The Survival Factor Renalase and Pancreatic Cancer
Abstract
This proposal relates to the Fiscal Year 2018 (FY18) Peer Review Cancer Research Program (PRCRP) topic area of Pancreatic Cancer and is submitted as an Idea Award with Special Focus. Scientific objectives and rationale: Pancreatic cancer is the most lethal of common cancers and is projected to be the second most common cause of cancer deaths in the United States within a decade. We have assembled a highly accomplished team of clinicians, clinical investigators, physician scientists, and basic scientists who propose to study a novel protein called renalase. This protein is found in the blood and is also made by some cancers. It appears to drive the growth of pancreatic cancer, and in doing so, shortens the life span of patients. Treatment of pancreatic cancer has seen little progress over the past 25 years; the only chance to cure this disease are those rare patients who have a curative surgical resection (perhaps ~5% of pancreatic cancer patients). In the great majority of patients who undergo curative surgery, the intervention is not curative. Chemotherapy provides minor increases in survival, and immunotherapy, which has prolonged survival in other cancers, has not been useful in pancreatic cancer to date. Both new therapies and ways to decide which patient might benefit from attempts at curative surgery are needed. We have reported that renalase is produced by many pancreatic cancers and is also found in the blood stream. In experimental pancreatic cancer models, we find that renalase is essential for cancer growth. When we use an antibody that we developed on renalase, it greatly decreases tumor growth. We have also found that renalase is found in the blood, and its levels increase in patients with pancreatic cancer. There are several types of renalase in the blood and to best design new therapies, we need to know which: (1) have biologic activity, (2) are recognized by our therapeutic antibodies, and (3) increased in the blood of patients with pancreatic ductal adenocarcinoma cancer (PDAC). Applicability of research: We believe that the proposed work represents research that could substantially impact the treatment of pancreatic cancer by guiding therapies that would inhibit a new and potent factor that drives the growth of many pancreatic cancers. Further, serum levels of renalase might serve as a biomarker and a guide to whether the cancer is localized or widespread and whether there has been a response to therapy. In other work we have reported that renalase has activities in the skin cancer melanoma that are very similar to pancreatic cancer. Thus, the higher the levels of renalase in a melanoma, the shorter a patients life expectancy. Similar to pancreatic cancer, we have shown that an antibody we generated to renalase also dramatically slows the growth of melanoma (the 5th most common cancer in United States (U.S.) military Veterans. Though not investigated in depth, we find levels of renalase are also increased in breast cancer and urinary bladder cancer. Thus, the work proposed here could have a substantial impact on addition types of cancer. FY18 PRCRP Military Relevance Focus Area to be Addressed: Pancreatic cancer ranks is the deadliest common cancer and is seen in about 2% of U.S. Veterans. Its risk increases with cigarette smoking, alcohol abuse, diabetes, and select toxin exposure, all factors that are more common in our Veterans than non-Veterans. For example, pancreatic cancer risks were much greater (2- to 5-fold) for military nurses who served in Vietnam versus those who were not deployed. Our study will examine a novel blood protein that might provide prognostic information relating to the stage (whether it is contained or has spread) of pancreatic cancer and further test whether it could also be a target for therapy that is directed at inhibiting its positive growth effects in pancreatic cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910439
Entities
People
- Fred S. Gorelick
Organizations
- United States Army
- Yale University