ORCID ID
Graduation Date
Spring 5-9-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Cancer Research
First Advisor
Adam Karpf
Abstract
High-grade serous ovarian carcinoma (HGSOC), the most common and deadliest subtype of ovarian cancer, is characterized by high rates of relapse, necessitating the development of novel therapeutic approaches. The transcription factor, forkhead box M1 (FOXM1) serves as one such target given its frequent dysregulation and oncogenic activity in HGSOC. Recently, NB compounds were developed as small molecule inhibitors of FOXM1, exhibiting anti-cancer activity in breast cancer, multiple myeloma, melanoma, and small cell lung cancer. Herein, we show that NB compounds downregulate FOXM1 and its transcriptional network in a dose and time-dependent manner in HGSOC cells, which may be a consequence of their ability to act as hydrophobic tags. Expression of FOXM1 and its head-to-head gene partner RHNO1 were also significantly decreased, indicating that NB compounds may be disrupting regulation of the bidirectional promoter. Importantly, NB compounds decreased HGSOC cell viability more potently than the chemotherapeutic carboplatin and induced cell cycle arrest. While both compounds triggered apoptosis, their inhibitory effect on FOXM1 and its pathway was independent of this. Additionally, NB compounds maintained durable effects on FOXM1, its pathway, and HGSOC cell viability following short-term treatments. To further understand the mechanism of action of NB compounds in HGSOC, we employed an unbiased proteomics approach. We observed downregulation of proteins and pathways associated with FOXM1, further supporting NB compounds as FOXM1 inhibitors. Interestingly, NB compounds downregulated MYC, an oncogenic transcription factor known to regulate and be regulated by FOXM1. Among proteins upregulated by NB compounds, we identified an unfolded protein response (UPR) signature. NB compound mediated UPR activation is not a consequence of FOXM1 or non-specific tagging of proteins, and the mechanism driving this effect requires further investigation. While activating the UPR to drive cancer cells to apoptosis is a therapeutic strategy, we observed an antagonistic interaction between NB compounds and UPR activators. Together, these data support NB compound FOXM1 inhibitors as a potential therapeutic strategy for HGSOC, though further analysis is needed to identify additional pathways that could be targeted for combination treatments.
Rights
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Recommended Citation
Vorderbruggen, Makenzie, "Understanding the Mechanism of Action of NB Compound Small Molecule Inhibitors in High-Grade Serous Ovarian Carcinoma" (2026). Theses & Dissertations. 1052.
https://digitalcommons.unmc.edu/etd/1052