Mark W' Kieran, MD, PhD

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Pediatric Subcommittee for ODACBiology of
Pediatric Brain Tumors and the Heterogeneity of
the Disease

• Mark W. Kieran, MD, PhD

Childrens Hospital Boston
Dana-Farber Cancer Institute
Harvard Medical School
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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

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BackgroundDifferences Between Adult and
Pediatric CNS Tumors

• Site of origin of tumor
• Histology of tumor
• Presentation (related to site)
• Dissemination (related to histology)

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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

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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)

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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 VIIIve, 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

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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

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Markers for Pediatric CNS Tumors

• Molecular markers of prognosis could improve
• Diagnosis
• Treatment
• Pediatric classification schema integrating
• Histology
• Molecular
• Neurobiologic
• Neuroimaging

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Advances in Neuro-Radiology
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T1W Gd
ADC (Diff)
rCBV (Perf)
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MR
Fused
F18 FDG PET
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Tumor Specific Gene Expression Profiles
MD MGlio Rhab NC PNET
Pomeroy et al., Nature 2002
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Advances in Neuropathology
Maldi-TOF profile
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SELDI-TOF Angiogenesis Proteomic Profile
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VEGF-A Expression (4)
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pVEGFR2 Expression (4)
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EGFR Expression in Pediatric Diffuse Pontine
Glioma
A. Solid tumor HE B. EGFR ve area (40X) C. EGFR
-ve area (10X) D. Infiltrative tumor HE 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 (EF) are all derived from the same
patient
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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

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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

• VEGF/VEGFR
• Avastin (Bevacizumab)
• Sorafenib (Bay 43-9006)
• Semaxanib (SU5416)
• PTK787
• SU011248
• AEE788
• AZD2171
• ZD6474
• AMG 706
• GW786034
• CEP-7055

• PDGF
• Gleevec (imatinib mesylate)
• PTK787
• SU101
• SUO11248
• GW786034
• MLN518
• PKC
• Tamoxifen
• PKC ?2
• Enzastaurin (LY317615)
• Proteosome
• Bortezomib (Velcade)
• RAF kinase
• Sorafenib (Bay 43-9006)

From Reardon ASCO 2005
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Ligands/ growth factors
From Reardon ASCO 2005
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Ligands/ growth factors
extracellular compartment

cytoplasmic membrane
EGFR, PDGFR, IGFR1
K
intracellular compartment
K
RasGTP
PTEN
mTOR
FKHR, GSK-3, Bad
VEGF
Proliferation
Transcription
Protein-synthesis
Cell cycle regulation Cell survival
Angiogenesis
From Reardon ASCO 2005
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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).
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3-D reconstruction of intracranial µSPECT data
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Intracranial Glioma MR and SPECT Co-registration
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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
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What makes µSPECT special?
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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