Medulloblastoma is the most common malignant brain tumor in children. Standard treatment, which combines surgical resection, cytotoxic chemotherapy, and radiotherapy in patients older than three years, improves median survival; however, approximately 30% of patients die from recurrence, while survivors are left with severe long-term sequelae, including neurological and cognitive deficits. This disease is divided into four molecular subgroups (WNT, SHH, Group 3, and Group 4) with distinct signatures and cells of origin. The SHH (Sonic Hedgehog) subgroup, which accounts for nearly 30% of cases, is linked to mutations affecting key effectors of the corresponding signaling pathway, including the PTCH1 and SMO receptors. Inhibitors targeting SMO, such as vismodegib (GDC-0449), have been developed and tested in the clinic, but tumors become resistant and recur, making the identification of resistance mechanisms and new targets essential.
In this context, the authors focused on netrin-1, a neuronal guidance molecule during embryonic development whose signaling also regulates cell survival in several adult cancers. A netrin-1-blocking antibody (NP137) has, moreover, already been the subject of phase 1 and 2 clinical trials. The team reports that netrin-1 is overexpressed in medulloblastoma subgroups associated with developmental dysregulation, and most notably in SHH-activated tumors.
To assess the dependence of these tumors on netrin-1, the researchers used several orthotopic mouse models of SHH medulloblastoma, including transgenic models based on conditional inactivation of the gene and patient-derived xenografts. Both genetic deletion of netrin-1 and systemic treatment with the blocking antibody significantly reduced tumor growth in vivo. Unexpectedly, both in vitro and in vivo, tumors treated with an SMO inhibitor increased their netrin-1 expression, suggesting the value of a combinatorial strategy. The authors then show that blocking netrin-1 potentiates the efficacy of the SMO inhibitor in vivo, with drug combination analyses being conducted to characterize this interaction.
Taken together, this work establishes that SHH-activated medulloblastomas depend on netrin-1 for their survival. Blocking this molecule, as monotherapy or in combination with an SMO inhibitor, therefore constitutes a promising therapeutic strategy for this subgroup of tumors.