2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

NOVEL TARGETS IN THE TREATMENT OF DIPG
included ATM and MPL mutations, both in the same tumor,
and PDGFR amplification in an additional three (15%)
TP53-mutated tumors. The presence of detectable PI3Krelated
abnormalities in seven (35%) tumors suggests that
the PI3K pathway may play an important role in the genesis
of this disease. PTEN deletions (on chromosome 10q) were
seen in two tumors. Notably absent were mutations in many
genes commonly implicated in malignant gliomas and other
pediatric tumors, including RB1, EGFR, MET, CTNNB1, N-,
H-, or K-RAS, MLH1, EPHA genes and the tyrosine-kinase
domain of KIT or PDGFRA. 20 Expression analysis by immunohistochemistry
in an overlapping cohort showed EGFR
positivity without EGFR amplification in eight of 20 patients
(40%) and absent PTEN expression in the majority. This
reinforces the emerging importance of the RTK-PI3K pathway
in this disease. 21
The potential of identifying targetable mutations with
high-throughput mutational profiling suggests a new clinical
utility to biopsy at diagnosis. In the emerging era of
personalized medicine, tissue-less diagnosis may rapidly
cease to be a viable option. In the United States, a recently
opened multi-institutional trial for patients with DIPG mandates
tumor biopsy in all cases at the time of diagnosis, and
involves a treatment program determined by specific molecular
findings. The purpose of this study is fundamentally
two-fold: to enable detailed molecular analysis of a larger
number of primary specimens than has ever previously been
possible, and to evaluate a specific molecularly guided treatment
approach (ClinicalTrial.gov; NCT01182350).
Comparative Genomics
Molecular analysis has shown significant differences between
pediatric and adult HGG, 19,22,23 as well as between
DIPG and other pediatric HGG. 11,13,17 EGFR amplification,
for instance, the most common focal abnormality in adult
high-grade glioma, appears to be relatively rare in DIPG, as
in other pediatric high-grade gliomas. However, underlying
similarities are also seen. 17 Proneural, proliferative, and
mesenchymal expression subgroups described in adult GBM
have also been described in pediatric GBM regardless of
site. 19 Interestingly, PDFRA amplification, which is consistently
seen in a minority of DIPGs, is associated with
secondary GBM in both adults and children. 17,19
Preclinical Models
Until very recently, DIPG research has been limited by
the lack of faithful animal models. The development of a
genetically engineered mouse model of brainstem glioma
using the RCAS/tv-a system has recently been reported. 24
Upregulation of PDGF signaling in the Nestin� cells of the
subventricular zone in the fourth ventricle gives rise to
dorsal pontine glioblastoma. Similarly, a mouse model of
DIPG generated by retroviral vector-induced upregulation of
PDGF signal nonspecifically in cells of the dorsolateral pons
has also been reported. 25 These models provide a potential
tool for preclinical testing in DIPG, which had previously not
been possible.
A recent preclinical study highlights the potential role of a
unique pontine postnatal neural progenitor cell population
in the genesis of DIPG. A human Nestin� and Olig2�
neural progenitor cell population that is unique to the
ventral pons and immunophenotypically similar to DIPG
has generated significant interest in the cell type that gives
rise to DIPG. 26 This cell population wanes after infancy,
but then peaks again at 6 years, the age at which DIPG
incidence is highest. A similar Olig2� postnatal cell progenitor
cell population was noted in the mouse pons, and was
characterized by Hedgehog (Hh) pathway activation. Selective
further upregulation of the Hh pathway in these Olig-2
positive cells resulted in postnatal DIPG-like pontine hypertrophy,
with proliferation of PDGFR-alpha� oligodendrocyte
precursor cells, although without dysplastic
transformation. Upregulation of Hh pathway in neurospheres
from a DIPG autopsy-derived cell line cells resulted
in increased self-renewal. These findings suggest that DIPG
may represent a deregulation of Hh-activated neuronal
progenitor cells, with additional molecular events causing
malignant transformation.
Conclusion
Any conclusion regarding the biology of DIPG must, at
this point, be considered preliminary. Existing series are
small; with the one exception, all rely at least partially if
not exclusively on autopsy specimens. Nonetheless, there
are certain consistent findings that provide an important
window into the biology of this disease. P53 loss or mutation
is clearly present in a substantial portion of tumors. The
RTK-Ras-PI3K-Akt pathway is affected in a substantial
portion of tumors as well. The prevalence of PTEN loss
suggests that mTOR may be a valid target for further
study. 27 The identification of a possible Hh-dependent cancer
stem cell provides an intriguing additional potential
target, and raises the possibility of rational multitarget
combinations. Significant differences between DIPG and
both pediatric and adult HGG confirm that DIPG treatment
cannot simply be based on the biology or treatment of
nonbrainstem HGG. 28 Many important questions remain
unanswered. Ongoing collection and analysis of pretreatment
tumors using advanced molecular techniques such as
next-generation sequence and epigenetic profiling will be
vital. 20
The question may rightly be asked whether identification
of drugable targets will be sufficient to alter outcome of
DIPG. Adult high-grade glioma remains a poor-prognosis
disease despite the abundance of biologic data already
available. Indeed, for most cancers, with some notable exceptions,
the initial use of targeted strategies has not resulted
in the immediate dramatic changes in outcome that
some might have hoped. However, molecular targeting as a
therapeutic strategy is still in its infancy. Identification of
genomic aberrations and overexpressed genes is necessary
but not sufficient; a deeper understanding of tumor biology
is required for truly informed target selection. Other important
problems, such as ensuring adequate drug delivery and
overcoming drug resistance, must be dealt with. Nonetheless,
historic experience in such malignancies as pediatric
acute lymphoblastic leukemia, which over the span of a few
decades was transformed from an incurable to a largely
curable disease, teaches us that innovative approaches and
persistent concerted investigational efforts can ultimately
result in real and lasting change. We are optimistic that new
molecular information in DIPG will prove the crucial first
step toward a better understanding of the biology of this
disease, which, in turn, will be the crucial first step toward
better treatments and a better outcome.
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