Netrin-1 as an actionable target for the treatment of cancer
Netrin-1 is extensively known for its role during embryonic development (1). Netrin-1 has been described as a ligand for the prototypical dependence receptors DCC and UNC5B (2). DCC and UNC5B have been shown to have dual signaling depending on netrin-1 availability (3): in the presence of netrin-1, these receptors induce various intracellular signals including an Epithelial-to-Mesenchymal Transition (EMT) (4), in the absence of ligand, their activity trigger cell death (5). Experimental genetic silencing of DCC pro-death activity or genetic gain of netrin-1 in adult mice leads to tumoral progression (6-7).
Netrin-1 is up-regulated in the vast majority of human cancer
It was shown that netrin-1 is gained in the vast majority of human cancer as a pro-tumoral mechanism.
|Cancer Type||Autocrine Secretion or Over-expression of Netrin-1|
|Metastatic Breast Cancers||60%|
|Non-Hodgkin Lymphomas||> 50%|
|Gastric Cancer, IBD related tumors||21%|
|Gastric Cancer, CRC sporadic tumors||7%|
Netrin-1 titration is associated with tumor growth inhibition
Experimental silencing or titration of netrin-1 is associated with tumor growth inhibition in various preclinical models.
NP137 is a first-in-class, first-in-human, humanized monoclonal antibody of IGg1 isotype directed against netrin-1
NP137 was engineered to specifically and efficiently bind to netrin-1 and to inhibit the interaction ligand/receptor.
NP137 is alleviating resistance to chemotherapies and immune checkpoint inhibitors by modulating phenotypic plasticity
Because netrin-1 is both a survival factor and an inducer of EMT, disrupting netrin-1 with NP137 is associated with both tumor growth inhibition and EMT inhibition. Because EMT is a natural break for the efficacy of chemotherapies and immune-checkpoint inhibitors, NP137 was shown in preclinical model to potentiate the anti-tumor activity of both chemotherapies and immune-checkpoint inhibitors.
NP137 is a safe product currently assessed in several phase II trials
NP137 confirmed its excellence safety profile during the clinical Phase I monotherapy, while presenting early signs of clinical activity with objective responses and disease stabilization. These signs of clinical activity, together with the confirmation of the reversion of tumoral EMT in patients treated with NP137, have led to conduct the ambitious GYNET phase 2 trial assessing NP137 in combination with carbotaxol and/or pembrolizumab in patients with endometrial and cervix cancer.