Novel RTK Targeting Strategies in Glioblastoma

描述（由申请人提供）：受体酪氨酸激酶（RTK）通路在大多数胶质母细胞瘤（GBM）中是失调的，胶质母细胞瘤是最常见和最致命的原发性恶性脑肿瘤。因此，许多临床应用的RTK抑制剂已经被开发出来。然而，这些抑制剂未能显著改善GBM患者的临床结果。这种失败的主要原因是由于几个RTK的共同激活和导致对RTK抑制的抗性的补偿机制导致的信号冗余。在这一竞争性更新应用中，我们基于之前的研究结果，提出探索新的机制和策略，以提高MET和其他RTK抑制剂在GBM治疗中的疗效。更具体地说，我们建议全面揭示决定临床适用药物对MET抑制的敏感性和耐药性的因素，并利用所获得的知识来测试新的和更有效的联合疗法。我们还建议基于我们实验室最近的两个令人兴奋的发现，探索两种概念上新颖的RTK靶向GBM治疗方法。我们提出了四个具体目标。在Aim 1中，我们将确定

DESCRIPTION (provided by applicant): 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.