Phd in MOLECULAR MEDICINE

Thesis title: New therapeutic strategies to fight Sonic Hedgehog Medulloblastoma

The Sonic Hedgehog (SHH) signaling plays a crucial role during embryonic development and stem cell maintenance. Its aberrant activation is responsible of a wide range of human cancers, including medulloblastoma (MB), the most common pediatric brain tumor. The molecular complexity that characterizes SHH-MB, as well as its rapid progression and the occurrence of drug-resistance, limit the effectiveness of the therapeutic management making this malignancy difficult to treat. The characterization of molecular mechanisms underlying the regulation of SHH signaling is fundamental to identify new therapeutic targets for the development of more effective therapies. For these reasons, our studies were focused both on the identification of new molecules involved in SHH-MB tumorigenesis and the development of new targeted therapies. We discovered that the pro-oncogenic stemness regulator Spalt-like transcriptional factor (SALL4), is a new interactor of RENKCTD11, known to be a tumor suppressor lost in ~30% of human SHH-MB. Further, we found that SALL4, cooperating with Histone Deacetylase 1 (HDAC1), potentiates the SHH signaling enhancing the transcriptional activity of Gli1, the most powerful effector of SHH pathway. Consistent with these results, the inhibition of SALL4 suppresses SHH-MB growth both in murine allografts and patient-derived xenograft models, highlighting its potential as therapeutic target for SHH-dependent cancers. In addition to the identification of SALL4 as a positive regulator of the SHH pathway, we demonstrated the ability of a small molecules, here called N1, to counteract SHH activity directly inhibiting the Endoplasmic Reticulum Aminopeptidase 1 (ERAP1), a strong activator of SHH signaling. We demonstrated that N1 specifically impairs ERAP1 function and robustly reduces the SHH-MB tumor growth both in vitro and in vivo, making it as a good candidate for the treatment of SHH-driven cancers. Overall, these findings will contribute to be􀄴er understand SHH-MB tumor biology improving the opportunity to develop new therapeutic strategies.