Journal of Child Neurology
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2013 28: 768 originally published online 10 April 2013J Child Neurol
Nina F. Schor
Aiming at Neuroblastoma and Hitting Other Worthy Targets
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Aiming at Neuroblastoma and Hitting
Other Worthy Targets
Nina F. Schor, MD, PhD1
Neuroblastoma is, at once, the most common and deadly extracranial solid tumor of childhood. Efforts aimed at targeting the
neural characteristics of these tumors have taught us much about neural crest cell biology, apoptosis induction in the nervous
system, and neurotrophin receptor signaling and intracellular processing. But neuroblastoma remains a formidable enemy to the
oncologist and an enigmatic target to the neuroscientist.
neural crest tumors, neurotrophin receptors, apoptosis
Received December 26, 2012. Received revised February 26, 2013. Accepted for publication February 27, 2013.
Neuroblastoma is a cancer that occurs almost exclusively in
children and that derives from the sympathetic nervous system,
usually in the chest or abdomen. The origin of neuroblastoma
cells is the primitive neural crest and as such, its histological
appearances include cells with neuronlike, Schwann cell–like,
and stem cell characteristics. These cells variably express
neurotransmitters, neurotransmitter receptors and uptake pro-
teins, neurotrophin receptors, and Schwann cell proteins.1
Thus, targeting therapies to neuroblastoma might best involve
targeting these classes of molecules. Not surprisingly, this is
easier said than done. But the paths traversed in the quest for
therapies for neuroblastoma have enriched our understanding
of neurotrophin receptors and glutathione synthetic enzymes,
changed our understanding of anti-apoptotic signaling, and
informed our view of Alzheimer disease as a disorder of late
development and protein processing.2,3
Off-Target Effects? Find a New Drug or a New Target
One of the first approaches we took to neuroblastoma was to
exploit the catecholamine uptake system on the surfaces of
many neuroblastoma cells by administering an oxygen radi-
notion was that neuroblastoma cells would actively concentrate
this drug, which would, in turn, generate toxic reactive oxygen
species in situ and destroy these tumor cells. Others had admi-
nistered 6-hydroxydopamine intrathecally to destroy central
dopaminergic neurons in an early model of Parkinson’s
disease.5Studies that administered 6-hydroxydopamine parent-
erally to mice demonstrated destruction of the sympathetic
nervous system. In fact, destruction of the sympathetic nervous
system by 6-hydroxydopmaine impaired the growth of subse-
quently implanted subcutaneous neuroblastomas.6
Given these prior studies, it was not surprising that our ini-
tial studies of 6-hydroxydopamine alone demonstrated that
doses high enough to ablate neuroblastomas also were prohibi-
tively toxic to the sympathetic nervous system. So we set about
identifying a compound that would selectively protect normal
cells while leaving the neuroblastoma cells susceptible to
oxygen radical attack. We thought it might be possible to find
such a compound because of our experience many years earlier
with a compound that had been developed at the Walter Reed
Army Institute of Research as a radioprotective agent.7We
had piloted its use as a mucolytic agent in patients with cystic
fibrosis.8If ever there was an example of the nonlinear path to
discovery, this was it!
Amifostine (WR2721; ethiofos) is a thiophosphate that is
actively taken up and cleaved to a sulfhydryl by most normal
cells but not by most cancer cells.7The sulfhydryl compound
reduces reactive oxygen species, itself getting oxidized to a
disulfide in the process. We reasoned that adjunctive use of
amifostine with 6-hydroxydopamine might afford protection
to normal cells without compromising toxicity to neuroblas-
toma cells. However, although single-dose studies in mice
1Departments of Pediatrics, Neurology, and Neurobiology & Anatomy,
University of Rochester School of Medicine and Dentistry, Rochester, NY,
Nina F. Schor, MD, PhD, Golisano Children’s Hospital at URMC, 601 Elmwood
Avenue, Box 777, Rochester, NY 14642, USA.
Journal of Child Neurology
ª The Author(s) 2013
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looked promising, repeated doses produced synergistic toxicity
to normal cells.4,9As is illustrated in Figure 1, it turned out that
the disulfide metabolite of amifostine, which was assumed to
freely cross the cell membranes of both normal and cancer
cells, is among the most potent inhibitors of g-glutamylcysteine
synthetase—the rate-limiting enzyme for glutathione synth-
esis—known.10Glutathione, in turn, is the one of the most
important intrinsic antioxidants; inhibiting its synthesis with
a metabolite of a putative extrinsic antioxidant is a curious
irony, indeed! These studies characterized both a novel reagent
for biochemical studies of glutathione synthesis and a potential
mechanism for the cumulative side effects of amifostine.11
Discovery of the unfortunate ‘‘fit’’ and covalent affixing of
the disulfide of amifostine into the active site of g-glutamylcys-
teine synthetase led to structure-activity relationship studies
aimed at identifying a normal-selective protective agent, the
disulfide of which would not interfere with glutathione synth-
esis.12This work provided some of the early stereochemistry
of the active site of this important enzyme and raised the
possibility of dissociating the efficacy from the toxicity of
cell-selective antioxidants, a concept under most intensive
study in the area of neuroprotection, rather than cancer.
‘‘When You Come to a Fork in the Road, Take It.’’—Yogi
A central dogma of biology as it was taught 2 or 3 decades ago
was ‘‘One gene, one polypeptide.’’13The notion that prevailed
at the beginning of the molecular genetic era was that if one
knew the gene sequence, one knew the one and only one pro-
tein that was made off of it. We now know that this is far from
the truth—that many more than one protein can be made off of
a single genetic template, that proteins frequently get made
from noncontiguous genetic sequences, that some of the most
‘‘important’’ genes do not make proteins at all.14–16Similarly,
the dogma with respect to receptor-ligand pairs was that if one
knew the receptor-ligand pair, one could unambiguously
predict the array of signal transduction pathways that would
be activated in a given type of cell.17We now know that the
same receptor-ligand pair in a single cell type can initiate dif-
ferent downstream pathways in different circumstances and
milieu and that proximal signaling pathways can branch further
downstream and result in diametrically opposed outcomes for
the cell depending on the branch that is enacted.18,19
Why is this important for our patients? As an example, con-
sider the role of the TrkA receptor and its ligand, nerve growth
factor (NGF) in a developing sensory or sympathetic neuron.
Mutations in the intracellular tyrosine kinase domain of TrkA
result in the syndrome of congenital insensitivity to pain and
anhydrosis.20A normal intracellular domain of TrkA is there-
fore critical for the normal development and function of
sensory and sympathetic neurons.20On the other hand, con-
sider the role of the TrkA receptor and NGF in a pheochromo-
cytoma cell. The signal transduction pathway triggered by
binding of NGF to TrkA depends on the level of expression
of TrkA. Native-level expression of TrkA leads to MEK1-
ERK1/2-p-CREB-mediated antiapoptotic signaling and cell
survival; overexpression of TrkA in the same cells leads to
MEK3/6-p-P38MAP-mediated proapoptotic signaling and cell
death.21Therefore, under some circumstances and with regard
to some cellular contexts, antagonists of NGF signaling
through TrkA would be therapeutic, and under others, it would
Another example of a branch point distal to a receptor-
ligand pair involves another neurotrophin receptor, p75NTR.
p75NTR was originally thought only to be a coreceptor that
bound to TrkA and, in so doing, enhanced the affinity of TrkA
for NGF. It is now known that, in addition to its coreceptor
function, p75NTR is an independently signaling receptor with
a so-called death domain sequence that led to its identification
as a proapoptotic protein.19However, dependent on cellular
and environmental context, but not obviously related to level
of expression, p75NTR can signal through phosphoinositol-3-
kinase and Akt to be antiapoptotic22or through de novo choles-
terol synthesis to be proapoptotic.23,24Although branch points
from a receptor-ligand pair can complicate using the receptor
or the ligand as a therapeutic target, knowing the alternative
downstream effectors of receptor-ligand signaling identifies
novel targets that can be unique to a particular outcome of
Developing targeted therapies for our patients that truly tar-
get species responsible for either the pathologic outcome or its
desirable counterpart requires an understanding of the branch
points and contingencies inherent in the complex network we
now know signaling to be. Understanding these pathways can
predict otherwise unforeseen therapeutic failures or side effects
and can identify more specific targets for effective, nontoxic
Location, Location, Location
If we were going to solve the problem of chemotherapeutic
resistance of neuroblastoma cells, given the dichotomous
2 R-S- γ-Glutamylcysteine synthetase
Figure 1. Amifostine (R-S-OPO3) is preferentially cleaved to a sulfhy-
dryl (R-SH) in normal cells relative to tumor cells. In these normal
cells, R-SH acts as an antioxidant, reducing reactive oxygen species
and, in turn, becoming oxidized (to R-S-S-R) itself. R-S-S-R reacts with
g-glutamylcysteine synthetase, the rate-limiting enzyme for glutathione
synthesis, and glutathione synthesis ceases.
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behavior of their neurotrophin receptors vis-a `-vis life and death
of the cell, we needed to evolve an algorithm to predict whether
expression of a particular neurotrophin in a particular neuro-
blastoma would be proapoptotic or antiapoptotic. We knew
that translating such an algorithm from the single cell into
the cell-heterogeneous tumor would be an enormous challenge,
but at least understanding the mechanism at the life-or-death
decision point would be a start.26–28The story ends up being
more complex and more interesting than we could ever have
Our initial studies used hydrogen peroxide or 6-hydro-
xydopamine as the in vitro ‘‘chemotherapy’’ and asked by what
mechanism p75NTR was proapoptotic or antiapoptotic in
neural crest tumor cells. In PC12 rat pheochromocytoma cells,
p75NTR was antiapoptotic and functioned as a cytoplasmic
antioxidant, enhancing recycling of glutathione to its reduced
form. The antiapoptotic, antioxidant effects of p75NTR could
be replicated with the intracellular domain of p75NTR alone;
that is, intracellular expression of the intracellular domain of
p75NTR in cells that did not make holo-p75NTR resulted in
protection from hydrogen peroxide-induced glutathione oxida-
tion and apoptosis.26
In SH-EP1 human neuroblastoma cells, p75NTR was proa-
poptotic by itself, but facilitated the antiapoptotic activity of
TrkA when they were engineered to coexpress TrkA and
p75NTR with a p75NTR/TrkA ratio less than 10/1.27Perhaps
knowing the ratio of p75NTR/TrkA in the cell would allow
us to predict whether the preponderant effect of NGF binding
to its receptors would be proapoptotic or antiapoptotic.
But neither hydrogen peroxide nor 6-hydroxydopamine was
used clinically in neuroblastoma. We were anxious to discern
the potential role of p75NTR in chemoresistance of clinical
neuroblastoma. We treated SH-EP1 cells with the chemothera-
peutic agent fenretinide, an agent that is in clinical trials specif-
ically for neuroblastoma.28Fenretinide is hypothesized to have
several chemotherapeutic mechanisms, one of which is the
generation of reactive oxygen species.29We and others29,30
have demonstrated that fenretinide specifically induces accu-
mulation of mitochondrial superoxide.
Expression of p75NTR or just its intracellular domain
enhances induction of apoptosis by fenretinide in SH-EP1 cells.
In fact, it enhances accumulation of mitochondrial superoxide
after fenretinide treatment by a mechanism that can be inhib-
ited by inhibition of mitochondrial complex II or by pretreat-
ment with mitochondria-specific, but not cytoplasm-specific,
antioxidants.30The effectiveness of p75NTR and its intracellu-
lar domain in the mitochondrion led us to examine the mechan-
ism by which p75NTR works.
As an independently signaling receptor,27p75NTR forms an
asymmetric dimer in the cell membrane and binds to NGF or
pro-NGF. This complex recruits one or more interactors that
bind to the intracellular domain.19The intracellular domain is
then cleaved from the holo-receptor by a- and g-secretase and
is thought to be a transcription factor.31,32In addition, there is
recent evidence that the intracellular domain of p75NTR goes
directly to the mitochondria.33This latter finding makes it
tempting to hypothesize that the mitochondrial antioxidant
effect is a direct effect of the intracellular domain of p75NTR.
But given that mitochondrial complex II, inhibition of which
has a mitochondrial antioxidant effect, is composed of 4 subu-
nits all of which are encoded by nuclear genes,34it is possible
that the mitochondrial antioxidant effect of p75NTR intracellu-
lar domain is the result of its effect on transcription of the sub-
unit proteins of complex II. This possibility is currently under
Why are we working so hard to understand the mechanisms
behind the effects of p75NTR on the cell? If expression of
p75NTR by neuroblastoma cells enhances the effectiveness of
fenretinide against them, why does it matter how this occurs?
For one thing, expression of p75NTR by neuroblastoma cells
from cell to cell within a single neuroblastoma. But if we knew
the downstream pathway that resulted in its effects, we could
perhaps mimic this activity with molecules smaller than pro-
teins. For another, understanding the mechanisms of action of
a developmentally- and spatially-regulated receptor in the cen-
tral and peripheral nervous system might lead to unexpected
revelationsabout nervous systemdisorders other thanneuroblas-
toma. An evolving example, depicted in Figure 2, follows.
Aging is Development for Grown-ups
In the embryonic human brain, p75NTR is ubiquitously
expressed. As the brain develops, however, its expression is
increasingly restricted. In the adult brain, p75NTR is most
abundant in the basal forebrain (particularly in the nucleus
basalis of Meynert), the hippocampus, and the cerebellum.35
In the course of our studies of p75NTR, we decided to study
differences in the transcriptome between PC12 cell lines that
either did or did not express p75NTR in their native state. As
it happens, we were guided in performance of these microarray
upregulated mitochondrial complex II
Figure 2. p75NTR is a trans-membrane protein. Cleavage of p75NTR
by a- and g-secretase (labelled ‘‘g’’) liberates its intracellular domain
(p75ICD). p75ICD is thought to translocate to the nucleus and
mitochondria, altering its transcriptome and redox state.
770Journal of Child Neurology 28(6)
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studies and interpretation of their results by a postdoctoral fel-
low in the laboratory next door to ours. She was working on
Alzheimer disease and comparing the whole-brain transcrip-
tomes of mice that expressed wild-type or familial Alzheimer
disease mutant presenilin, respectively.36At the end of the
side-by-side experiments, we (with our difference map of
p75NTR-positive vs p75NTR-negative PC12 cells) and she
(with her difference map of wild-type presenilin vs mutant pre-
senilin brains) sat down to discuss the next step—data mining
and interpretation. To all of our shock, the differences were
almost superimposable! The same set of mRNAs was altered
in the 2 very different scenarios. We came to the conclusion
that p75NTR and presenilin must be part of the same signaling
This should not have been too surprising to us. p75NTR is
activated by cleavage by g-secretase and presenilin is a member
of the g-secretase family of proteins.37Furthermore, the brain
loci most affected in Alzheimer disease are among those in
which expression of p75NTR persists throughout life.24But it
was not until this serendipitous juxtaposition of 2 seemingly
unrelated datasets that we began thinking of Alzheimer disease
as a developmental aberration, the seeds of which could have
been sown or at least prepared at some remote time in the past.38
Perhaps most interesting from a clinical standpoint, in
both cases, expression of the 5 major enzymes involved in
cholesterol biosynthesis is altered. In fact, expression of 7-
dehydrocholesterol reductase, 3-hydroxy-3-methyl-glutaryl–
coenzyme A (HMG-CoA) reductase, diphospho-mevalonate
decarboxylase, geranyl-trans transferase component B, and
farnesyl diphosphate synthase is coregulated with that of
p75NTR.24In addition, treatment of oxidant stress-resistant
p75NTR-positive PC12 cells with mevastatin, an HMG-CoA
reductase inhibitor, converts their sensitivity to oxidant stress
to that of p75NTR-negative cells,23implying that the oxidant
resistance conferred by expression of p75NTR is dependent
on the activity of HMG-CoA reductase.
It is not yet clear what all of this will mean for attempts to
stem the tide of Alzheimer disease using statins or g-secretase
inhibitors, particularly as patients with sporadic Alzheimer dis-
ease do not express mutant presenilin39and as it is not clear
whether p75NTR is a pro-oxidant or antioxidant in neurons
of the basal forebrain, hippocampus, or cerebellum.19
But it is clear that exploiting these findings clinically will
require development of more specific drugs that target specific
g-secretases or that affect specific branch points off of the cho-
lesterol biosynthetic pathway.25
Less Is Sometimes More
The 26-kDa protein Bcl-2 is a mitochondrial protein that pre-
vents apoptosis.40In neural crest cells, including cells of the
neuralcrest tumor,neuroblastoma,overexpressionofBcl-2 fam-
ily members results in enhanced sulfhydryl content of the cell.41
That is, recycling of oxidized (ie, disulfide) cytoplasmic glu-
tathione to its reduced (ie, sulfhydryl) state is more efficient in
cells that overexpress Bcl-2.42This was intriguing to us because,
although Bcl-2 makes cancer cells resistant to conventional che-
motherapeutic agents, it might be expected to enhance the sensi-
tivity of cancer cells to chemotherapeutic prodrugs that are
mitotic, proapoptotic natural product, neocarzinostatin.44
Sulfhydryl activation of neocarzinostatin results in forma-
tion of a DNA-cleaving agent that induces mitotic arrest, differ-
entiation, and subsequent apoptosis in neuroblastoma cells in
culture.44Overexpression of Bcl-2 indeed potentiates this
effect.43We assumed that this was because neocarzinostatin
would be activated to a greater extent in the more reducing
environment of Bcl-2-overexpressing cells than in native cells.
But this mechanism turned out to be unlikely.
Shortly after we published our work on the potentiation of
the activity of neocarzinostatin by Bcl-2, data were published
that made it clear that Bcl-2 exerted its conventional activity
downstream of neocarzinostatin activation.45Even if more
reduced glutathione resulted in more activated neocarzinosta-
tin, Bcl-2 should have prevented that activated neocarzinostatin
from inducing apoptosis. How, then, was Bcl-2 enhancing
apoptosis induction by neocarzinostatin?
One clue came when we asked whether other cancer cell
lines transfected with a Bcl-2 expression construct would exhi-
bit the same potentiation of neocarzinostatin as our neuroblas-
toma cells. One breast cancer cell line, MCF-7, did not
demonstrate this phenomenon. MCF-7 cells differed from the
other cell lines we tested in that they did not express the
enzyme caspase-3.46Caspase-3 cleaves Bcl-2 from a 26-kDa
antiapoptotic protein to a 19-kDa proapoptotic protein.47
Treatment of neuroblastoma cells with neocarzinostatin
resulted in cleavage of Bcl-2 to its 19-kDa fragment.48Pretreat-
this effect. Treatment of neuroblastoma cells with cisplatin and
treatment of MCF-7 cells with neocarzinostatin did not result
in cleavage of Bcl-2. But transfection of MCF-7 cells with a
caspase-3 expression construct followed by treatment with neo-
carzinostatin resulted in cleavage of Bcl-2.46In accordance with
this, transfection of neuroblastoma cells with Bcl-2 resulted in
potentiation of neocarzinostatin-induced apoptosis, whereas
transfection of MCF-7 breast cancer cells with Bcl-2 did not.
However, transfection of caspase-3-transfected MCF-7 cells
with Bcl-2 resulted in potentiation of neocarzinostatin-induced
apoptosis.46Thus, both Bcl-2 and caspase-3 were necessary and
sufficient for potentiation ofneocarzinostatin-inducedapoptosis.
measuring Bcl-2 and caspase-3 content in each case afforded an
algorithm by which one could predict susceptibility of any given
cell to neocarzinostatin-induced apoptosis.49
nogenic in humans, and light- and heat-labile when stored on the
shelf.50It is not the perfect chemotherapeutic agent.
The Value of the Near or Not-So-Near Miss
New techniques that look in an unbiased fashion at all of the
transcription products made in a given cell or tumor are already
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identifying novel targets unique to particular subsets of tumor
cells in the neural crest lineage. For example, Schwannomas
express neither the neural markers doublecortin and Kidins220
nor the cytoskeletal protein strathmin-like 2. Ganglioneuromas
express small amounts of all 3. Ganglioneuroblastomas express
yet higher amounts and neuroblastomas express the highest
amounts of these proteins. Thus, the expression profile of a
given neural crest tumor allows determination of its degree
of differentiation and, conversely, its degree of malignancy.51
Studies of this kind can identify targets for chemotherapy spe-
cific to a particular patient’s tumor. Similarly, studies of the
mitochondrial electron transport chain have recently revealed
that release of reactive oxygen species leading to cell death,
previously ascribed to complexes I and III, can also come from
complex II.52Complex II is therefore a drugable target for
cancer chemotherapy. This appears to be at least one of the
mechanisms of action of fenretinide, a chemotherapeutic agent
in phase II studies for neuroblastoma.28–30
The evolution of these studies from looking for the che-
motherapeutic panacea to looking for the characteristics of the
tumor and host that would predict effectiveness of a particular
chemotherapeutic regimen serves as a prototype for the future
of cancer therapeutics—individualization of therapy based on
the tumor, the host, the environment, and the interaction among
the 3. These studies taught us the importance of understanding
the enemy before designing the magic bullet that takes it down.
Context, it seems, is everything.
The work described in this manuscript was performed at the
University of Pittsburgh School of Medicine (1986-2006) and the
University of Rochester School of Medicine and Dentistry (2006-
present). Portions of this work were presented in preliminary form
at meetings of the Child Neurology Society, the American Neuro-
logical Association, the American Academy of Neurology, the
Society for Neuroscience, and the Pediatric Academic Societies
NFS is the sole author of this manuscript. She and her laboratory
colleagues (many of them her students) performed many of the experi-
ments described herein. In all cases, the references in which this work
was first described and published are cited.
Declaration of Conflicting Interests
The author declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
The author disclosed receipt of the following financial support for the
research, authorship, and/or publication of this article: The studies
described in this review were funded by grants from the National Can-
cer Institute (R01-CA074289), the National Institute of Neurological
Disease and Stroke (R01-NS038569; R01-NS041297), the Wyman-
Potter Foundation, and the William H. Eilinger endowment of the
University of Rochester Medical Center.
All studies described involving the use of animals were approved by
the Institutional Animal Care and Use Committee of the relevant insti-
tution. All studies involving biological materials obtained from human
subjects were judged to be exempt by the Human Rights Committee of
Children’s Hospital of Pittsburgh and the Research Subjects Review
Board of the University of Rochester.
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