title: Anti-metastatic action of FAK inhibitor OXA-11 in combination with VEGFR-2 signaling blockade in pancreatic neuroendocrine tumors.
abstract: The present study sought to determine the anti-tumor effects of OXA-11, a potent, novel small-molecule amino pyrimidine inhibitor (1.2 pM biochemical IC(50)) of focal adhesion kinase (FAK). In studies of cancer cell lines, OXA-11 inhibited FAK phosphorylation at phospho-tyrosine 397 with a mechanistic IC(50) of 1 nM in TOV21G tumor cells, which translated into functional suppression of proliferation in 3-dimensional culture with an EC(50) of 9 nM. Studies of OXA-11 activity in TOV21G tumor-cell xenografts in mice revealed a pharmacodynamic EC(50) of 1.8 nM, indicative of mechanistic inhibition of pFAK [Y397] in these tumors. OXA-11 inhibited TOV21G tumor growth in a dose-dependent manner and also potentiated effects of cisplatin on tumor cell proliferation and apoptosis in vitro and on tumor growth in mice. Studies of pancreatic neuroendocrine tumors in RIP-Tag2 transgenic mice revealed OXA-11 suppression of pFAK [Y397] and pFAK [Y861] in tumors and liver. OXA-11 given daily from age 14 to 17 weeks reduced tumor vascularity, invasion, and when given together with the anti-VEGFR-2 antibody DC101 reduced the incidence, abundance, and size of liver metastases. Liver micrometastases were found in 100 % of mice treated with vehicle, 84 % of mice treated with OXA-11, and 79 % of mice treated with DC101 (19-24 mice per group). In contrast, liver micrometastases were found in only 52 % of 21 mice treated with OXA-11 plus DC101, and those present were significantly smaller and less numerous. Together, these findings indicate that OXA-11 is a potent and selective inhibitor of FAK phosphorylation in vitro and in vivo. OXA-11 slows tumor growth, potentiates the anti-tumor actions of cisplatin and--when combined with VEGFR-2 blockade--reduces metastasis of pancreatic neuroendocrine tumors in RIP-Tag2 mice.
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute, and Department of Anatomy, University of California - San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA, 94143-0452, USA.|Department of Biomedicine, University of Bergen, Bergen, Norway.|Oxy Solutions, Parkveien 33B, Oslo, Norway.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Moen
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute, and Department of Anatomy, University of California - San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA, 94143-0452, USA.|School of Medicine, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gebre
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute, and Department of Anatomy, University of California - San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA, 94143-0452, USA.|Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Alonso-Camino
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute, and Department of Anatomy, University of California - San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA, 94143-0452, USA.|School of Medicine, University of California - Davis, Sacramento, CA, USA.
authors.forename: Debbie
authors.initials: D
authors.lastname: Chen
authors.affiliation: Cancer & Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: David
authors.initials: D
authors.lastname: Epstein
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute, and Department of Anatomy, University of California - San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA, 94143-0452, USA. donald.mcdonald@ucsf.edu.
authors.forename: Donald M
authors.initials: DM
authors.lastname: McDonald
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D051379:Mice; D009361:Neoplasm Invasiveness; D061206:Neoplasm Micrometastasis; D018358:Neuroendocrine Tumors / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D040301:Vascular Endothelial Growth Factor Receptor-2; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: Cisplatin; Focal adhesion kinase; Liver metastasis; Pancreatic islet cell tumors; RIP-Tag2 transgenic mice; Vascular endothelial growth factor receptor-2