2018 Grantee: Darren Carpizo, MD, PhD
University of Rochester
Co-PI: Patrick Mehlen, PhD, Université Claude Bernard Lyon 1
Research Project: Investigating Netrin-1 as a New Therapeutic Target in Pancreatic Cancer
Award: 2018 Pancreatic Cancer Action Network Translational Research Grant
Award Period: July 1, 2018 – June 30, 2021
Dr. Carpizo is a surgical oncologist that specializes in the management of patients with pancreatic cancer, and serves as the director of the hepatobiliary oncology program at Rutgers Cancer Institute. He also is the principal investigator of a cancer research lab that studies developmental therapeutics in cancer, and he received a PanCAN Career Development Award in 2012, funded by the Daniel and Janet Mordecai Foundation. Dr. Carpizo did his undergraduate studies at Cornell University, and received his MD at the University of Illinois at Chicago. He then completed a residency in surgery at the UCLA Medical Center. During that time he also completed a PhD in molecular, cell and developmental biology. Following completion of his surgical residency, he went on to complete a fellowship in surgical oncology at the Memorial Sloan Kettering Cancer Center. He is now an associate professor of surgery and pharmacology and is also the co-director of the gastrointestinal oncology research program. Dr. Carpizo has developed several novel mouse models of pancreatic cancer that mimick early stage pancreatic cancer patients undergoing surgery for purposes of studying the biology of metastasis and in particularly mechanisms of dormancy.
Dr. Mehlen is the international leader of the dependence receptor paradigm and has applied this leadership to decipher the role of these receptors in pathological contexts. His work has been acknowledged by numerous awards such the bronze (1999) and silver medal of CNRS (2004), the Pius XI Gold Medal from Pontificia Academia Scientiarum City of Vatican (2010), the Grand Prix Lilianne Bettencourt pour les Sciences du vivant (2009) and the Prix Duquesne (2016). He was elected European Molecular Biology Organization (EMBO) member in 2006 and more recently as member of the French Academy of Sciences in 2013. Since 2006, he has also been appointed as adjunct professor at the Buck Institute for Age Research, Calif. His team was awarded by a senior European Research Council (ERC) grant in 2012, and Dr. Mehlen currently coordinates two major French national research agency projects involving several high-level research teams.
Pancreatic cancer suffers from a lack of effective chemotherapy, highlighting the urgent need for new therapeutics. Most patients (85 percent) with pancreatic cancer have locally advanced or metastatic disease (stage IV) at the time of diagnosis – meaning their tumor has spread just outside their pancreas or distantly to other organs.
While surgery remains the only chance for long-term survival, more than 75 percent of patients undergoing surgery for pancreatic cancer go on to die of metastatic recurrent disease. Recently, new research in the science of pancreatic cancer has revealed genetic changes that are important for the survival of metastatic cells. One such biological event is activation of the Netrin-1 protein signaling pathway. Netrin-1 functions as a survival signal to cancer cells, so without Netrin-1, cancer cells die.
This is important because therapies that target Netrin-1 would in theory kill cancer cells by depriving them of this survival mechanism. In this proposal, Drs. Carpizo and Mehlen and their research teams provide evidence that Netrin-1 gets turned on in both mouse and human pancreatic cancer. They also show that silencing (turning off) Netrin-1 or its receptor leads to pancreatic cancer cell death and prevents metastasis. This suggests that Netrin-1 would be a useful therapeutic target in pancreatic cancer. This proposal is designed to confirm this idea in mouse models of pancreatic cancer. There is evidence that anti-Netrin-1 therapy also makes chemotherapy work better, and the investigators propose to test this idea as well in a mouse model of pancreatic cancer. Lastly, they will determine whether this treatment strategy would be best suited for patients with metastatic disease or those with early-stage disease who are candidates for surgery.