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Pediatric Subcommittee for ODAC Biology of Pediatric Brain Tumors and the Heterogeneity of the Disease

Pediatric Subcommittee for ODAC Biology of Pediatric Brain Tumors and the Heterogeneity of the Disease. Mark W. Kieran, MD, PhD. Children’s Hospital Boston. Dana-Farber Cancer Institute. Harvard Medical School. Objectives. Review of the biology of pediatric brain tumors

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Pediatric Subcommittee for ODAC Biology of Pediatric Brain Tumors and the Heterogeneity of the Disease

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  1. Pediatric Subcommittee for ODACBiology of Pediatric Brain Tumors and the Heterogeneity of the Disease Mark W. Kieran, MD, PhD Children’s Hospital Boston Dana-Farber Cancer Institute Harvard Medical School

  2. Objectives • Review of the biology of pediatric brain tumors • Are adult and pediatric tumors of the CNS different and will that impact on the applicability of adult studies regarding safety and efficacy • Development of better endpoints and trial design in pediatric CNS tumors • improve approval of drugs (standard and biologic) for this population

  3. BackgroundDifferences Between Adult and Pediatric CNS Tumors • Site of origin of tumor • Histology of tumor • Presentation (related to site) • Dissemination (related to histology)

  4. Risk Stratification by Disease Location • Glial • Brain stem location (pons versus other) • Brain stem versus non-brain stem • Bithalamic LGGs versus bilateral optic radiations • Diencephalic syndrome • Neural • Posterior fossa • Pineal • Supratentorial • Infratentorial

  5. Risk Stratification by Disease Histology • Glial • Grade I vs II vs III vs IV astrocytomas • Sampling errors • Diffuse pontine glioma (independent of histology) versus other HGG • LGG +/- NF1 (COG A9952) • Grade II versus grade III ependymoma • 1p, 19q loss in oligodendroglioma • Neural • Chang staging for medullo • ATRT • Pineoblastoma versus PNET • Choroid Plexus and Craniopharyngiomas will require a unique pediatric commitment (virtually absent in adults)

  6. Risk Stratification by Age • Glial • Grade II LGG  Grade III AA in adults but rarely do so in peds (while pilocytic astrocytomas behave similarly after GTR in both) • Pediatric LGG often chemo responsive (not clearly the same in adults although not tested) • Primary (EGFR VIII+ve, p53 wt) and secondary GBM (EGFR wt, p53-ve) in adults versus only primary GBM in peds (and not EGFR mutated or p53 mutant – depending on the series) • Rarity of oligodendroglioma in peds vs adults • Abundance of ependymomas in peds vs adults • Neural • Desmoplastic medullo in infants • Outcome in adults versus children

  7. Etiology of Disease and Age Differences • The result of differences in up-front treatment • Medullo outcome worse in adults, but less therapy given • The result of differences in the origin and stage of the ‘cancer stem cell’ • Adult HGGs have frequent p53, VIII EGFR mutations, which are rare in peds • The result of differences in the tumor cell environment of the brain • Optic pathway gliomas and role of CXCR4

  8. Markers for Pediatric CNS Tumors • Molecular markers of prognosis could improve: • Diagnosis • Treatment • Pediatric classification schema integrating: • Histology • Molecular • Neurobiologic • Neuroimaging

  9. Cho Cho tCr 2 L L Cho NAA tCr 3 4 Advances in Neuro-Radiology 4 4 4 3 3 3 1 1 1 2 2 2 T1W Gd ADC (Diff) rCBV (Perf) 1

  10. MR Fused F18 FDG PET

  11. Tumor Specific Gene Expression Profiles MD MGlio Rhab NC PNET Pomeroy et al., Nature 2002

  12. Advances in Neuropathology Maldi-TOF profile

  13. SELDI-TOF Angiogenesis Proteomic Profile

  14. VEGF-A Expression (#4)

  15. pVEGFR2 Expression (#4)

  16. EGFR Expression in Pediatric Diffuse Pontine Glioma A. Solid tumor H&E B. EGFR +ve area (40X) C. EGFR -ve area (10X) D. Infiltrative tumor H&E E. EGFR +ve cells (10X) F. EGFR +ve cells (40X) The dense tumor with strong +ve EGFR staining (B), dense tumor with -ve EGFR staining (C) and the infiltrative cerebellum with occasional +ve EGFR cells (E&F) are all derived from the same patient

  17. EGFR Molecular Targeting in BSG • In spite of significant staining within tumor cells, unclear that this molecular target inhibition alters disease activity. • Problem with target • Problem with heterogeneity of target • Problem with activity of drug • Wrong dose • Wrong schedule

  18. Targeted Molecular Agents: Malignant Glioma • EGFR • Gefitinib (ZD1839, Iressa) • Erlotinib (OSI-774, Tarceva) • Lapatinib (GW-572016) • AEE788 • ZD6474 • Farnesyltransferase • Tipifarnib (R115777, Zarnestra) • Lonafarnib (Sch66336, Sarasar) • Histone Deacetylase • Depsipeptide • Suberoylanilide hydroxamic acid (SAHA) • Integrins • Cilengitide (EMD 121974) • M200 • mTOR • Temsirolimis (CCI 779) • Everolimus (RAD 001) • Rapamycin (Sirolimus) • AP23573 • PDGF • Gleevec (imatinib mesylate) • PTK787 • SU101 • SUO11248 • GW786034 • MLN518 • PKC • Tamoxifen • PKC 2 • Enzastaurin (LY317615) • Proteosome • Bortezomib (Velcade) • RAF kinase • Sorafenib (Bay 43-9006) • TGF-/TGF- Receptor • SB-431542 • AP12009 • VEGF/VEGFR • Avastin (Bevacizumab) • Sorafenib (Bay 43-9006) • Semaxanib (SU5416) • PTK787 • SU011248 • AEE788 • AZD2171 • ZD6474 • AMG 706 • GW786034 • CEP-7055 From Reardon ASCO: 2005

  19. R R extracellular compartment cytoplasmic membrane VEGF, EGFR, PDGFR, IGFR1 K intracellular compartment K PI3K Raf cytosol RasGTP PLC PKC PDK MEK1,2 PTEN Akt MAPK/ Erk1,2 mTOR FKHR, GSK-3, Bad HIF 1 VEGF Protein-synthesis Cell cycle regulation Cell survival Transcription Proliferation Angiogenesis Ligands/ growth factors From Reardon ASCO: 2005

  20. R R Toxin-conjugates MR-I; TP-38 PI3K Raf FTIs: Tipifarnib, Lonafarnib PLC PKC Tarceva Gefitinib AEE788 Gleevec PDK Sorafenib MEK1,2 Akt Rapamycin RAD001 AP23573 CCI 779 MAPK/ Erk1,2 PTK787 AEE788 Avastin Ligands/ growth factors extracellular compartment cytoplasmic membrane EGFR, PDGFR, IGFR1 K intracellular compartment K RasGTP PTEN mTOR FKHR, GSK-3, Bad VEGF Protein-synthesis Cell cycle regulation Cell survival Transcription Proliferation Angiogenesis From Reardon ASCO: 2005

  21. Validation of receptor-specific tracer uptake in xenografts Tracer uptake was assessed by μSPECT in v3 integrin positive (U87) and negative (Hela) tumors, with only the v3 positive tumor showing uptake. In the same animal, tracer uptake was blocked by pre-injection of an unlabeled v3-directed agent (EMD121974, Merck KGaA).

  22. 3-D reconstruction of intracranial μSPECT data

  23. Intracranial Glioma MR and SPECT Co-registration

  24. Excellent spatial resolution of multiple tiny intracranial tumors For perspective- the whole mouse brain is about the size of a dime, & each tumor is the same diameter as one of the letters in the word ‘Liberty’

  25. What makes μSPECT special?

  26. Summary • There are significant differences in adult and pediatric brain tumors • Sometimes related to location • Sometimes related to histology/cell of origin • Sometimes related to age • There are increasing numbers of molecular inhibitors • Specific agents against specific targets often do not result in specific activity • Molecular markers of activity

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