Repurposing nirogacestat, a gamma secretase enzyme inhibitor in desmoid tumors

Summary

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.