The Notch signaling pathway in desmoid tumor: Recent advances and the therapeutic prospects

Desmoid tumor (DT) is a rare fibroblastic soft-tissue neoplasm that is characterized by local aggressiveness but no metastatic potential. Although the prognosis is relatively favorable, the unpredictable disease course and infiltrative growth lead to significant impairments and morbidity. Aberrant activation of Wnt/beta-catenin signaling has been well-established in the pathogenesis of sporadic DT and familial adenomatous polyposis (FAP) or Gardners syndrome-associated DT, suggesting therapy targeting this pathway is an appealing treatment strategy. However, agents against this pathway are currently in their preliminary stages and have not yet been implemented in clinical practice. Increasing studies demonstrate activation of the Notch pathway is closely associated with the development and progression of DT, which provides a potential alternative therapeutic target against DT. Early stage clinical trials and preclinical models have indicated that inhibition of Notch pathway might be a promising treatment approach for DT. The Notch signaling activation is mainly dependent on the activity of the gamma-secretase enzyme, which is responsible for cleaving the Notch intracellular domain and facilitating its nuclear trans location to promote gene transcription. Two gamma-secretase inhibitors called nirogacestat and AL102 are currently under extensive investigation in the advanced stage of clinical development. The updated findings from the phase III randomized controlled trial (DeFi trial) demonstrated that nirogacestat exerts significant benefits in terms of disease control and symptom resolution in patients with progressive DT. Therefore, this review provides a comprehensive overview of the present understanding of Notch signaling in the pathogenesis of DT, with a particular emphasis on the prospective therapeutic application of gamma-secretase inhibitors in the management of DT.