Modulation of Oncogenic Signaling in Gliomas. A hallmark of human glioblastomas is that oncogenic signalings stimulated by overexpressed genes such as EGFR and EGFRvIII are aberrantly active, rendering these tumors highly malignant, and inherently resistant to combination therapies, resulting in an extremely poor prognosis of patients with malignant gliomas. A major barrier of this clinical challenge is the lack of a complete understanding of the mechanisms underlying the aggressiveness of these tumors and ineffectiveness of therapies for gliomas. The goal of this project is to define the role of ESDN, endothelial and smooth muscle cell-derived neuropilin-like protein (other names, DCBLD2 and CLCP1) in tumorigenesis and therapy-resistance of malignant human glioblastomas. ESDN is expressed at high levels in vascular injury, metastatic lung cancer and breast cancer. Our preliminary studies show that the ESDN gene is amplified in ~50% of clinical glioma specimens and preferentially up-regulated in classical and mesenchymal subtypes of glioblastomas that overexpress EGFR and EGFRvIII. Knockdown of ESDN in tumor xenografts significantly suppressed EGFRvIII-promoted glioma growth and invasion in the brain of animals. Mechanistically, EGFRvIII and EGF induce tyrosine phosphorylation (p-Y) of Y621 and Y750 of ESDN that activate TRAF6-Akt- and CrkII-Rac1- signaling and promote glioblastoma cell survival and invasion. Based on these observations, in this project, we propose a research plan directed at elucidating mechanisms by which ESDN augments EGFRvIII-stimulated glioma tumorigenesis and exploring therapeutic application of targeting ESDN to inhibit EGFRvIII-expressing brain gliomas. We will first investigate how ESDN affects EGFRvIII-stimulated glioma growth and invasion through dissociation of TRAF6 and binding of CrkII to specific tyrosine residues of ESDN that are phosphorylated by EGF and EGFRvIII stimulation. We will then determine clinical significance of the induced p-Y of ESDN with activation of oncogenic EGFR/EGFRvIII signaling pathways in primary glioma tumor specimens (Aims 1 and 2). Using short-term cultured primary glioblastoma (GBM) xenograft and an induced de novel brain glioma models, we will explore pre-clinical approaches to assess the impact of inhibition of ESDN on the efficacies of chemotherapeutic agents, cisplatin and temozolomide on EGFR- and EGFRvIII-expressing glioblastomas in the brain of animals (Aim 3). Therefore, this proposal reveals an unrecognized signaling path by which EGFR and EGFRvIII stimulate TRAF6-Akt- and CrkII-signaling through ESDN, thereby promoting glioma growth and invasion. Elucidation of this novel mechanism holds promise to a better understanding of the oncogenic signaling-promoted glioma tumorigenesis and to overcome the insidious glioma resistance to current therapies. This project also addresses an urgent challenge in neuro-oncology and offers an enormous potential for developing novel therapies that could prove effective, thus eliminating the major barrier in treating patients with malignant glioblastomas.
Modulation of Oncogenic Signaling in Glioblastomas Human glioblastomas are characterized with malignant growth, rapid progression and intrinsic invasiveness, rendering these tumors virtually resistant to existing therapies, and the great propensity for tumor recurrence. In this application, we propose to investigate a novel mechanism by which oncogenic EGFRvIII and EGFR promote glioblastoma malignancy and resistant to therapies through activation of ESDN- TRAF6/CrkII signaling. The proposed work holds promise to elucidate the glioblastoma malignancy and to overcome the tumor resistance to combination therapies.
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|Hashizume, Rintaro; Zhang, Ali; Mueller, Sabine et al. (2016) Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth. Neuro Oncol 18:1519-1528|
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|Huang, Tianzhi; Alvarez, Angel A; Pangeni, Rajendra P et al. (2016) A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways. Nat Commun 7:12885|
|Bell, Jonathan B; Eckerdt, Frank D; Alley, Kristen et al. (2016) MNK Inhibition Disrupts Mesenchymal Glioma Stem Cells and Prolongs Survival in a Mouse Model of Glioblastoma. Mol Cancer Res 14:984-993|
|Kim, Sung-Hak; Ezhilarasan, Ravesanker; Phillips, Emma et al. (2016) Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-?B-dependent Manner. Cancer Cell 29:201-13|
|Zhang, L; Zhang, W; Li, Y et al. (2016) SHP-2-upregulated ZEB1 is important for PDGFR?-driven glioma epithelial-mesenchymal transition and invasion in mice and humans. Oncogene 35:5641-5652|
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