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Mouse Models of Human Brain Tumors: From Cage to Clinic David H. Gutmann, MD, PhD Donald O. Schnuck Family Professor Dep

Mouse Models of Human Brain Tumors: From Cage to Clinic David H. Gutmann, MD, PhD Donald O. Schnuck Family Professor Department of Neurology Washington University School of Medicine Director, Neurofibromatosis Center Co-Director, Neuro-Oncology Program. © Washington University, 2009.

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Mouse Models of Human Brain Tumors: From Cage to Clinic David H. Gutmann, MD, PhD Donald O. Schnuck Family Professor Dep

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  1. Mouse Models of Human Brain Tumors: From Cage to Clinic David H. Gutmann, MD, PhD Donald O. Schnuck Family Professor Department of Neurology Washington University School of Medicine Director, Neurofibromatosis Center Co-Director, Neuro-Oncology Program ©Washington University, 2009

  2. Brain Tumors • Leading cause of cancer-related death in children • 4th leading cause of cancer-related death in adults ©Washington University, 2009

  3. GeneChromosomeProtein Cyclin-dependent kinase inhibitor 2A 9p p16 Cyclin-dependent kinase inhibitor 2B 9p p15 Cyclin-dependent kinase 4 12q cdk4 Epidermal growth factor receptor 7q EGF-R Murine double minutes 12q MDM2 Phosphatase and tensin homology 10q PTEN p14 alternative reading frame 9p p14-ARF Retinoblastoma 1 13q Rb TP53 17p p53 Tumor gradep5317p LOH10q LOHEGF-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% ©Washington University, 2009

  4. Paleo-neuro-oncology Limited insights into the molecular and cellular changes critical for tumor formation or continued growth ©Washington University, 2009

  5. ©Washington University, 2009

  6. sporadic cancer loss of tumor suppressor gene function increased cell proliferation cancer predisposition syndrome CANCER ©Washington University, 2009

  7. Familial syndromes associated with nervous system tumors 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 University, 2009

  8. 15-20% of children with NF1 Typically young children WHO grade I pilocytic astrocytoma Commonly involving optic pathway Composed of GFAP-immunoreactive (glial) cells Brain Tumors in NF1 ©Washington University, 2009

  9. 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 One of the most common genetic mutations in adult high-grade glioma (TCGA) ©Washington University, 2009

  10. Nf1 +/- +/- Nf1 gene -/- neo +/+ embryonic lethal +/- wild-type viable E12.5-13.5 no gliomas no neurofibromas Brannan C. et al., Genes & Development 1994 Jacks T. et al., Nature Genetics 1994 ©Washington University, 2009

  11. LoxP LoxP Nf1 gene Cre recombinase LoxP LoxP disrupted Nf1 gene Zhu Y. et al., Genes & Development 2001 ©Washington University, 2009

  12. LoxP LoxP Nf1flox alleles hGfap promoter Cre IRES nLacZ Bajenaru ML, Mol Cell Biol.2002 NO BRAIN TUMORS normal Nf1-deficient ©Washington University, 2009

  13. hGfap promoter Cre IRES nLacZ LoxP LoxP Nf1flox allele Nf1mut allele neoR Nf1+/- Nf1-deficient astrocytes OPTIC GLIOMAS NF1+/- (body) NF1-/- (tumor) ©Washington University, 2009 Bajenaru ML, Cancer Res.2003

  14. Opportunities • Identify new targets for therapeutic drug design • Determine why certain therapies fail • Evaluate new therapies in preclinical models ©Washington University, 2009

  15. Nf1+/- Nf1-deficient astrocytes NO TUMOR contribution(s) of other cell types in the tumor microenvironment normal Nf1-deficient TUMOR ©Washington University, 2009

  16. Appropriate stromal cells and signals Susceptible preneoplastic cells ©Washington University, 2009

  17. normal 1. What stromal cell types and molecular signals drive NF1 brain tumor cell growth? • Enhance tumor growth by secreting cytokines and growth factors • Increase tumor invasiveness • Evade immune surveillance MICROGLIA ©Washington University, 2009 Bajenaru ML, Annals of Neurology 2005

  18. Nf1+/-, but not wild-type, microglia promote Nf1-/- astrocyte proliferation in vitro • Nf1+/- microglia elaborate paracrine factors that promote Nf1-/- astrocyte proliferation in vitro brain microglia/astrocyte co-cultures culture supernatant brain microglia cultures (Nf1+/+ or Nf1+/-) ©Washington University, 2009 Daginakatte & Gutmann, Human Mol. Genet.2007

  19. “specialized” microglia elimination equilibration enhancement ©Washington University, 2009

  20. tumor elimination promote tumor growth endothelial cells CSCs glioma cells ©Washington University, 2009

  21. differentiated tumor cells cancer stem cells stromal cells blood vessel endothelial cells Future targeted therapies • microglia • microglia-produced growth factors ©Washington University, 2009

  22. neurofibromin GTP GDP ras ras “active” “inactive” cell growth cell growth “ON” “OFF” neurofibromin X GDP GTP cell growth 2. Evaluate why certain therapies fail ©Washington University, 2009

  23. X neurofibromin GDP GTP farnesyltransferase inhibitors RAS RAS “inactive” “active” cell growth H-RAS N-RAS K-RAS ©Washington University, 2009 Blocked by FTIs Not blocked by FTIs

  24. 3. Evaluate new therapies in preclinical models treatment 10-12 week old Nf1+/-GFAPCKO mice vehicle ©Washington University, 2009

  25. Treatment with chemotherapy used for children with low-grade brain tumors blocks mouse optic glioma tumor growth in vivo ©Washington University, 2009

  26. Mechanism of action Target validation “Off-target” effects Effect on normal brain ©Washington University, 2009

  27. differentiated tumor cells cancer stem cells stromal cells blood vessel endothelial cells PATIENTS mouse models surrogate outcome measurements molecular & cellular targets ©Washington University, 2009 targeted treatment strategies

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