Abstract
The gamma secretase (GS) enzyme controls cell-cell adhesion, neural stem cell proliferation, neo-angiogenesis, spinal maturation, and metabolism of amyloid precursor proteins (APP). Pathological production of abnormal amyloid-beta isoforms and senile plaques serves as the basis for pathogenesis of Alzheimer's disease (AD). GS enzyme inhibitors such as semagacestat and avagacestat were explored in AD but the studies were paused because of adverse events attributed to their influence on the Notch pathway.Crosstalk between Notch and Wnt signaling pathways created a potential role for GS inhibitors in the treatment of malignancies such as glioblastoma multiforme, pancreatic, and breast cancers. In a phase I study on nirogacestat among refractory solid malignancies, overall response rate (ORR) of 71.4% was observed in desmoid tumor (DT). The pivotal DeFi phase III trial established superiority of nirogacestat in terms of progression-free survival and ORR, reducing the likelihood of progression by 71%. Emphasis was placed on patient-reported outcomes (PRO) including the DT-specific tool, GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom Scale (GODDESS).Nirogacestat received Food and Drug Administration (FDA) approval in November 2023 and European Commission approval in August 2025 for adults with progressing desmoid tumors (DT) who require systemic treatment. Further studies are underway to investigate other GS inhibitors such as AL-102 in the management of DT.