Therapeutic Efficacy of CEP-33779, a Novel Selective JAK2 Inhibitor, in a Mouse Model of Colitis-induced Colorectal Cancer
Menée sur un modèle murin de cancer colorectal, cette étude évalue l'activité antitumorale d'un nouveau composé par voie orale appelé CEP-33779, un inhibiteur de l'activité de JAK2
Constitutively activated STAT3 and STAT5 are expressed in a wide variety of human malignancies including solid and hematopoietic cancers and often correlate with a poor prognosis and resistance to multiple therapies. Given the well established role of STAT3 in tumorigenesis, inhibition of JAK2 activity might represent an attractive therapeutic approach. Using a mouse model of colitis-induced colorectal cancer we show that a novel, orally active, selective JAK2 inhibitor, CEP-33779, induced regression of established colorectal tumors, reduced angiogenesis and proliferation of tumor cells. Histopathological analysis confirmed reduced incidence of histological-grade neoplasia by CEP-33779. Tumor regression correlated with inhibition of STAT3 and NF-kB (RelA/p65) activation in a CEP-33779-dose dependent manner. In addition, the expression of pro-inflammatory, tumor-promoting cytokines IL-6 and IL-1b was strongly reduced upon JAK2 inhibition. The ability of CEP-33779 to suppress growth of colorectal tumors by inhibiting the IL-6/JAK2/STAT3 signaling suggests a potential therapeutic utility of JAK2 inhibitors in multiple tumors types, particularly those with a strong inflammatory component.
http://mct.aacrjournals.org/content/early/2012/02/14/1535-7163.MCT-11-0951.abstract 2012