Receptor tyrosine kinase (RTK) pathways are deregulated in a majority of glioblastoma (GBM), the most common and most deadly primary malignant brain tumor. Consequently, a number of clinically applicable RTK inhibitors have been developed. However, these inhibitors failed to significantly improve the clinical outcomes of GBM patients. The main reasons for this failure are signal redundancy due to co-activation of several RTKs and compensatory mechanisms that lead to resistance to RTK inhibition. In this competitive renewal application, we build on our previous findings and propose to explore new mechanisms and strategies for improving the efficacy of MET and other RTK inhibitions in GBM therapy. More specifically, we propose to comprehensively uncover the factors that determine sensitivity and resistance to MET inhibition with clinically applicable drugs and use the acquired knowledge to test new and more efficient combination therapies. We also propose to explore two conceptually novel approaches for RTK targeting in GBM therapy that are based on two recent exciting discoveries from our lab. We propose four specific aims.
In Aim 1, we will identify the not well known factors that determine sensitivity to MET inhibition. We will use RNA-seq, reverse phase antibody arrays, and PCR to comprehensively identify the genetic and molecular factors that determine responsiveness to clinically applicable small molecule kinase inhibitor (crizotinib) and MET neutralizing antibody (MetMAb) in GBM cells, stem cells, animal models and MetMAb clinical trial-derived human tumors.
In Aim 2, we will comprehensively elucidate the mechanisms of resistance to MET inhibition by the above drugs and develop new combination therapies that overcome resistance.
In Aim 3, we will study and develop ligand pre-treatment as a new strategy for improving the efficacy of MET, EGFR and PDGFR inhibitors. This is based on a recent intriguing discovery form our lab that shows that short-term pre-treatment of RTKs with their respective ligands enhances the anti-tumor effects of their inhibitors.
In Aim 4, we will explore the role of microRNA-134 (miR- 134) in RTK signaling and experimental therapy. This is based on the recent discovery in our lab of miR-134 as a new tumor suppressive hub that mediates the effects of RTKs in GBM and that is required for the anti-tumor effects of their inhibitors.
For Aims 3 and 4, we will develop and test new pre-clinical approaches for the systemic and local deliveries of RTK ligands and microRNAs to GBM xenografts using focused ultrasound and microbubbles/nanoparticles as well as convection enhanced delivery. Altogether, successful completion of the proposed studies would lead to a better understanding of the mechanisms of MET and RTK-induced malignancy and to the development of novel and more efficient RTK targeting strategies for GBM therapy.

Public Health Relevance

Receptor tyrosine kinases (RTK) promote the malignancy of glioblastoma (GBM), the most common and most deadly human brain tumor. Drugs that target RTK have therefore been developed. However, these drugs have failed to improve the dismal survival of GBM patients. In this application, we propose to develop and pre- clinically test new approaches for a better targeting of RTK in GBM therapy. We will determine which patients are more likely to respond to RTK targeting. We will find out what makes the tumors resistant to anti-RTK therapies and develop new strategies to overcome resistance. We will also test and develop two novel strategies that use short-term RTK stimulation and microRNAs to improve the anti-tumor effects of anti-RTK drugs. The successful completion of these studies would lead to new and better therapies of patients with GBM.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Fountain, Jane W
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University of Virginia
Schools of Medicine
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