Investigating Netrin-1 as a novel therapeutic target in metastatic pancreatic cancer

Pancreatic cancer is a highly metastatic cancer.  The majority of patients with pancreatic cancer are stage IV at the time of diagnosis and the majority of patients (>80%) who have early stage disease go on to suffer from metastatic relapse following curative intent surgery.  Novel therapies that target the molecular mechanisms that govern pancreatic cancer metastasis are highly needed.  The Carpizo laboratory is currently investigating a novel target, Netrin-1, which is an axonal guidance molecule that is typically expressed during embryonic developing in neurons to guide axonal growth.  Several cancers upon metastasizing upregulate Netrin-1 as a survival mechanism.  The Carpizo lab first identified the upregulation of Netrin-1 in a mouse model of liver metastasis.  After confirming this was upregulated in human pancreatic cancer metastases, the Carpizo lab teamed up with one of the world’s experts in Netrin-1 biology (Dr. Patrick Mehlen, Lyon France) to study the potential benefit of targeting Netrin-1 in pancreatic cancer.  Dr. Mehlen leads a company (Netris Pharma) which has produced the first humanized monoclonal antibody to Netrin-1 (NP137) which is currently in clinical trials.  The Carpizo lab is conducting translational research to evaluate the utility of designing a clinical trial of NP137 in pancreatic cancer.  This project is funded by the Pancreatic Cancer Action Network.

Evolution of the model for effects of Netrin-1 signaling inhibition. Our initial model (top) of Netrin-1 signaling inhibition was that of disruption of a survival signal that tumor cells adopt which induces apoptosis. Currently (bottom) we believe inhibition of Netrin-1 signaling not only induces tumor cell apoptosis but also promotes a mesenchymal to epithelial transition.

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