Ricerc@Sapienza

Medulloblastoma (MB) is an invasive pediatric brain tumor caused by morphogenetic anomalies, consequent to alterations of specific signaling pathways. The management of this type of tumor requires aggressive treatments consisting in surgical resection followed by radiation and standard chemotherapy. Unfortunately, current therapies have serious adverse effects and patients with recurrent disease after primary therapy have a particularly poor prognosis.
In the last years, Hedgehog (Hh) pathway has emerged as a druggable therapeutic target in cancer, since its crucial role in development, proliferation and tissue homeostasis. Inappropriate reactivation of Hh is responsible for the formation and progression of several human cancers. Deregulation of Hh pathway occurs in MB, also confirmed by mouse models of the human disease in which mutations in key component genes of the pathway (Smoothened, Patched, SuFu) result in tumor development.
Experimental use of the Hh antagonists has demonstrated an inhibitory effect on tumor growth and a number of Hh inhibitors have been developed and patented. Major progress has been made in the development of Smoothened (Smo, the activating receptor of Hh signaling) antagonists, although they have shown several limitations due to Smo-downstream pathway activation or the occurrence of drug-resistant Smo mutations.
Recently, particular interest has been elicited by the identification of small molecules able to hit Gli factors, the final effectors of the Hh pathway, which provide a valid tool to overcome anti-Smo resistance.
The aim of this proposal is to discover novel powerful Gli inhibitors targeting Hh signaling at downstream level, and to investigate their pharmacological effects on MB.