Perioperative Stromal Depletion Strategies in Pancreatic Ductal Adenocarcinoma

Abstract public domain (NIH RePORTER)

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) stroma has a complex and unique tumor microenvironment, consisting of pancreatic stellate cells, endothelial cells, immune cells and fibroblasts with an extensive paracrine and autocrine network residing in a stiff extracellular matrix. This stroma promotes aggressive malignant behavior. Therefore, depleting stroma is a promising new therapeutic approach in order to improve chemotherapy delivery. The target of interest is hyaluronan (HA), a glycosaminoglycan polymer, which has been shown to accumulate in the PDAC stroma and cause increased tumor interstitial fluid pressure (IFP). This increase in IFP has been shown to compress the tumor vasculature and hinder delivery of chemotherapy. Preclinical studies with PEGPH20 (PEG), which is pegylated recombinant human hyaluronidase and gemcitabine (G) reduced IFP, increased vessel diameter and improved survival in mice. The role of tumor microenvironment in formation of desmoplastic reaction, cell proliferation, migration and metastatic potential makes it an important target for therapeutic intervention. We hypothesize that preoperative treatment with PEG will deplete the stroma, increase intratumoral perfusion (and hopefully drug delivery) without increased risk of post- operative complication of pancreatic fistula formation. We will address this in patients with borderline resectable PDAC by the following specific aims: (1) To investigate the effect of preoperative treatment with the combination of PEG, G and n-P on the risk of post-operative pancreatic fistula formation. (2) To evaluate the sequential effect of PEG on the fibrotic character and vascular perfusion of PDAC stroma in patients with borderline resectable pancreatic cancer via functional MRIs. (3) To determine the degree of stromal depletion and the effects of PEG on cell proliferation and apoptosis.

Public health relevance public domain (NIH RePORTER)

PUBLIC HEALTH RELEVANCE: Pancreatic cancer (PC) tumor is composed of a unique fibrous tissue, called the "stroma", which may act as a biological barrier to delivery of chemotherapy. Our clinical trial is the first study that will investigate a stroma-targeting drug, PEGPH20, in borderline resectable PC in the pre-operative setting. We hypothesize that preoperative therapy with PEGPH20 combined with chemotherapy will decrease this biological barrier, with hopes of increased drug delivery to the tumor, without increased post- operative risk. Better drug delivery to the tumor may ultimately result in increased rates of successful surgeries and dramatical improvement in outcomes and cure rate.