANNUBPs, and MPNSTs. FOXM1 KD slowed MPNST cell growth. FOXM1 inhibitors (thiostrepton, FDI-6, and multiple NB drugs) effectively inhibited MPNST proliferation and induced apoptosis. Synergistic killing of MPNST cells was obtained by combining thiostrepton with a MEK inhibitor (mirdametinib), CDK4/6 inhibitor (palbociclib), or EGFR inhibitor (gefitinib), while NB drugs synergized best with gefitinib. Excitingly, targeted in vivo deletion of Foxm1 in the sciatic nerve significantly slowed tumor progression. Conclusion: Our data demonstrate FOXM1 is an important driver of MPNST pathogenesis. FOXM1 expression and transcriptional activity are greatly increased in MPNSTs compared to benign precursors from the same patients. In agreement, genetic and therapeutic inactivation of FOXM1 promoted MPNST cell arrest and death. Synergistic killing of MPNSTs was achieved by combined inhibition of FOXM1 with MEK, CDK4/6, or EGFR while Foxm1 ablation in the sciatic nerve significantly slowed tumor progression in vivo. Together, these findings reveal that FOXM1 inhibition in specific combination therapies represents a new treatment strategy for MPNST patients. Citation Format: Ellen M. Voigt, Quinn Hanigan, Joshua J. Lingo, Altay Koyas, Rebecca D. Dodd, Benjamin W. Darbro, Dragana Kopanja, Sung Hoon Kim, Benita S. Katzenellenbogen, John A. Katzenellenbogen, Dawn E. Quelle. FOXM1 as a drug target in NF1-associated malignant peripheral nerve sheath tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3040.