title: Extended survival of Pyk2 or FAK deficient orthotopic glioma xenografts.
abstract: Disease progression of glioblastoma involves a complex interplay between tumor cells and the peri-tumor microenvironment. The propensity of malignant glioma cells to disperse throughout the brain typifies the disease and portends a poor response to surgical resection, radiotherapy, and current chemotherapeutics. The focal adhesion kinases FAK and Pyk2 function as important signaling effectors in glioma through stimulation of pro-migratory and proliferative signaling pathways. In the current study, we examined the importance of Pyk2 and FAK in the pathobiology of malignant glioma in an intracranial xenograft model. We show that mice with xenografts established with glioma cells with specific knockdown of Pyk2 or FAK expression by RNA interference had significantly increased survival compared to control mice. Furthermore, the effect of inhibition of Pyk2 activity in xenografts was compared to the effect of knockdown of Pyk2 expression. Inhibition of Pyk2 activity by stable expression an autonomous FERM domain in glioma cells slowed disease progression in the intracranial xenograft model. In contrast, expression of a variant FERM domain that does not inhibit Pyk2 activity did not alter survival. These results substantiate the disease relevance of both Pyk2 and FAK in glioma and suggest a novel approach to target Pyk2 for therapeutic benefit.
authors.affiliation: Mayo Clinic Arizona, 13400 East Shea Blvd, 85259, Scottsdale, AZ, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lipinski
authors.forename: Nhan L
authors.initials: NL
authors.lastname: Tran
authors.forename: Carole
authors.initials: C
authors.lastname: Viso
authors.forename: Jean
authors.initials: J
authors.lastname: Kloss
authors.forename: Zhongbo
authors.initials: Z
authors.lastname: Yang
authors.forename: Michael E
authors.initials: ME
authors.lastname: Berens
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Loftus
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000172:deficiency*; D051418:Focal Adhesion Kinase 2 / Q000172:deficiency*; D005910:Glioma / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000379:methods; D034741:RNA, Small Interfering / Q000627:therapeutic use; D016019:Survival Analysis; D014161:Transduction, Genetic
chemical_list: D034741:RNA, Small Interfering; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496050:PTK2 protein, human