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Abstract Introduction: Adult type ovarian granulosa cell tumors (GCTs) represent 5-7% of ovarian cancers and are the most common subtype of ovarian sex cord stromal tumors. Primarily driven by a C134W mutation in FOXL2 (present in ~97% of tumors), GCTs have a tendency for late recurrence without effective treatment options. Expression of mutant FOXL2 results in modified binding to transcription factors, including members of the SMAD family, and changes in apoptotic pathway signaling. Notch is an essential pathway for development of the ovary and plays important roles in the post-natal ovary including regulation of folliculogenesis, meiosis, vasculogenesis, and steroid hormone production. Notch signaling has been shown to promote FOXL2 expression, and cleavage of the Notch intracellular domain (NICD) by the enzyme gamma secretase (GS) can enhance SMAD signaling and promote interactions of SMADs with binding partners, including NICD. Emerging evidence suggests that Notch signaling, which is activated by GS-mediated cleavage, can promote tumor growth. Nirogacestat is an investigational, oral, small-molecule, selective gamma-secretase inhibitor (GSI) which, in a phase 3 study in patients with progressing desmoid tumors, significantly improved progression-free survival compared with placebo. Previous studies showed that inhibition of Notch signaling in a granulosa tumor cell line by the GSI “DAPT” could increase apoptosis and inhibit proliferation. Therefore, this study sought to evaluate effects of nirogacestat in FOXL2 C134W mutant granulosa cells. Methods: The effects of nirogacestat were evaluated in vitro using the “KGN” GCT cell line, which harbors a FOXL2 C134W mutation. Cell proliferation of KGN cells was analyzed by MTT assay, and clonogenic survival was analyzed using crystal violet staining in a dose-response assay. Furthermore, gene expression analysis of markers of cell cycle (TOP2A, CCNE2), epithelial to mesenchymal transition (SNAI2, MMP2), and apoptosis (CASP6) was performed by qPCR. Results: Nirogacestat significantly inhibited the proliferation of KGN cells in a dose-dependent manner. Similarly, clonogenic survival was significantly reduced after 10 days of treatment and correlated with administered concentration of nirogacestat treatment in vitro. We also observed a significant reduction in the expression of cell cycle markers TOP2A and CCNE2 by qPCR after 1 week of treatment with nirogacestat. Additionally, we found a significant induction of the apoptotic marker CASP6 and reductions of the EMT markers SNAI2 and MMP2 after high-dose treatment with nirogacestat. Conclusion: Treatment of the KGN GCT cell line with nirogacestat in vitro inhibited cell proliferation and growth in a concentration-dependent manner. Furthermore, nirogacestat markedly inhibited the expression of cell cycle markers, suggesting a cytostatic effect in granulosa cells which aligns with results from studies in desmoid tumor models. Collectively, these data suggest that nirogacestat represents a potential novel therapeutic agent for treatment of adult type GCTs. Citation Format: Maeva Y. Chauvin, David Pépin. Pre-clinical evaluation of the gamma-secretase inhibitor nirogacestat in an adult-type ovarian granulosa cell tumor model abstract. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₂): Abstract nr A023.
Chauvin et al. (Mon,) studied this question.