For decades, we have known that overexpression of the epidermal growth factor receptor (EGFR) is a major component of the etiology of glioblastoma multiforme (GBM), yet little is known regarding the signaling events that emanate from activated EGFR in GBM. It is becoming increasingly clear that signaling pathways are complex and highly dynamic and cannot be studied in a vacuum. This certainly helps define GBM's plasticity and explain failures of targeted therapies for GBMs. It is therefore imperative that we study EGFR signaling events globally and in the context of a relevant animal model that we can genetically manipulate at will. We have developed a genetically engineered mouse model (GEMM) of GBM, based on the most common genetic aberrations observed in human tumors, that is overexpression of EGFR along with loss of function of the p16lnk4a/p19ARF and PTEN tumor suppressor genes. We hypothesize that investigating global EGFR signaling pathways in our model using phosphoproteomic methods will reveal key nodal signaling events that are responsible for tumor cell growth, migration and resistance to therapies. By using our model to study signaling events responsible for these effects, our GEMM of GBM will reveal new and insightful information on the etiology of GBMs. This will be accomplished by fulfilling the following goals: 1) To determine and study network dynamics of phosphotyrosine and phosphoserine/threonine signaling events in GBM tumors from our mouse models using mass spectrometry. 2) To study the effects of targeted therapeutic treatment of our GBMs on global signaling phospho-networks. 3) To systematically eliminate the signaling events usurped by EGFR in our GBM tumor cells using custom-made short hairpin RNA (shRNA) libraries, and determine resulting phenotypes (tumor cell growth, invasion, resistance to targeted, chemo and radiation therapies). 4) To validate those key phosphoevents for mouse GBM biology in human GBM samples. 5) To ascertain toxicity profiles and efficacy spectrum of various nanotechnology platforms for the efficient delivery of small interfering RNA (siRNA) molecules to GBM tumor cells in vivo. This application will establish the groundwork for evaluating specific gene function in the context of RNA interference-mediated therapeutic intervention for GBM in a pre-clinical setting, using various nanoplatforms as delivery tools. The power of the prospective research program proposed herein lies in our ability to manipulate gene expression and perform genetic experiments in live animals. Together, these features commensurably complement the retrospective studies brought forward by The Cancer Genome Atlas by providing a much-needed animal system capable of efficient analysis of gene function.

Public Health Relevance

People don't survive glioblastoma multiforme, the most aggressive type of brain cancer, because of its inherent resistance to therapy, making glioblastoma a major public health issue. This research will determine the causes of therapeutic resistance and test a methodology to eliminate key mediators of resistance in an accurate and relevant genetically engineered mouse model of glioblastoma. We believe that these steps will lead to a better understanding of the disease, which will translate into major clinical advancements.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZCA1-SRLB-Q (M1))
Program Officer
Marks, Cheryl L
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Tufts University
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Jun, Hyun Jung; Roy, Jeremy; Smith, Tegan B et al. (2014) ROS1 signaling regulates epithelial differentiation in the epididymis. Endocrinology 155:3661-73
Jun, Hyun Jung; Bronson, Roderick T; Charest, Alain (2014) Inhibition of EGFR induces a c-MET-driven stem cell population in glioblastoma. Stem Cells 32:338-48
Johnson, Hannah; Lescarbeau, Rebecca S; Gutierrez, Jesus A et al. (2013) Phosphotyrosine profiling of NSCLC cells in response to EGF and HGF reveals network specific mediators of invasion. J Proteome Res 12:1856-67
Shao, Huilin; Chung, Jaehoon; Balaj, Leonora et al. (2012) Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy. Nat Med 18:1835-40
Jun, H J; Acquaviva, J; Chi, D et al. (2012) Acquired MET expression confers resistance to EGFR inhibition in a mouse model of glioblastoma multiforme. Oncogene 31:3039-50
Johnson, Hannah; Del Rosario, Amanda M; Bryson, Bryan D et al. (2012) Molecular characterization of EGFR and EGFRvIII signaling networks in human glioblastoma tumor xenografts. Mol Cell Proteomics 11:1724-40
Jun, Hyun Jung; Johnson, Hannah; Bronson, Roderick T et al. (2012) The oncogenic lung cancer fusion kinase CD74-ROS activates a novel invasiveness pathway through E-Syt1 phosphorylation. Cancer Res 72:3764-74
Hambardzumyan, Dolores; Parada, Luis F; Holland, Eric C et al. (2011) Genetic modeling of gliomas in mice: new tools to tackle old problems. Glia 59:1155-68
Acquaviva, Jaime; Jun, Hyun Jung; Lessard, Julie et al. (2011) Chronic activation of wild-type epidermal growth factor receptor and loss of Cdkn2a cause mouse glioblastoma formation. Cancer Res 71:7198-206
Zhu, Haihao; Woolfenden, Steve; Bronson, Roderick T et al. (2010) The novel Hsp90 inhibitor NXD30001 induces tumor regression in a genetically engineered mouse model of glioblastoma multiforme. Mol Cancer Ther 9:2618-26

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