Glioblastomas are the most common primary malignancy of the central nervous system and are typically rapidly proliferating tumors resistant to chemotherapeutic intervention. Their complex and heterogeneous nature has hampered progress towards the development of successful therapies. The mammalian target of rapamycin (mTOR) kinase and the YAP oncoprotein have recently emerged as an attractive targets for therapeutic intervention in glioblastoma. Two multisubunit complexes containing mTOR exist, mTORC1 and mTORC2 which differ in their regulatory subunit compositions containing Raptor and Rictor, respectively. While hyperactive mTORC1 activity has been targeted in many cancers, including glioblastoma with limited success, dysregulated mTORC2 function has only recently begun to be investigated. The downstream effector of the Hippo cascade, YAP has been found to be overexpressed in brain cancers and recently, experimental evidence has supported crosstalk mechanisms coordinating the activities of these cascades to promote glioblastoma proliferation, motility and invasiveness. In this application we propose to 1). identify and characterize glioblastoma-associated activating mutations in YAP which render this oncoprotein constitutively active, 2). clarify recently identified signaling crosstalk interactions between mTORC2 and Hippo signaling cascade components and 3.) evaluate a novel YAP-TEAD specific small molecule inhibitor alone and in combination with mTORC2 specific inhibitors in xenografts and genetically engineered mouse (GEM) models of the disease. We also propose to investigate and chemically modify the YAP inhibitor to build in desired anti-glioblastoma effects.
Successful completion of this project will substantiate a preclinical rationale for cotargeting the mTOR and YAP signal transduction pathways for trials in patients with glioblastoma. Additionally, this study will provide information as to the operative mechanisms leading to constitutive activation of the YAP oncoprotein, as well as clarify signaling interactions between these two key cascades in brain tumors.