Molecular Pharmacology,
Год журнала:
2020,
Номер
98(5), С. 559 - 576
Опубликована: Сен. 10, 2020
The
Notch
family
consists
of
four
highly
conserved
transmembrane
receptors.
release
the
active
intracellular
domain
requires
enzymatic
activity
γ-secretase.
is
involved
in
embryonic
development
and
many
physiologic
processes
normal
cells,
which
it
regulates
growth,
apoptosis,
differentiation.
Notch1,
a
member
family,
implicated
types
cancer,
including
breast
cancer
(especially
triple-negative
cancer),
leukemias,
brain
tumors,
others.
Notch1
tightly
connected
to
signaling
pathways
that
are
therapeutically
tumorigenesis.
Together,
they
impact
proliferation,
chemosensitivity,
immune
response,
population
stem
cells.
inhibition
can
be
achieved
through
various
diverse
methods,
most
common
γ-secretase
inhibitors,
produce
pan-Notch
inhibition,
or
use
short
interference
RNA
monoclonal
antibodies,
more
specific
blockade.
Downregulation
used
alone
combination
with
chemotherapy,
achieve
synergistic
effect
decrease
chemoresistance.
Targeting
cancers
harbor
high
expression
levels
offers
an
addition
therapeutic
strategies
recruited
for
managing
cancer.
Considering
available
evidence,
legitimate
target
might
incorporated
future
combating
In
this
review,
possible
clinical
applications
obstacles
hinder
its
application
discussed.
SIGNIFICANCE
STATEMENT:
plays
important
role
different
Numerous
approaches
possess
potential
benefits
management
aspects
modalities
faces
challenges.
Signal Transduction and Targeted Therapy,
Год журнала:
2021,
Номер
6(1)
Опубликована: Апрель 23, 2021
Abstract
The
extracellular
matrix
(ECM)
is
one
of
the
major
components
tumors
that
plays
multiple
crucial
roles,
including
mechanical
support,
modulation
microenvironment,
and
a
source
signaling
molecules.
quantity
cross-linking
status
ECM
are
factors
determining
tissue
stiffness.
During
tumorigenesis,
interplay
between
cancer
cells
tumor
microenvironment
(TME)
often
results
in
stiffness
ECM,
leading
to
aberrant
mechanotransduction
further
malignant
transformation.
Therefore,
comprehensive
understanding
dysregulation
TME
would
contribute
discovery
promising
therapeutic
targets
for
treatment.
Herein,
we
summarized
knowledge
concerning
following:
(1)
constituents
their
functions
both
normal
conditions;
(2)
TME;
(3)
key
receptors
alteration
during
carcinogenesis;
(4)
current
strategies
targeting
Journal of Hematology & Oncology,
Год журнала:
2016,
Номер
9(1)
Опубликована: Окт. 4, 2016
Anlotinib
is
a
novel
multi-target
tyrosine
kinase
inhibitor
that
designed
to
primarily
inhibit
VEGFR2/3,
FGFR1-4,
PDGFR
α/β,
c-Kit,
and
Ret.
We
aimed
evaluate
the
safety,
pharmacokinetics,
antitumor
activity
of
anlotinib
in
patients
with
advanced
refractory
solid
tumors.
(5–16
mg)
was
orally
administered
tumor
once
day
on
two
schedules:
(1)
four
consecutive
weeks
(4/0)
or
(2)
2-week
on/1-week
off
(2/1).
Pharmacokinetic
sampling
performed
all
patients.
Twenty-one
were
further
enrolled
an
expanded
cohort
study
recommended
dose
schedule.
Preliminary
response
also
assessed.
On
4/0
schedule,
dose-limiting
toxicity
(DLT)
grade
3
hypertension
at
10
mg.
2/1
DLT
fatigue
16
assessment
indicated
had
long
elimination
half-lives
significant
accumulation
during
multiple
oral
doses.
The
schedule
selected,
12
mg
daily
as
maximum
tolerated
for
expanding
study.
Twenty
21
(with
colon
adenocarcinoma,
non-small
cell
lung
cancer,
renal
clear
medullary
thyroid
carcinoma,
soft
tissue
sarcoma)
assessable
anlotinib:
partial
response,
14
stable
disease
including
burden
shrinkage,
progression.
main
serious
adverse
effects
hypertension,
triglyceride
elevation,
hand-foot
skin
reaction,
lipase
elevation.
At
displayed
manageable
toxicity,
circulation,
broad-spectrum
potential,
justifying
conduct
studies.
Lung Cancer,
Год журнала:
2018,
Номер
124, С. 53 - 64
Опубликована: Июль 20, 2018
Highlights•In
Western
countries,
the
most
frequent
oncogene
driver
mutation
in
NSCLC
is
KRAS.•The
biological
heterogeneity
of
KRAS-mutant
imposes
many
treatment
challenges.•We
provide
an
update
on
molecularly
driven
therapies
for
this
disease.•Recent
data
suggest
that
immunotherapy
may
be
a
promising
approach.•Treatment
will
need
to
individualised
future.AbstractIn
patients
with
non-small
cell
lung
cancer
(NSCLC),
countries
Kirsten
rat
sarcoma
viral
homolog
(KRAS),
and
associated
smoking.
There
are
various
sources
NSCLC,
including
different
genotypes
specific
clinical
outcomes,
presence
other
co-mutations
exhibit
features
drug
sensitivity
patterns,
mutant
allelic
content.
The
efficacy
chemotherapy
generally
poor
numerous
novel
therapeutic
strategies
have
been
developed.
These
approaches
include
targeting
KRAS
membrane
associations,
downstream
signalling
pathways,
use
synthetic
lethality,
direct
KRAS,
immunotherapy.
Of
these,
one
NSCLC.
Recent
also
potential
distinct
according
co-mutations.
In
view
likely
and,
future,
require
rational
combinations
treatment,
which
currently
under
investigation.
Lung
neoplasms
are
the
leading
cause
of
death
by
cancer
worldwide.
Non-small
cell
lung
(NSCLC)
constitutes
more
than
80%
all
malignancies
and
majority
patients
present
advanced
disease
at
onset.
However,
in
last
decade,
multiple
oncogenic
driver
alterations
have
been
discovered
each
them
represents
a
potential
therapeutic
target.
Although
KRAS
mutations
most
frequently
oncogene
aberrations
adenocarcinoma
patients,
effective
therapies
targeting
yet
to
be
developed.
Moreover,
role
NSCLC
remains
unclear
its
predictive
prognostic
impact
controversial.
The
study
underlying
biology
could
help
determine
candidates
evaluate
novel
targeted
agents
combinations
that
may
allow
tailored
treatment
for
these
patients.
aim
this
review
is
update
current
knowledge
about
KRAS-mutated
adenocarcinoma,
including
historical
overview,
molecular
pathways
involved,
clinical
relevance
as
marker
approaches
personalized
