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.
Hedgehog (Hh) pathway plays a crucial in development and tumorigenesis. One of the most relevant Hh-dependent tumors is medulloblastoma (MB), a highly aggressive pediatric malignancy arising from cerebellar granule cell progenitors (GCPs) mainly mutated in Ptch1 or Smo receptors. The non-canonical Hh/Gli activation regardless of the presence of mutations in the components of the pathway or overexpression of the ligand is also frequently observed in MB and other tumors. This emphasizes the importance of the mechanisms that control Gli activity, which are impaired in disease.
Our preliminary findings lead us to hypothesize that ERAP1, an endoplasmic reticulum aminopeptidase involved in antigen processing, may play a key role in Hh-tumorigenesis by upregulating Gli proteins, and that its inhibition may abrogate Hh-dependent tumor growth.
We believe that we can improve therapeutic Hh inhibition by the characterization of the oncogenic role of ERAP1, which appears a novel Hh modulator and a promising druggable target for Hh-cancer treatment. Further, loss of ERAP1 function could result in the generation of a new immunopeptidome, which stimulates anti-tumor immune responses leading to tumor regression.
Since innovative and more promising treatments are designed on the combination of therapeutic agents able to hit the Hh pathway at the both upstream and downstream levels, we hypothesize that the efficacy improvement on tumor growth inhibition could be achieved by combined treatments with Smo/Gli (the most used Hh antagonists) and ERAP1 inhibitors. The use of such as combination of drugs with different targets could open new and highly promising perspectives to kill Hh-dependent cancer.