Ricerc@Sapienza

The Hedgehog (Hh) pathway is a signalling cascade that plays an essential role in many fundamental processes including morphogenesis, tissue homeostasis and stemness. Constitutive activation of Hh signalling leads to uncontrolled proliferation and it is associated with neoplastic transformation and tumorigenesis. Mutations in components of this pathway have been identified in basal-cell carcinoma (BCC) and in medulloblastoma (MB).
Medulloblastoma is a highly malignant childhood brain tumour. Current treatment for medulloblastoma combines surgery, radiotherapy and chemotherapy, which have severe adverse effects. In the last years, the identification of small molecules able to block the pathway at the upstream receptor Smoothened (Smo, the activating receptor) or the downstream effector Gli1 (final and most powerful effector of Hh signalling) have thus emerged as valuable anticancer agents.
Major progress has been made in the development of Smo antagonists, although they have shown several limitations due to Smo-downstream pathway activation or the occurrence of drug-resistant Smo mutations. Therefore the discovery of novel Hh inhibitors able to overcome anti-Smo resistance is needed. A significant contribution to the Hh inhibitors toolbox is made by natural compounds, particularly isoflavone molecules. New Hh inhibitors take advantage of the highly versatile isoflavone scaffold. The introduction of specific substituents on the isoflavone ring B allowed the identification of molecules targeting key components of the pathway.
This research proposes a pharmacological inhibition of Hh signalling both at upstream and downstream levels as an innovative therapeutic approach for Hh-driven cancer, and as a way of promoting the development of a less aggressive therapy for MB and other diseases that are also Hh-dependent.