The median survival for patients with recurrent glioblastoma is six to nine months highlighting the need for better therapeutic strategies for this deadly disease. The revolution in cancer genomics has identified multiple amplification events as potential targets for therapeutic intervention in many cancers including glioblastoma. Multiple factors such as incorrect patient selection, inadequate drug delivery across the blood brain barrier, acquired resistance and drug-target heterogeneity may all lead to clinical failure of targeted therapies. Through an unbiased high-throughput screen utilizing our glioma stem-like cells (GSCs) we discovered that glioblastoma cells harboring focal EGFR ampl...

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The median survival for patients with recurrent glioblastoma is six to nine months highlighting the need for better therapeutic strategies for this deadly disease. The revolution in cancer genomics has identified multiple amplification events as potential targets for therapeutic intervention in many cancers including glioblastoma. Multiple factors such as incorrect patient selection, inadequate drug delivery across the blood brain barrier, acquired resistance and drug-target heterogeneity may all lead to clinical failure of targeted therapies. Through an unbiased high-throughput screen utilizing our glioma stem-like cells (GSCs) we discovered that glioblastoma cells harboring focal EGFR amplification are uniquely vulnerable to mitogen-activated protein kinase kinase (MEK) inhibitors. Based on our preliminary data, we propose that focal EGFR amplification is a biomarker of MEK inhibitor sensitivity (Aim1). MEK inhibitor sensitivity in EGFR amplified cells is due to neuronal differentiation via down regulation of ETS subfamily PEA3 transcription factor ETV5 (Aim 2). Long term efficacy of MEK inhibition can be enhanced in cells with acquired resistance by targeting the ETS subfamily PEA3 transcription factor ETV1 (Aim 3). These conceptually related Aims will not only demonstrate the potential of using MEK inhibitors for glioblastoma patients with EGFR amplification, but it will validate the concept of selective vulnerability to targeted therapy following induction of neuronal differentiation. We believe that upon completion of this project we will reduce a gap in knowledge surrounding identification and selection of glioblastoma patients eligible for targeted therapies and mechanisms of acquired resistance.

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