The long-term goals of this project are to understand the role of phospholipase D1 (PLD1) in pancreatic ductal adenocarcinoma (PDA) pathogenesis, chemoprevention, and therapeutics. PDA is a complex and lethal cancer with a five-year survival of <9%. Surgery, which offers the only realistic hope, has a limited role, whereas current chemotherapy or radiation therapy regimens offer minimal or no help. Therefore, the magnitude of this problem mandates the search for new strategies to combat this disease; being the identification of new targets for treatment a critical component. Phospholipase D1 (PLD1), a lipid-signaling enzyme, has been shown to play a role in the progression of various types of cancer. For example, PLD1: a) is increased in abundance or activity in various human cancers; b) is linked with proliferative signaling and resistance to cell death, and c) promotes tumor growth and metastasis. In addition, PLD1 has been recently shown to be elevated in clinical samples of pancreatic cancer, and inversely correlate with patient survival. These findings suggest the potential use of PLD inhibitors as cancer therapeutics. However, to date, there is a dearth of information regarding the exact role played by PLD1 in PDA. Preliminary studies in our laboratory have shown in animal models of pancreatic cancer, that inhibiting PLD1 reduces pancreatic tumor growth, extends survival and enhances the chemotherapeutic effect of gemcitabine, the most commonly used drug for treating pancreatic cancer patients. Based on the above, the objective of this R21 proposal is to define the role of PLD1 in PDA growth. We hypothesize that PLD1 is a key enzyme in PDA growth. We will employ, biochemical, molecular, and in vivo studies to evaluate this hypothesis and to advance PLD1 as a novel therapeutic target. We will focus on the following specific aims: 1) Establish and define the role of phospholipase D1 (PLD1) in regulating PDA progression, by a) defining the in vivo role of PLD1 in the development of PDA using genetically-engineered mouse models; and b) determining the cellular roles of PLD1 (both the tumor and the microenvironment) in regulating cell growth in pancreatic cancer; and 2) Determine the mechanisms underlying the inhibition of PDA progression by disruption of PLD1. At the completion of these studies, we expect to have deciphered key functions of PLD1 in pancreatic cancer. These results may allow us to define and establish PLD1 as a novel and heretofore unappreciated major regulator of pancreatic cancer progression. Given the importance of PDA and the lack of effective agents against it, we believe that the proposed work holds the promise of a significant advance in this area.
The poor prognosis of pancreatic ductal adenocarcinoma (PDA) requests the exploration of new targets for treatment. This proposal proposes to evaluate the role of phospholipase D1 (PLD1), a lipid-signaling enzyme, in PDA growth. At the completion of these studies, we expect to have deciphered key functions of PLD1 in PDA and establish PLD1 as a potential new target for PDA treatment.