Characterization of MET alteration using glioblastoma patient-derived xenograft models

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Project Summary Glioblastoma (GBM) is the most malignant type of brain cancer resistant to alkylating agents and radiation. Glioma stem cells (GSCs), a subpopulation of highly invasive GBM cells resistant to the irradiation and chemotherapy, are the major targets of effective therapeutics. Identifying and targeting molecular determinants of GSCs are important for treating malignant GBM. Our long-term goal is to define and deploy well-characterized, clinically relevant MET-driven GBM models to enable effective therapeutic targeting of MET. Aberrant MET receptor tyrosine kinase (RTK) activation, such as MET amplification (METamp), mutation, and PTPRZ1-MET (ZM) fusion, are frequently found in primary or secondary GBM. Elevated MET signaling provokes tumor invasion in GBM and is also responsible for GSC maintenance and invasive repopulation. Clinically, bevacizumab treatment inducing MET activation is a major mechanism of tumor recurrence with more aggressive phenotype, further demonstrating the significance of targeting MET pathway in GBM. Although MET tyrosine kinase inhibitors (TKIs) are entering clinical trials, their therapeutic efficacy remains controversial. Furthermore, MET inhibitor therapy alone can be defeated by acquired resistance. Therefore, it is important to use clinically relevant GBM models to study the molecular mechanisms in association to therapeutic response to improve the combination strategy. In this application, we hypothesize that GBM PDX models bearing different genetic MET alterations manifest distinct therapeutic vulnerability to MET-targeting agents as well as mechanisms of escape from MET TKIs. We are particularly interested in METamp and ZM fusion models as both molecular features indicate sensitivity to MET inhibitors. For this application, we will 1) Characterize the GBM PDX models bearing various MET alterations found in patients for their MET pathway activation and orthotopic tumor growth. 2) Determine the therapeutic response to MET inhibitors using GSCs in vitro and orthotopic xenograft models in vivo. For MET-targeting reagents we will apply MET TKIs and specific-MET targeting chimeric antigen receptor (CAR) T cells developed at our lab. We will also determine whether irradiation or DNA repair inhibition may enhance the therapeutic efficacy of MET TKIs in these models, and whether MET TKI resistant GBM models may continue respond to MET-targeting CAR T cells. We expect to understand how HGF/MET alteration may serve as biomarkers to indicate the therapeutic response to MET inhibitors as well as the combination strategies. In addition, the GSC models established from this project will become valuable tools for studying MET-mediated GBM biology and therapeutic strategies.