Sonic Hedgehog Medulloblastomas are dependent on netrin-1 for survival

Netrin-1 (NTN1) signaling is an essential prototypical neuronal guidance mechanism during embryonic development that also regulates tumor cell survival in a variety of adult cancer entities. In line with these data, a monoclonal netrin-1 blocking antibody (anti-NTN1, mAb/NP137) has been preclinically developed and netrin-1 blockade has recently been investigated in phase 1 and 2 clinical trials in several adult cancers. Here, we have explored the role of netrin-1 in the most common malignant pediatric brain cancer, medulloblastoma (MB). Interestingly, we found that netrin-1 is upregulated in MB subgroups associated with developmental dysregulation, in particular in MB with Sonic Hedgehog (SHH) activation. We first demonstrated that genetic deletion of netrin-1 or systemic treatment with the clinical stage anti-netrin-1 blocking antibody significantly reduced tumor growth in vivo in various orthotopic models of SHH MBs. Second, in vitro and in vivo, we unexpectedly uncovered that SHH MBs treated with SHH-inhibitor targeting Smoothened (SMO) increased netrin-1 expression, paving the way for combinatorial therapy. In line with that, we next found that netrin-1 blockade potentiated the efficacy of SMO inhibitor therapy in vivo. Together, our data indicate that, netrin-1 blockade, used as monotherapy or in combination with SMO inhibitors, is a promising therapeutic strategy in SHH MB.