Mark W. Kieran, MD, PhD
Pediatric Subcommittee for ODACBiology of Pediatric Brain Tumors and the
Heterogeneity of the Disease
Children’sHospitalBoston
Dana-FarberCancerInstitute
HarvardMedicalSchool
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
BackgroundDifferences Between Adult and
Pediatric CNS Tumors
• Site of origin of tumor• Histology of tumor• Presentation (related to site)• Dissemination (related to
histology)
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
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)
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
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
Markers for Pediatric CNS Tumors
• Molecular markers of prognosis could improve:– Diagnosis– Treatment
• Pediatric classification schema integrating:– Histology– Molecular– Neurobiologic– Neuroimaging
Advances in Neuro-Radiology
T1W Gd ADC (Diff) rCBV (Perf)
31
2
4
1
31
2
43
1
2
4
Cho
tCr 2Cho
L
3
L
4
Cho
NAAtCr
MR
Fused
F18 FDGPET
MD MGlio Rhab NC PNET
Distinction Feature Descclass 0 M93119_at INSM1 Insulinoma-associated 1 (symbol provisional)class 0 M30448_s_at Casein kinase II beta subunit mRNAclass 0 S82240_at RhoEclass 0 U44060_at Homeodomain protein (Prox 1) mRNAclass 0 D80004_at KIAA0182 gene, partial cdsclass 0 D76435_at Zic proteinclass 0 X83543_at APXL Apical protein (Xenopus laevis-like)class 0 X62534_s_at HMG2 High-mobility group (nonhistone chromosomal) protein 2class 0 Y10514_s_at CD152 proteinclass 0 M96739_at NSCL-1 mRNA sequenceclass 1 X86693_at High endothelial venuleclass 1 M93426_at PTPRZ Protein tyrosine phosphatase, receptor-type, zeta polypeptideclass 1 U48705_rna1_s_atReceptor tyrosine kinase DDR geneclass 1 X86809_at Major astrocytic phosphoprotein PEA-15class 1 U45955_at Neuronal membrane glycoprotein M6b mRNA, partial cdsclass 1 U53204_at Plectin (PLEC1) mRNAclass 1 X13916_at LDL-receptor related proteinclass 1 D87258_at Cancellous bone osteoblast mRNA for serin protease with IGF-binding motifclass 1 Z31560_s_at SOX2 SRY (sex determining region Y)-box 2class 1 M32886_at SRI Sorcinclass 2 J04164_at RPS3 Ribosomal protein S3class 2 M12125_at Skeletal beta-tropomyosinclass 2 D17400_at PTS 6-pyruvoyltetrahydropterin synthaseclass 2 D29958_at KIAA0116 gene, partial cdsclass 2 D84454_at UDP-galactose translocatorclass 2 D83174_s_at CBP1 Collagen-binding protein 1class 2 D83735_at Adult heart mRNA for neutral calponinclass 2 L38969_at Thrombospondin 3 (THBS3) geneclass 2 U12465_at RPS11 Ribosomal protein S11class 2 U47621_at Nucleolar autoantigen No55 mRNAclass 3 D87463_at KIAA0273 geneclass 3 U90902_at Clone 23612 mRNA sequenceclass 3 D26070_at Type 1 inositol 1,4,5-trisphosphate receptorclass 3 X63578_rna1_atParvalbuminclass 3 Z15108_at PRKCZ Protein kinase C, zetaclass 3 L35592_at Germline mRNA sequenceclass 3 L10338_s_at SCN1B Sodium channel, voltage-gated, type I, beta polypeptideclass 3 L33243_at PKD1 Polycystic kidney disease protein 1class 3 L77864_at Stat-like protein (Fe65) mRNAclass 3 J04469_at Mitochondrial creatine kinase (CKMT) geneclass 4 M80397_s_at POLD1 Polymerase (DNA directed), delta 1, catalytic subunit (125kD)class 4 X14830_at CHRNB1 Cholinergic receptor, nicotinic, beta polypeptide 1 (muscle)class 4 K02882_cds1_s_atIGHD gene (immunoglobulin delta-chain) extracted from Human germline IgD chain gene, C-region, C-delta-1 domainclass 4 HG4178-HT4448_atAf-17class 4 U97018_at Echinoderm microtubule-associated protein homolog HuEMAP mRNAclass 4 X52228_at MUC1 Mucin 1, transmembraneclass 4 L18920_f_at MELANOMA-ASSOCIATED ANTIGEN 2class 4 X55668_at PRTN3 Proteinase 3 (serine proteinase, neutrophil, Wegener granulomatosis autoantigen)class 4 U64805_s_at Brca1-delta11b (Brca1) mRNAclass 4 X98337_s_at Complement factor H-related protein 4
Tumor Specific Gene Expression Profiles
Pomeroy et al., Nature 2002
Advances in Neuropathology
Maldi-TOF profile
SELDI-TOF Angiogenesis Proteomic Profile
VEGF-A Expression (#4)
pVEGFR2 Expression (#4)
A. Solid tumor H&EB. EGFR +ve area (40X)C. EGFR -ve area (10X)
D. Infiltrative tumor H&EE. EGFR +ve cells (10X)F. EGFR +ve cells (40X)
The dense tumor with strong +ve EGFR staining (B), dense tumorwith -ve EGFR staining (C) and the infiltrative cerebellum with occasional +ve EGFR cells (E&F) are all derived from the same patient
EGFR Expression in Pediatric Diffuse Pontine Glioma
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
Targeted Molecular Agents: Malignant Glioma
From Reardon ASCO: 2005
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
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)
TGF-/TGF- Receptor• SB-431542• AP12009
RR
K K
PI3K RasGTP
PLC
Raf
MEK1,2
MAPK/Erk1,2
AktPKC
mTOR
FKHR, GSK-3, Bad
PDKPTEN
HIF 1VEGF
Angiogenesis ProliferationTranscription
cytosol
cytoplasmic membrane
Protein-synthesis
Cell cycle regulationCell survival
extracellular compartment
VEGF, EGFR, PDGFR, IGFR1
intracellular compartment
Ligands/growth factors
From Reardon ASCO: 2005
RR
K K
PI3K RasGTP
PLC
Raf
MEK1,2
MAPK/Erk1,2
AktPKC
mTOR
FKHR, GSK-3, Bad
PDKPTEN
VEGF
Angiogenesis ProliferationTranscription
cytoplasmic membrane
Protein-synthesis
Cell cycle regulationCell survival
extracellular compartment
EGFR, PDGFR, IGFR1intracellular compartment
Ligands/growth factors
Toxin-conjugatesMR-I; TP-38
TarcevaGefitinibAEE788Gleevec
FTIs: Tipifarnib, Lonafarnib
RapamycinRAD001AP23573CCI 779
PTK787AEE788Avastin
Sorafenib
From Reardon ASCO: 2005
Tracer uptake was assessed by μSPECT in v3 integrin positive (U87) and negative (Hela) tumors, with only the v3 positive tumor showing uptake. In the same animal, tracer uptake was blocked by pre-injection of an unlabeled v3-
directed agent (EMD121974, Merck KGaA).
Validation of receptor-specific tracer uptake in xenografts
3-D reconstruction of intracranial μSPECT data
Intracranial Glioma MR and SPECT Co-registration
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’
What makes μSPECT special?
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