PG545, an angiogenesis and heparanase inhibitor, reduces primary tumor growth and metastasis in experimental pancreatic cancer
Menée in vitro et in vivo, cette étude évalue l'activité antitumorale d'un composé appelé PG545, un inhibiteur de l'angiogenèse et de l'héparanase, pour le traitement d'un adénocarcinome canalaire du pancréas
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-KrasG12D; Cdkn2alox/lox; p48Cre) 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 and 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 to control or gemcitabine treated tumors. These results highlight the potent anti-tumor activity of PG545 and support the further exploration of heparanase inhibitors as a potential clinical strategy for the treatment of PDAC.
http://mct.aacrjournals.org/content/early/2013/05/21/1535-7163.MCT-12-1123.abstract