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Mouse Models of Human Brain Tumors: From Cage to Clinic David H. Gutmann, MD, PhD ©Washington Director, Neurofibromatosis Center Co-Director, Neuro-Oncology Program University, 2009 Donald O. Schnuck Family Professor Department of Neurology Washington University School of Medicine Brain Tumors • Leading cause of cancer-related death in children ©Washington University, 2009 • 4th leading cause of cancer-related death in adults Cyclin-dependent kinase inhibitor 2A Cyclin-dependent kinase inhibitor 2B Cyclin-dependent kinase 4 Epidermal growth factor receptor Murine double minutes Phosphatase and tensin homology p14 alternative reading frame Retinoblastoma 1 TP53 17p LOH 9p 9p 12q 7q 12q 10q 9p 13q 17p 10q LOH Protein p16 p15 cdk4 EGF-R MDM2 PTEN p14-ARF Rb p53 Tumor grade p53 EGF-R amp WHO grade I 71% 0% 0% 0% WHO grade II 63% 0% 0% 0% WHO grade III 63% 31% 13% 6% WHO grade IV 68% 26% 38% 21% University, 2009 Chromosome ©Washington Gene Paleo-neuro-oncology Limited insights into the molecular and cellular changes ©Washington University, 2009 critical for tumor formation or continued growth ©Washington University, 2009 sporadic cancer loss of tumor suppressor gene function increased cell proliferation ©Washington CANCER University, 2009 cancer predisposition syndrome Genes Nervous system tumors von Hippel-Lindau vHL (3p25-26) hemangioblastoma Tuberous sclerosis complex TSC1 (9p34) TSC2 (16p13) subependymal giant cell astrocytoma Li-Fraumeni p53 (17p13) astrocytoma primitive neuroectodermal tumor Neurofibromatosis 1 NF1 (17q11) optic pathway glioma, astrocytoma neurofibroma Neurofibromatosis 2 NF2 (22q12) schwannoma, meningioma ependymoma ©Washington Syndrome University, 2009 Familial syndromes associated with nervous system tumors Brain Tumors in NF1 • 15-20% of children with NF1 • Typically young children • WHO grade I pilocytic astrocytoma ©Washington • Composed of GFAPimmunoreactive (glial) cells University, 2009 • Commonly involving optic pathway Neurofibromatosis type 1 as a model system for understanding the molecular and cellular pathogenesis of glioma? Most common inherited genetic mutation in pediatric low-grade glioma ©Washington University, 2009 One of the most common genetic mutations in adult high-grade glioma (TCGA) Nf1 gene neo Nf1 +/- +/- -/- wild-type viable embryonic lethal E12.5-13.5 no gliomas no neurofibromas Brannan C. et al., Genes & Development 1994 Jacks T. et al., Nature Genetics 1994 University, 2009 +/- ©Washington +/+ LoxP LoxP Nf1 gene Cre recombinase disrupted Nf1 gene Zhu Y. et al., Genes & Development 2001 University, 2009 LoxP ©Washington LoxP Bajenaru ML, Mol Cell Biol. 2002 LoxP LoxP Nf1 flox alleles Cre IRES nLacZ NO BRAIN TUMORS Nf1-deficient University, 2009 normal ©Washington hGfap promoter LoxP LoxP Nf1 mut allele neoR hGfap promoter Nf1 flox allele Cre IRES nLacZ OPTIC GLIOMAS Bajenaru ML, Cancer Res. 2003 NF1-/(tumor) Nf1-deficient astrocytes ©Washington NF1+/(body) University, 2009 Nf1+/- Opportunities 1. Identify new targets for therapeutic drug design 2. Determine why certain therapies fail ©Washington University, 2009 3. Evaluate new therapies in preclinical models NO TUMOR normal Nf1-deficient Nf1+/- Nf1-deficient astrocytes ©Washington TUMOR University, 2009 contribution(s) of other cell types in the tumor microenvironment Appropriate stromal cells and signals ©Washington University, 2009 Susceptible preneoplastic cells 1. What stromal cell types and molecular signals drive NF1 brain tumor cell growth? normal MICROGLIA growth factors • Increase tumor invasiveness • Evade immune surveillance Bajenaru ML, Annals of Neurology 2005 ©Washington secreting cytokines and University, 2009 • Enhance tumor growth by brain microglia/astrocyte co-cultures culture supernatant 1. Nf1+/-, but not wild-type, microglia promote Nf1-/- astrocyte proliferation in vitro 2. Nf1+/- microglia elaborate paracrine factors that promote Nf1-/- astrocyte proliferation in vitro Daginakatte & Gutmann, Human Mol. Genet. 2007 ©Washington University, 2009 brain microglia cultures (Nf1+/+ or Nf1+/-) equilibration enhancement ©Washington elimination University, 2009 “specialized” microglia tumor elimination promote tumor growth glioma cells ©Washington CSCs University, 2009 endothelial cells Future targeted therapies cancer stem cells endothelial cells University, 2009 stromal cells ©Washington • microglia • microglia-produced growth factors differentiated tumor cells 2. Evaluate why certain therapies fail neurofibromin GTP “active” GDP ras ras cell growth “inactive” cell growth “ON” “OFF” neurofibromin X cell growth University, 2009 GDP ©Washington GTP X neurofibromin GTP farnesyltransferase inhibitors GDP RAS cell growth H-RAS N-RAS K-RAS University, 2009 “active” “inactive” Blocked by FTIs Not blocked by FTIs ©Washington RAS 3. Evaluate new therapies in preclinical models treatment 10-12 week old Nf1+/-GFAPCKO mice vehicle ©Washington University, 2009 ©Washington University, 2009 Treatment with chemotherapy used for children with lowgrade brain tumors blocks mouse optic glioma tumor growth in vivo Mechanism of action Target validation ©Washington Effect on normal brain University, 2009 “Off-target” effects PATIENTS mouse models differentiated tumor cells stromal cells cancer stem cells targeted treatment strategies ©Washington molecular & cellular targets University, 2009 endothelial cells surrogate outcome measurements
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