title: Therapeutic efficacy of CEP-33779, a novel selective JAK2 inhibitor, in a mouse model of colitis-induced colorectal cancer.
abstract: 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 Janus-activated kinase 2 (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 reduced proliferation of tumor cells. Histopathologic analysis confirmed reduced incidence of histologic-grade neoplasia by CEP-33779. Tumor regression correlated with inhibition of STAT3 and NF-κB (RelA/p65) activation in a CEP-33779 dose-dependent manner. In addition, the expression of proinflammatory, tumor-promoting cytokines interleukin (IL)-6 and IL-1β 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.
authors.affiliation: Cephalon, Inc., Worldwide Discovery Research, West Chester, PA 19380, USA. mseavey@cephalon.com
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Seavey
authors.forename: Lily D
authors.initials: LD
authors.lastname: Lu
authors.forename: Kristine L
authors.initials: KL
authors.lastname: Stump
authors.forename: Nate H
authors.initials: NH
authors.lastname: Wallace
authors.forename: William
authors.initials: W
authors.lastname: Hockeimer
authors.forename: Teresa M
authors.initials: TM
authors.lastname: O'Kane
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
authors.forename: Pawel
authors.initials: P
authors.lastname: Dobrzanski
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003092:Colitis / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C567989:CEP 33779; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014230:Triazoles; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2