Ricerc@Sapienza

The Hedgehog (Hh) signaling pathway is a master regulator of tissue development. Inappropriate activation of Hh signaling leads to different types of cancer, including medulloblastoma (MB), the most common brain malignancy in childhood. Pharmacological inhibition of the Hh pathway has been proposed as a therapeutic strategy in typical Hh-dependent tumors. Major progress has been made in the development of antagonists targeting key components of the pathway, although they have shown several limitations due to pharmacokinetic, low selectivity and occurrence of drug-resistance. For this reason, the identification of the molecular mechanisms that control the Hh pathway is essential to identify novel target for the development of innovative therapeutic approaches. We have recently identified a new mechanism of Hh signal regulation involving the endoplasmic reticulum aminopeptidase 1 (ERAP1). So far, ERAP1 has been well studied for its role in the antigen processing, a mechanism resulting in the production of high affinity peptides for the binding to MHC class I molecules. Our preliminary data suggest unexpected oncogenic properties of ERAP1, acting through Hh pathway activation. We have found that ERAP1 promotes the stabilization of Gli transcription factors, the final effectors of the pathway, causing its improper activation. Of note, we have observed that the genetic or pharmacological inhibition of ERAP1 inhibits the growth of Hh-MB cells in vitro and in vivo. The present research project aims to study and characterize the role of ERAP1 in Hh signaling control and tumors that, like MB, are caused by an hyperactivation of the Hh pathway.
We expect our effort will provide: i) an increased understanding of the molecular mechanisms linking ERAP1 function and Hh carcinogenesis; ii) a proof-of-concept that targeting ERAP1 alone or in combination with SMO or GLI1 inhibitors can open new perspectives for effective therapeutic approaches in the treatment of Hh-driven tumors.