Invasion of malignant gliomas cells into surrounding normal brain tissue contributes significantly to poor clinical prognosis. The commitment of these cells to migration precludes effective tumor resection, reduces the efficacy of radiation treatment, and increases resistance to chemotherapeutic agents. The molecular mechanisms that regulate the migration of gliomas from primary tumor sites have not been defined but adhesive interactions with extracellular matrix (ECM) play an important role in this process. The relative activation states of integrin regulated signaling pathways involved in cell proliferation, migration, and survival/death are likely to be important determinants of the aggressiveness of malignant cells in tumor invasion. We hypothesize that the focal adhesion kinases FAK and Pyk2 function as important signaling effectors in the malignant behavior of invasive gliomas. Furthermore, we hypothesize that the dynamic balance between FAK and Pyk2 activity and their differential regulation are determining factors in the temporal manifestation of proliferative or migrational phenotypes. The objective of this proposal is to define the specific roles of FAK and Pyk2 in the abnormal growth and invasion of malignant gliomas. The proposed studies will first define the basis for the differential effects of FAK and Pyk2 in regulation of glioblastoma migration and proliferation by identifying specific functional domains of FAK and Pyk2 that are required for their differential effects on glioblastoma cell migration or proliferation. Secondly, we will determine the effect of specific inhibition of FAK and Pyk2 on glioblastoma proliferation and migration and determine whether these phenotypic behaviors are inversely linked or can be modulated independently. Finally, we will investigate the role of Pyk2 and FAK function on the invasive behavior of glioblastomas in the 3-dimensional brain microenvironment in vivo and use differential gene expression profiling to identify alterations in sets of genes associated with migration/proliferation/apoptosis. Overall, these studies will provide additional insight into the cellular signaling networks by which the effector kinases FAK and Pyk2 function to influence glioblastoma migration and proliferation. Since both proliferation and migration are integral to the severity of this disease, greater insights into the molecular mechanisms that regulate these distinct cellular behaviors are required for the development of novel therapeutic strategies to improve clinical outcomes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA103956-05
Application #
7620919
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Jhappan, Chamelli
Project Start
2005-08-25
Project End
2010-11-30
Budget Start
2009-06-01
Budget End
2010-11-30
Support Year
5
Fiscal Year
2009
Total Cost
$263,952
Indirect Cost
Name
Mayo Clinic, Arizona
Department
Type
DUNS #
153665211
City
Scottsdale
State
AZ
Country
United States
Zip Code
85259
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Loftus, Joseph C; Dhruv, Harshil; Tuncali, Serdar et al. (2013) TROY (TNFRSF19) promotes glioblastoma survival signaling and therapeutic resistance. Mol Cancer Res 11:865-74
Loftus, Joseph C; Yang, Zhongbo; Kloss, Jean et al. (2013) A Novel Interaction between Pyk2 and MAP4K4 Is Integrated with Glioma Cell Migration. J Signal Transduct 2013:956580
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Loftus, Joseph C; Ross, Julianna T D; Paquette, Kimberly M et al. (2012) miRNA expression profiling in migrating glioblastoma cells: regulation of cell migration and invasion by miR-23b via targeting of Pyk2. PLoS One 7:e39818
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Lipinski, Christopher A; Loftus, Joseph C (2010) Targeting Pyk2 for therapeutic intervention. Expert Opin Ther Targets 14:95-108
Meurice, Nathalie; Wang, Lei; Lipinski, Christopher A et al. (2010) Structural conservation in band 4.1, ezrin, radixin, moesin (FERM) domains as a guide to identify inhibitors of the proline-rich tyrosine kinase 2. J Med Chem 53:669-77
Paulino, Vincent M; Yang, Zhongbo; Kloss, Jean et al. (2010) TROY (TNFRSF19) is overexpressed in advanced glial tumors and promotes glioblastoma cell invasion via Pyk2-Rac1 signaling. Mol Cancer Res 8:1558-67

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