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8
General discussion and future directions
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GENERAL DISCUSSION
After acute leukemia, brain tumors constitute the most common form of childhood cancer. On
average, 120 children are diagnosed with a brain tumor every year in the Netherlands1.
Although the implementation of dose-intensive cytotoxic chemotherapy and radiotherapy
regimens has led to a large increase in survival in other areas in pediatric oncology, the
overall survival rates for children with a high-grade brain tumor are still poor, especially in
patients suffering from high-grade gliomas and anaplastic ependymomas. For some types,
such as medulloblastoma, survival has improved over recent decades, but quality of life is often
compromised by debilitating long-term sequelae in these patients. There is thus a great urgency
to boost preclinical and clinical research in the field of childhood brain tumors, investigating
new, tumor specific, targets for therapy, not only to improve the survival of these children, but
also to reduce the deleterious late effects. During the writing of this thesis, phase I/II clinical
trials (listed in Table 1) have explored therapies directed against several tumor-specific targets,
mostly extrapolated from other cancers, to study their effect in (mainly relapsed) high-grade
pediatric brain tumors and de novo DIPG. Thus far, with limited success.
This thesis has therefore explored new treatment targets for high-grade (pediatric) brain
tumors by use of in silico genomics and proteomics, and literature studies, expanding even to
other types of other cancer.
As AMPA-type glutamate receptors were described in the literature to have a tumor-promoting
role in adult glioblastoma multiforme, with glioma cells being able to produce large amounts
of the neurotransmitter glutamate, these receptors were investigated as targets for therapy
(Chapter 2). In discrepancy with previously published data, we found these receptors
to be down-regulated in adult glioblastoma compared to normal brain in silico and to be
electrophysiologically non-functional in cultured glioma cells. Our observations partly explained
why these cells are able to survive in their self-created glutamate-rich environment, but did not
support a rationale for AMPA receptor inhibition, since no effect of these inhibitors on cultured
glioma cells was observed2. Recent research however, describes that subpopulations within
these tumors, glioblastoma stem or tumor-initiating cells, might actually benefit from AMPA
receptor targeting, since these specific cells do show up-regulation of these receptors3. This
emphasizes that potential drug target expression should also be investigated in subpopulations
of tumor-initiating cells, which could be overlooked when focusing on ‘whole tumor’ target
gene expression. Furthermore, the mechanism by which high-grade glioma cells release
glutamate, via the glutamate-cysteïne antiporter system xc-, causing excitotoxic cell death of
neurons, provides an interesting option for targeted therapy. Specific inhibitors against nonAMPA type (ionotropic and metabotropic) glutamate receptors are subject to investigation4.
Whether these will have significant anti-tumor effects remains to be seen, since we found
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that these receptors were also not differentially expressed in high-grade gliomas compared to
normal brain2.
Identification of new targets in high-grade pediatric brain tumors depends on the availability
of cell biological data from these tumors. Publicly available data on the genome, transcriptome
and proteome are rich sources of information, allowing for the identification of potential genes
or pathways for therapeutic targeting. These sources were used in this thesis for in silico
analyses, comparing data from pediatric or adult high-grade brain tumors with normal brain
tissues. PBXIP1 was discovered as a protein overexpressed in high-grade astrocytomas by use
of The Human Protein Atlas, in which a large number of tissue micro-arrays of multiple cancers
and normal tissues are banked (Chapter 5). Using this in silico proteomic approach, differential
protein expression between glioma and normal brain can be investigated, allowing for the
identification of new therapeutic targets with potential low toxicity to the normal brain. The
disadvantage of this proteomic database is, that it currently does not include pediatric brain
tumors. Interestingly, inhibition of PBXIP1 via RNA interference resulted in strong reduction
of viability and motility of high-grade astrocytoma cells, which will be subject for further
research within our group. Ultimately, new agents directed against this target may provide
new therapies in high-grade astrocytomas.
Recently, new studies were published by other groups exploring the transcriptome of pediatric
high-grade glioma5, DIPG6, ependymoma7,8 and medulloblastoma9-12. These data revealed that
the classically ‘histology defined’ disease entities can now be redefined by molecular profiling,
classify these diseases in distinct subgroups with distinct prognostic characteristics. For further
research and diagnostics, histopathology will be redefined by new molecular techniques, allowing
for better outcome prediction and definition of patient subgroups for treatment stratification.
In particular, for medulloblastoma, four prognostic subgroups have been defined based on
gene expression: a subgroup with aberrant Sonic Hedgehog (SHH) pathway signaling, a subtype
with aberrant signaling in the Wingless (WNT) pathway, Group 3 tumors (harbouring strong
MYC amplification) and Group 4 tumors9-12. Group 3 and 4 tumors are often metastasized
and have a poor prognosis, whereas WNT-type tumors have a good outcome. Young children
under the age of three years, presenting with medulloblastoma have an excellent prognosis
when biology shows SHH pathway activation (with a desmoplastic or extensive nodularity
histopathology). Based on these risk profiles, therapy needs to be adapted accordingly. As a
result, in the very near future, WNT-type tumors will we treated with less intensive treatment
regimens, hopefully resulting in excellent outcome, with less long-term side effects. Relapsed
SHH-type tumors, often characterized by a mutation in the PTCH1 gene will be subject to
targeted therapy with SHH inhibitors, in addition to standard cytotoxic therapies. For Group
3 and Group 4 tumors, current therapies are insufficient and therefore more intensive and/or
targeted therapy approaches are needed for these tumors.
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For childhood ependymoma, molecular classification studies are currently underway. Prognostic
modeling of these tumors based on histopathological WHO grading has proved to be a
difficult task, with inter-observer variation and irreproducibility over trials13. Looking for better
prognostic markers, recent molecular profiling has resulted in the definition of two distinct
prognostic subgroups (A and B) of posterior fossa ependymomas14. Also for infratentorial
ependymomas, based on gene expression, two specific subgroups could be defined15, whereas
in supratentorial ependymomas, using array CGH, gain of 1q, and homozygous deletion of
CDKN2A were found to be strong, negative, prognostic markers16.
Expression profiling in high-grade glioma and DIPG have revealed focal high-level amplifications
in PDGFRA and MET in a substantial number of tumors17. In DIPG, based on its transcriptome,
a mesenchymal / pro-angiogenic subgroup and an oligodendroglial subgroup were defined,
with distinct prognostic differences18.
Following up on expression profiling, more recently, exome and whole genome sequencing
studies in pediatric high-grade brain tumors have identified interesting new mutations in genes
that involve epigenetic regulators, such as MLL2 and KDM6A in medulloblastoma19-21, and
H3F3A and HIST1H3B in up to 80% of DIPG and non-brainstem high-grade glioma22, which have
prognostic significance17. 450k DNA methylation analyses in medulloblastoma also indicate
that these tumors are characterized by epigenetic deregulation of normal developmental
processes10,23-29. Likewise, the recently discovered histone mutations in pediatric high-grade
glioma seem to influence the epigenome in these cancers to a large extent17,30,31. Furthermore,
also in childhood ependymoma, epigenomic arrays have revealed DNA methylation as an
important oncogenic mechanism, for which therapies targeting the epigenetic machinery
might be of benefit32,33. Interestingly, in our study on SIRPα in medulloblastoma (Chapter
6), we found that targeting of epigenetic modulator genes strongly affected viability of these
cells. Because of their epigenetic deregulation, targeting the epigenetic machinery seems to be
an interesting option in medulloblastoma, ependymoma and pediatric high-grade glioma, but
fine-tuning these therapies is important, since they might interfere with normal developmental
processes. Therefore, the biggest challenge may be to render this into a tumor-specific therapy,
leaving normal cells unharmed.
Mutations or genomic aberrancies in high-grade pediatric brain tumor cells can also be ‘indirectly
targeted’ through synthetic lethality, which can be induced in tumor cells when a certain signal
transduction pathway is deregulated by a mutation of a particular gene. Inhibition of the
salvage pathway, that the tumor cells now depend on, results only in lethality of the tumor
cells and not of normal cells which still have the intact signal transduction pathway available.
An example of this approach is the inhibition of the DNA repair gene PARP1 (Chapter 3)34.
The targeting of genes which are synthetically lethal to a cancer-relevant mutation has the
advantage of killing tumor cells and sparing normal cells, thereby avoiding treatment-related
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toxicity. In this respect, defects in tumor cells’ double strand break repair or cell cycle regulation
provide a rationale for PARP inhibition35. Using in silico analyses, PARP1 (Chapter 3) and EGFR
and ERBB2 (Chapter 4) overexpression compared to normal brain tissues was observed in
adult and pediatric high-grade brain tumors and inhibition of these genes sensitized these
tumors to radiation36,37. PARP-inhibitors have entered the arena of new drugs in the treatment
of pediatric brain tumors, both in combination with temozolomide and radiotherapy. Currently,
in controlled Phase II and III studies, combining radiotherapy with inhibitory monoclonal
antibodies directed against EGFR, encouraging response rates and longer survival time of highgrade glioma patients are being observed38. Since high-grade gliomas in adults seem to be
more EGFR-driven than their pediatric counterparts39, the role of combining these agents in
pediatric high-grade glioma and DIPG remains to be elucidated. In pediatric high-grade glioma
however, interesting responses were observed combining EGFR inhibition with radiotherapy
and vinorelbine, warranting further Phase III studies40.
In vitro radiosensitization studies have some drawbacks. Potential increased neurotoxicity
upon treatment with radiosensitizers is difficult to assess. Furthermore, radiosensitization in
vitro is determined by classical dose-response curves, in which tumor cells are exposed to
a radiosensitizer and increasing doses of radiation. In clinical practice, pediatric high-grade
brain tumor patients are treated with fractionated radiotherapy schedules, with daily doses
of 1.8 Gy, up to a cumulative dose of 54 Gy, depending on the tumor site and normal brain
regions at risk. How these fractionated schedules used in the clinic relate to in vitro single
dose radiation tumor cell sensitivity assessment is unclear. Future in vitro and in vivo research
into potential radiosensitizers in brain tumors should therefore also take into account these
radiation schedules used in clinical practice. This might provide additional clues for optimal
radiosensitization.
FUTURE DIRECTIONS
For an outstanding translational research program in pediatric neuro-oncology, collaboration
between pediatric neurosurgeons, pediatric neuro-oncologists, neurologists, radiotherapists,
neuropathologists, nuclear medicine physicians, radiologists, molecular (radio)biologists, bioinformaticians and statisticians is essential. Integrating clinical patient data, genomic profiles
from patients’ normal and tumor material and by use of patient-derived cell lines and xenografts,
knowledge on potential treatment targets will undeniably increase. With Connectivity
Mapping, gene signatures from pediatric high-grade brain tumors are linked to corresponding
drug sensitivity patterns from drug screens and data from genetic manipulations, such as RNA
interference studies.
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Besides their value as new prognostic tools in groups of patients, these novel molecular
techniques also allow for patient-tailored, quick analyses of potential treatment targets in
newly diagnosed and relapsed tumors, enabling personalized treatment with the best possible,
individualized, targeted therapy41. Using drug libraries and loss of function RNAi screens in
patient-derived cell lines, mechanisms of resistance to targeted therapy can be investigated,
and drug combinations can be explored that have synergistic, or even synthetic lethal effects,
for use in these patients42.
In the current era, ever-increasing amounts of genomic data of normal and tumor tissues are a
challenge to the human mind. Unbiased analysis of these large and complex ‘Big Data’ ask for
new technologies43. Computer networks and grids will be used to process these large quantities
of data within shorter timeframes. These systems are able to integrate information from a
multitude of databases, such as published data (e.g. Pubmed), mRNA-, miRNA-, methylome-,
proteome-datasets, RNAi screens and exome and whole genome sequencing from tumors and
normal tissues. Unbiased data analysis, searching for patterns, will potentially provide answers
in oncogenic mechanisms and the discovery of new targets for therapy.
New treatment target discovery at the same time raises the question whether drugs directed
against these targets are actually able to reach their brain tumor targets, as the blood-brain
barrier (BBB) prevents a lot of pharmaceuticals from entering the brain, by virtue of the
ultrastructure of the BBB with tight junctions and expression of ATP-binding cassette (ABC)
drug transporters44. The BBB is usually, at least partly, disrupted in high-grade brain tumors,
but one can question whether the extent of BBB disruption observed in these tumors is enough
to provide ample availability of drugs which normally would not cross this barrier. Tumor cells
use the intact BBB as a shelter from harm, suggesting that the inefficacy of cytotoxic therapies
in the past is likely to be, at least partly, explained by the inability of these agents to reach the
tumor cells. This could also imply that drugs, which have previously been unsuccessful in clinical
trials, might be effective when given via a different route, or modified into e.g. nanoparticles45.
Research into methods of enhancing brain tumor uptake of new and ‘old’ agents give new
opportunities for previously depreciated medication for the treatment of brain tumors. Future
studies should take into account how to circumvent the BBB to accomplish therapeutically
relevant concentrations of a drug. This could be reached by redesigning drugs to enhance BBB
transport, e.g. optimizing size and increasing hydrophobic properties and modifying the charge
of molecules. Nanotechnologies are currently being explored, making use of encapsulated
drugs in polymers and liposomes, which enhances passage over the BBB45,46.
Another possible solution to overcome the BBB is convection-enhanced delivery (CED). With
CED, drugs are delivered into the brain tumor via microcatheters under a continuous pressure
gradient47,48. This technique yields high concentrations of drugs in and around the tumor,
impossible to obtain via systemic delivery without causing toxicity. This method is suitable for
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drugs which are selectively toxic to tumor cells and leave normal cells unharmed, and have
excellent convection capacity. Translation of in vitro data on drug sensitivity of brain tumor
cells and toxicity on normal astrocytes is of help in choosing the ideal candidate drug for
delivery via CED44. These candidate drugs, both new agents and more ‘conventional’ cytotoxic
agents, can then be validated in vivo, allowing for swift translation into clinical studies.
In conclusion, the studies performed in this thesis have explored several targets for therapy,
using literature and in silico data mining and validation of these potential targets in functional
assays. For some targets, such as the AMPA-type glutamate receptors, more research is
needed to establish whether they could serve as targets for therapy. Potential treatment target
PBXIP1 will be subject to extended in vitro and in vivo, and, possibly, clinical studies. For
other targets, such as PARP1 and the ErbB family, clinical trials with inhibitors against these
targets, combined with radio- and/or chemotherapy in pediatric high-grade brain tumors are
already underway. Interesting new avenues are to be explored in targeting the deregulated
epigenome in medulloblastoma and pediatric high-grade glioma, as described in our study of
SIRPα in medulloblastoma.
Research into pediatric high-grade brain tumors should be focused on novel drug target
discovery, using large scale, bioinformatic analysis of ‘Big Data’, in vitro and in vivo models,
and studies on the optimal delivery method of the (targeted) drugs. Ideally, Academia also
develops new anti-cancer agents for small subgroups of patients, for whom the incentive for
pharmaceutical companies to do so may be lacking. Hereto, accelerating translational research
is of the highest importance. To this purpose, in the very near future, in the Netherlands, the
Princess Máxima Center for Pediatric Oncology will be opened. In this center, all Dutch children
with a malignancy will be diagnosed and treated according to standardized evidence-based
protocols. With an in-house Research Institute with its own Neuro-oncology Research Facility,
preclinical research programs will be highly interwoven with patient care and clinical studies,
from bench to bedside and back again, ultimately improving survival and quality survival of
children with a high-grade brain tumor.
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Year
2008
2008
2008
2009
2009
2009
2009
2009
2009
2009
2009
2009
2009
2009
2010
2010
2010
2010
2010
2010
2010
2010
2011
2011
2011
2011
2011
2012
2012
2012
2012
2012
2013
Clinical Trial Number
NCT00679354
NCT00788125
NCT00876993
NCT00822458
NCT00880061
NCT00929903
NCT00883688
NCT00879437
NCT00946335
NCT00994500
NCT00939770
NCT00994071
NCT01012609
NCT01032070
NCT01076530
NCT01088763
NCT01135563
EudraCT 2009-016870-33
NCT01189266
NCT01236560
NCT01239316
NCT01158300
EudraCT 2010-022978-14
EudraCT 2009-016080-11
EudraCT 2010-019348-37
NCT01393912
EudraCT 2009-011898-33
NCT01462695
NCT01518413
NCT01514201
EudraCT 2010-022189-28
EudraCT 2012-001306-20
NCT01677741
Inclusion
Recurrent or Progressive HGG
Metastatic or Recurrent Malignant Solid Refractory/Relapsed BT
Recurrent or progressive MBL
Progressive DIPG and Supratentorial HGG
Relapsed or Refractory Brain Tumors or Solid
Recurrent or Refractory Ep
HGG
Recurrent or Refractory BT
Refractory or Recurrent Solid Tumors, incl.BT
Relapsed or Refractory BT, Solid Tumors or ALCL
Recurrent or Refractory BT
Newly Diagnosed DIPG and High-Grade
Recurrent or Refractory Pediatric Ep
Relapsed or Refractory Primary BT or Spinal
Relapsed or Refractory Solid Tumors, BT, Recurrent or Refractory Solid Tumors Including BT
Newly diagnosed DIPG
Newly Diagnosed DIPG
Newly Diagnosed HGG
Recurrent or Refractory MBL
Refractory or Recurrent Primary BT
Tumors with ALK translocation, mutation
Malignant Pontine Gliomas
Recurrent or refractory MBL or other SHH
DIPG or Recurrent HGG
Relapsed or Refractory HGG or DIPG
Recurrent, Refractory or Progressive HGG
Brain Tumors and Solid Tumors
Newly Diagnosed DIPG
Newly diagnosed supratentorial HGG
Relapsed or Refractory Solid Tumors,
Brain Neoplasms
Phase
2
1-2
1
1
1
1
2
2
1
1
1-2
1
2
2
1
1-2
1
1
1-2
2-3
2
1
1
1-2
1-2
1
2
2
1
1-2
2
1
1
Targeting agent
Cilengitide
Dasatinib
Bevacizumab
Vismodegib
IL13-PE38QQR (CED)
Pazopanib
Bevacizumab, Lapatinib
Valproate, Bevacizumab
Veliparib
Vorinostat, Bortezomib
Crizotinib
Veliparib
Cetuximab
Erlotinib
Vorinostat
RO4929097
Sirolimus
Cilengitide
Vorinostat
Vorinostat, Bevacizumab
Vismodegib
PTC299
Crizotinib
Bevacizumab, Erlotinib
Erismodegib
Crenolanib
Cilengitide
Sunitinib
Sorafenib
Veliparib
Bevacizumab
Pazopanib
Dabrafenib
Target
αvβ3integrin
Src, PDGFR, c-kit
VEGF
PTCH/Smo
IL13R
VEGFR2, PDGFRB, c-kit
EGFR/ERBB2
HDAC & VEGF
PARP1/2
HDAC & proteasome
ALK
PARP1/2
EGFR
EGFR
HDAC
γ-secretase / Notch
mTOR
αvβ3integrin
HDAC
HDAC & VEGF
PTCH/Smo
VEGF
ALK
VEGF, EGFR, mTOR
Smo
PDGFRα
αvβ3 integrin
PDGFR, VEGFR, c-kit, RET
RAF, VEGFR, PDGFR
PARP1/2
VEGF
VEGFR2, PDGFRβ, c-kit
BRAF
Table 1: Overview of phase I and II clinical trials in pediatric high-grade brain tumors performed from 2008-2013.
Irinotecan
RT, TMZ
RT, TMZ
TMZ
Gemcitabine, RT, Irinotecan
RT
TMZ
TMZ
RT, Irinotecan
Etoposide
TMZ
Dexamethasone
Vinblastine
RT
TMZ
Carboplatin, VP16, Ifosfamide
Irinotecan, TMZ
Additionaltherapy
General discussion and future directions
Abbreviations: NCT – National Clinical Trials, EudraCT - European Union Drug Regulating
Authorities Clinical Trials, BT – Brain Tumors, CED – Convection Enhanced Delivery, Ep –
Ependymoma, MBL – Medulloblastoma, HGG – High-grade Glioma, DIPG – Diffuse Intrinsic
Pontine Glioma, LGG – Low-grade Glioma, BRAF – B-Rapidly Accelerated Fibrosarcoma,
EGFR – Epidermal Growth Factor Receptor, VEGF(R) – Vascular Endothelial Growth Factor
(Receptor), PDGFR – Platelet Derived Growth Factor Receptor, TMZ – Temozolomide,
RT – Radiotherapy, mTOR – Mammalian Target of Rapamycin, PARP – Poly-ADP Ribose
Polymerase, HDAC – histone deacetylase
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