title: PG545, an angiogenesis and heparanase inhibitor, reduces primary tumor growth and metastasis in experimental pancreatic cancer.
abstract: Aggressive tumor progression, metastasis, and resistance to conventional therapies lead to an extremely poor prognosis for pancreatic ductal adenocarcinoma (PDAC). Heparanase, an enzyme expressed by multiple cell types, including tumor cells in the tumor microenvironment, has been implicated in angiogenesis and metastasis, and its expression correlates with decreased overall survival in PDAC. We evaluated the therapeutic potential of PG545, an angiogenesis and heparanase inhibitor, in experimental PDAC. PG545 inhibited the proliferation, migration, and colony formation of pancreatic cancer cells in vitro at pharmacologically relevant concentrations. Heparanase inhibition also reduced the proliferation of fibroblasts but had only modest effects on endothelial cells in vitro. Furthermore, PG545 significantly prolonged animal survival in intraperitoneal and genetic models (mPDAC: LSL-Kras(G12D); Cdkn2a(lox/lox); p48(Cre)) of PDAC. PG545 also inhibited primary tumor growth and metastasis in orthotopic and genetic endpoint studies. Analysis of tumor tissue revealed that PG545 significantly decreased cell proliferation, increased apoptosis, reduced microvessel density, disrupted vascular function, and elevated intratumoral hypoxia. Elevated hypoxia is a known driver of collagen deposition and tumor progression; however, tumors from PG545-treated animals displayed reduced collagen deposition and a greater degree of differentiation compared with control or gemcitabine-treated tumors. These results highlight the potent antitumor activity of PG545 and support the further exploration of heparanase inhibitors as a potential clinical strategy for the treatment of PDAC.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA. Rolf.Brekken@utsouthwestern.edu
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Ostapoff
authors.forename: Niranjan
authors.initials: N
authors.lastname: Awasthi
authors.forename: Bercin Kutluk
authors.initials: BK
authors.lastname: Cenik
authors.forename: Stefan
authors.initials: S
authors.lastname: Hinz
authors.forename: Keith
authors.initials: K
authors.lastname: Dredge
authors.forename: Roderich E
authors.initials: RE
authors.lastname: Schwarz
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
mesh_terms: D020533:Angiogenesis Inhibitors / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005966:Glucuronidase / Q000037:antagonists & inhibitors; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011897:Random Allocation; D012503:Saponins / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use*; D000099175:Heparanase
chemical_list: D020533:Angiogenesis Inhibitors; D005966:Glucuronidase; D012503:Saponins; D000099175:Heparanase; C557899:PG 545