Regulatory Signaling Pathways in Ovarian Cancer Stem Cells: Their Role in Tumor Progression and Therapeutic...

In ovarian cancer, ovarian cancer stem cells (OCSCs) not only contribute to tumor formation but also drive the progression, metastasis, and chemoresistance. The defining properties of OCSCs are sustained through the Wnt/β-catenin, Notch, and Hedgehog signaling pathways, which can synergize rather than act independently to form a triad that enhances key functional capabilities of OCSCs. Various therapeutic agents have been studied to target these pathways in OCSCs, including γ-secretase inhibitors (nirogacestat), smoothened inhibitors (vismodegib and sonidegib), and Wnt/β-catenin inhibitors (PRI-724 and ipafricept). While these agents have demonstrated antitumor activity in preclinical and early clinical studies, their clinical use remains challenging due to compensatory interactions among signaling pathways, which diminish the efficacy of single-agent treatments. To improve treatment outcomes, strategies involving combination approaches and personalized treatments need to be explored. This review aims to summarize current evidence on the role of Wnt/β-catenin, Notch, and Hedgehog signaling pathways in OCSCs and their therapeutic implications in ovarian cancer.