Netrin-1 blockade alleviates resistance to first line chemotherapy in locally advanced pancreatic cancer

Netrin-1, a developmental cue, is a master regulator of tumor Epithelial-to-mesenchymal transition (EMT). Pancreatic cancer is a challenging indication where netrin-1 and its receptor neogenin have been shown to promote tumor progression and metastasis in animal models. Here we report the results of a single arm phase 1b study assessing the combination of an anti-netrin-1 antibody (NP137) with standard chemotherapy (mFOLFIRINOX) in first-line patients with locally advanced pancreatic cancer. Fourty-three patients were included in this trial and received mFOLFIRINOX plus NP137 once every two weeks for up to 12 cycles (6 months). NP137 was well tolerated. Median PFS was 10.85 months (95% CI, 10.03 – 15.61) and median OS was 16.43 months (95% CI, 12.75 – NR) with 21 patients still alive at time of the data cut-off. Laser capture microdissection followed by microbulk RNA sequencing was performed on 22 pre-therapeutic and 6 surgery samples and revealed that the main pathway downregulated with the combination mFOLFIRINOX+NP137 is EMT, strengthening the mechanism of action of NP137. Moreover, analysis of pre-therapeutic samples revealed extended survival outcomes of patients with tumor cells expressing high levels of the netrin-1 receptor Neogenin, an observation validated by Neogenin immunostaining. Our results support netrin-1 blockade alleviates resistance to standard of care chemotherapy by inducing tumor re-epithelialization, particularly in neogenin-high pancreatic cancer.