Graduation Date

Spring 5-7-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Adam R. Karpf, PhD

Abstract

Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases, and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell (CSC) properties, (5) genomic instability, and (6) altered cellular metabolism. There is ample evidence for FOXM1 as a cancer biomarker and rationale for FOXM1 as a cancer therapeutic target. Therapeutic strategies targeting FOXM1 for cancer treatment are actively pursued in the cancer research field. As an oncogenic transcription factor highly upregulated in numerous cancer types and responsible for promoting multiple hallmarks of the disease, FOXM1 is a promising target for treatment against high-grade serous ovarian carcinoma (HGSC), a lethal and aggressive cancer that overexpresses FOXM1 and its transcriptional pathway. Several FOXM1 inhibitors have been discovered and characterized, but none have advanced to clinical trials. The Katzenellenbogen groups at the University of Illinois at Urbana-Champaign recently developed novel 1,1-diarylethylene FOXM1 inhibitors (NB compounds). We show that these NB compounds decreased FOXM1 expression through proteasomal degradation, which resulted in decreased expression of its downstream target cyclin B1 (CCNB1), without affecting other FOX family members. The NB compounds also exhibited robust anti-cancer effects by promoting apoptosis, suppressing colony formation more potently than other FOXM1 inhibitors, and synergizing with carboplatin to inhibit the viability of HGSC cells. Moreover, these NB compounds potently and selectively inhibited HGSC cell viability, more so than a panel of other reported FOXM1 inhibitors. Our data demonstrate that the NB compounds are promising FOXM1 inhibitors that may serve as a novel therapeutic strategy for HGSC and other cancers whose aggressive biology is driven by FOXM1 and its oncogenic transcriptional pathway.

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