Inappropriate activation of the Hedgehog (HH) pathway is responsible for a wide spectrum of cancers including medulloblastoma (MB), the most common and aggressive pediatric brain malignancy. Multi-omics analysis identified four different MB molecular subgroups; HH-MB is the most abundant and genetically understood, making HH signaling an attractive target for the treatment of this tumor. Given the high heterogeneity of MB, the identification of novel players involved in HH signaling regulation is essential to advance innovative and more effective therapeutic approaches. Recently, we identified the aminopeptidase ERAP1 as a strong activator of the HH pathway. In particular, our preliminary findings unveil the oncogenic properties of ERAP1 in HH-MB and demonstrate that its inhibition impairs HH-dependent tumor growth. ERAP1 represents a valuable druggable target for HH-MB clinical management. Thus, the combination of different targeted-drugs, including ERAP1 inhibitors, could be highly effective for HH-MB treatment.
The main goal of this project is to provide a proof-of-principle that targeting ERAP1 in combination with current pharmacological therapies for HH-MB may represent a valuable strategy for MB treatment. Our efforts could open new perspectives for more effective clinical protocols in the treatment of HH-driven tumors.
Medulloblastoma (MB) is the most common pediatric brain malignancy and aberrant activation of the HH pathway is responsible for the occurrence of about 30% of all MBs. MB is manageable with aggressive surgery, radiotherapy and chemotherapy affecting the quality of life of younger survivor patients. Other current treatment strategies largely target SMO, but they have demonstrated limitations such as drug resistance due to acquired SMO mutations or oncogenic mutations downstream this receptor (1). The need to develop less invasive and toxic therapies and overcome drug resistance represents for the research an important goal that can be pursued through the discovery of novel antagonists able to block the HH pathway especially at downstream level.
A detailed understanding of tumor biology can reduce the intensity of treatment and limit the incidence of adverse effects while maintaining high cure rates. This project presents important implications in HH-MB therapy since is aimed to provide pre-clinical validation of experimental multiple drug treatments for HH-dependent MB to improve the efficacy of therapy.
1) Huang SY and Yang JY, Cancers, 7.4: 2110-2123 (2015)