EMBO Molecular Medicine,
Journal Year:
2025,
Volume and Issue:
unknown
Published: April 1, 2025
Abstract
Genomics
has
transformed
the
diagnostic
landscape
of
pediatric
malignancies
by
identifying
and
integrating
actionable
features
that
refine
diagnosis,
classification,
treatment.
Yet,
translating
precision
oncology
data
into
effective
therapies
for
hard-to-cure
childhood,
adolescent,
young
adult
remains
a
significant
challenge.
We
present
case
combining
proteomics
with
patient-derived
xenograft
models
to
identify
personalized
treatment
an
adolescent
primary
metastatic
spindle
epithelial
tumor
thymus-like
elements
(SETTLE).
Within
two
weeks
biopsy,
identified
elevated
SHMT2
as
target
therapy
anti-depressant
sertraline.
Drug
response
was
confirmed
within
months
using
chicken
chorioallantoic
membrane
model
patient’s
SETTLE
tumor.
Following
failure
cytotoxic
chemotherapy
second-line
therapy,
patient
received
sertraline
showed
decreased
growth
rates,
albeit
clinically
progressive
disease.
demonstrate
fast-track
provide
supportive
pre-clinical
in
meaningful
timeframe
impact
clinical
practice.
By
this,
we
show
proteome-guided
functional
are
feasible
valuable
complements
current
genome-driven
practices.
Scientific Reports,
Journal Year:
2025,
Volume and Issue:
15(1)
Published: April 18, 2025
Abstract
The
mitogen-activated
protein
kinase
(MAPK)
pathway
is
one
of
the
most
frequently
altered
pathways
in
pediatric
cancer.
Activating
genomic
MAPK-alterations
and
phosphorylation
MAPK
downstream
target
ERK
(pERK)
were
analyzed
PTT2.0
registry
to
identify
potential
targets
for
MAPK-directed
treatment
relapsed
CNS
tumors,
sarcomas
other
solid
tumors.
present
study
investigates
association
alterations
(mutations,
fusions,
amplifications)
dataset.
cases
with
available
immunohistochemistry
data
(
n
=
235)
included.
Samples
without
detected
activating
compared
regarding
phosphorylation,
quantified
by
H-score.
pERK
intensity
presence
alteration
was
using
a
univariable
binary
logistic
regression
model.The
mean
H-score
significantly
higher
samples
alterations.
positively
correlated
However,
predicted
only
sensitivity
58.3%
specificity
83.8%.
highest
H-scores
observed
low-grade
gliomas,
enriched
alterations,
ependymoma,
where
absent.
Although
there
an
between
level
genetic
predictive
power
low
Tumors/groups
absent
but
high
indicate
dissociation
two
parameters,
as
well
possible
activation
absence
Communications Biology,
Journal Year:
2024,
Volume and Issue:
7(1)
Published: July 30, 2024
Retinoblastoma
are
childhood
eye
tumors
arising
from
retinal
precursor
cells.
Two
distinct
retinoblastoma
subtypes
with
different
clinical
behavior
have
been
described
based
on
gene
expression
and
methylation
profiling.
Using
consensus
clustering
of
DNA
analysis
61
retinoblastomas,
we
identify
a
MYCN-driven
cluster
subtype
2
retinoblastomas
characterized
by
hypomethylation
high
genes
involved
in
protein
synthesis.
Subtype
outside
the
mesodermal
development,
including
NKX2-5.
Knockdown
MYCN
cell
models
causes
growth
arrest
reactivates
1-specific
photoreceptor
signature.
These
molecular
changes
suggest
that
removing
driving
force
oncogenic
activity
rescues
circuitry
1
biology.
The
MYCN-RB
signature
generated
better
identifies
than
amplification
can
cases
may
benefit
MYCN-targeted
therapy.
drives
tumor
progression
molecularly
defined
subgroup,
inhibiting
could
restore
more
differentiated
less
aggressive
Frontiers in Oncology,
Journal Year:
2024,
Volume and Issue:
14
Published: Feb. 19, 2024
Introduction
Advances
in
molecular
diagnostics
led
to
improved
targeted
interventions
the
treatment
of
pediatric
CNS
tumors.
However,
capacity
test
for
these
is
limited
LMICs,
and
thus
their
value
needs
exploration.
Methods
We
reviewed
our
experience
with
NGS
testing
(TruSight
RNA
Pan-Cancer-seq
panel)
tumors
at
KHCC/Jordan
(March/2022–April/2023).
Paraffin
blocks’
scrolls
were
shipped
SickKids
laboratory
based
on
multidisciplinary
clinic
(MDC)
recommendations.
patients’
characteristics,
tumor
types,
results’
impact
treatment.
Results
Of
237
patients
discussed
during
MDC
meetings,
32
(14%)
included.
They
16
boys
girls;
median
age
time
was
9.5
years
(range,
0.9–21.9
years).
There
21
samples
sent
diagnosis
11
upon
progression.
The
main
diagnoses
low-grade-glioma
(15),
high-grade-glioma
(10),
other
histologies
(7).
Reasons
request
included
searching
a
targetable
alteration
(20)
better
characterize
behavior
(12).
turnaround
from
samples’
shipment
receiving
results
23.5
days
15–49
days)
processing
8–39
cost
US$1,000/sample.
19
(59%)
that
had
alterations
(FGFR/MAPK
pathway
inhibitors
(14),
checkpoint
(2),
NTRK
one
PI3K
inhibitor
or
IDH1
inhibitor).
Two
rare
BRAF
mutations
identified
(BRAFp.G469A,
BRAFp.K601E).
One
diagnosed
initially
as
undifferentiated
round
cell
sarcoma
harbored
NAB2::STAT6
fusion
reclassified
an
aggressive
metastatic
solitary
fibrous
tumor.
Another
grade
2
astroblastoma
absence
MN1
alteration.
failed
help
histologically
small
blue
Nine
received
therapy;
dabrafenib/trametinib
(6),
pembrolizumab
entrectinib
(1),
mostly
progression
Conclusion
In
this
highly
selective
cohort,
high
percentage
facilitating
therapies.
Outsourcing
feasible;
however,
criteria
case
selection
are
needed.
addition,
local
capacity-building
conducting
test,
interpretation
results,
access
“new
drugs”
continue
be
challenge
LMICs.
British Journal of Cancer,
Journal Year:
2024,
Volume and Issue:
131(4), P. 763 - 777
Published: June 28, 2024
Abstract
Background
Certain
paediatric
nervous
system
malignancies
have
dismal
prognoses.
Retinoic
acid
(RA)
is
used
in
neuroblastoma
treatment,
and
preclinical
data
indicate
potential
benefit
selected
brain
tumour
entities.
However,
limited
single-agent
efficacy
necessitates
combination
treatment
approaches.
Methods
We
performed
drug
sensitivity
profiling
of
76
clinically
relevant
drugs
with
RA
16
models
(including
patient-derived
tumouroids)
the
most
common
tumours.
Drug
responses
were
assessed
by
viability
assays,
high-content
imaging,
apoptosis
assays
pathways
RNAseq
from
treated
patient
samples
obtained
through
precision
oncology
programme
INFORM
(
n
=
2288).
Immunoprecipitation
detected
BCL-2
family
interactions,
zebrafish
embryo
xenografts
for
vivo
testing.
Results
Group
3
medulloblastoma
(MB
G3
)
highly
sensitive
to
treatment.
induced
differentiation
regulated
apoptotic
genes.
analysis
revealed
high
expression
BCL2L1
MB
BCL2
neuroblastomas.
Co-treatments
BCL-2/X
L
inhibitor
navitoclax
synergistically
decreased
at
achievable
concentrations.
The
disrupted
binding
BIM
BCL-X
neuroblastoma,
inducing
vitro
vivo.
Conclusions
primes
NB
cells
apoptosis,
triggered
cotreatment.
psychopraxis neuropraxis,
Journal Year:
2024,
Volume and Issue:
27(1), P. 43 - 47
Published: Jan. 16, 2024
Zusammenfassung
Biomarkerbasierte
zielgerichtete
Therapien
brachten
für
einige
solide
Tumoren
bahnbrechende
Erfolge.
In
der
Gliomtherapie
beschränkt
sich
Einsatz
dieser
auf
Subgruppen,
insbesondere
wenn
es
bei
fortschreitendem
oder
rezidivierendem
Gliom
keine
etablierten,
evidenzbasierten
Therapieempfehlungen
mehr
gibt.
Eine
Testung
seltenere
molekulare
Alteration
und
die
Diskussion
im
molekularen
Tumorboard
sind
obligat,
aggressive
wie
Glioblastome
sollte
dieses
Vorgehen
bereits
früh
erwogen
werden.
Funktionelle
Präzisionsmedizin
ergänzt
biomarkerbasierten
Therapiekonzepte
durch
Informationen
zur
besten
pharmakologischen
Wirksamkeit
eines
Medikaments,
getestet
an
Tumorzellen
betroffenen
Patient:innen
ex
vivo.
Mit
diesem
Ansatz
können
noch
personalisiertere
mit
umgewidmeten
neuen
Medikamenten
generiert
Die
multizentrische
klinische
Studie
„ATTRACT“
soll
diesen
Glioblastom-Patient:innen
unmethyliertem
MGMT
prüfen.
