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.
Keywords: Desmoid; drug development; gamma secretase inhibitor; patient advocacy; rare tumors.
The role of the enzyme gamma secretase (GS) was discovered in various processes of adhesion between various cells, formation of blood vessels and development of new nerve systems. This enzyme has been found to have a role in the onset and worsening of Alzheimer’s disease (AD), which is a type of dementia. Some clinical trials examined if GS-inhibiting drugs could help in the treatment of AD but were not pursued further due to significant side effects. However, in another study, it was discovered that the same class of medications was able to act against the rare disease known as desmoid tumor (DT). One of these drugs, nirogacestat, was initially examined in a small study which included patients with various cancers, including DT. The patients in this study had different types of cancers which had failed previous treatments. Among these patients, those with DT experienced good treatment outcome with 71.4% showing reduction in size of the tumor using nirogacestat. Being a rare disease, conducting trials with a greater number of patients was difficult in DT because of various reasons such as patients being scattered across countries, doctors being unaware of treatment options and the lesser efforts from the pharmaceutical industry. The patient advocacy group Desmoid Tumor Research Foundation (DTRF) came to the fore to help overcome these difficulties and act as a platform for the patients and physicians to help in collaborations and conduct further studies. Encouraging findings were obtained and finally the pivotal clinical trial (DeFi study) which demonstrated that nirogacestat was a new, superior treatment option for DT. Nirogacestat also improved the quality of life of the enrolled patients, which is an important factor in chronic diseases such as DT. The results of this study paved the way for the Food and Drugs Administration (FDA) approval of nirogacestat in the management of DT. We present the journey of these GS inhibitors, from the biological aspect to its role in the treatment of DT.