Pyk2 as a target for therapeutics in glioblastoma

Principal Investigator: Joseph Loftus, Ph.D.
Co-Principal Investigators: Joon Uhm, M.D. and Christopher Lipinski, M.D.

The propensity of malignant gliomas to aggressively invade surrounding normal brain tissue is a major factor in the poor clinical outcome. The heightened commitment to migration and reduced proliferation of invasive glioma cells increases their resistance to chemotherapeutic agents, precludes effective tumor resection, and reduces the effectiveness of radiation treatment. The molecular mechanisms that regulate the migration of gliomas from primary tumor sites have not been defined but integrin-mediated interactions with extracellular matrix (ECM) play an important role in this process. The relative activation states of adhesion regulated signaling pathways involved in cell migration, proliferation, 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 Pyk2 and FAK function as important signaling effectors in the malignant behavior of invasive gliomas. As the dynamic balance between Pyk2 and FAK activity is a determining factor in the temporal development of the proliferative or migrational phenotypes, we further hypothesize that inhibition of Pyk2 will limit glioma invasion and increase the efficacy of current therapeutic regimens.

The objective of this proposal is to define the roles of Pyk2 in the invasion and abnormal growth of human gliomas and identify effective inhibitors of its activity to improve clinical outcome.

The following specific aims are proposed:

• Define the mechanisms by which Pyk2 regulates the migration of glioblastoma cells. Define residues and domains critical for the promigratory effect of Pyk2. Identify important Pyk2 binding partners.
• Determine the effect of specific inhibition of Pyk2 on glioma migration and proliferation. Resolve whether inhibition of Pyk2 synergizes with standard chemotherapeutic agents.
• Investigate the effect of Pyk2 expression and activity on glioma migration and proliferation in an orthotopic xenograft model. Determine the effect of inhibition of Pyk2 on therapeutic response. Investigate the potential of Pyk2 as a prognostic indicator and therapeutic target in glioblastoma.