Nature Medicine,
Journal Year:
2023,
Volume and Issue:
30(1), P. 271 - 278
Published: Dec. 5, 2023
Abstract
KRAS
G12C
mutation
is
prevalent
in
~4%
of
colorectal
cancer
(CRC)
and
associated
with
poor
prognosis.
Divarasib,
a
inhibitor,
has
shown
modest
activity
as
single
agent
KRA
S
-positive
CRC
at
400
mg.
Epidermal
growth
factor
receptor
been
recognized
major
upstream
activator
RAS–MAPK
signaling,
proposed
key
mechanism
resistance
to
inhibition
CRC.
Here,
we
report
on
divarasib
plus
cetuximab
(epidermal
inhibitor)
patients
(
n
=
29)
from
arm
C
an
ongoing
phase
1b
trial.
The
primary
objective
was
evaluate
safety.
Secondary
objectives
included
preliminary
antitumor
activity.
safety
profile
this
combination
consistent
those
single-agent
cetuximab.
Treatment-related
adverse
events
led
dose
reductions
four
(13.8%);
there
were
no
treatment
withdrawals.
response
rate
62.5%
(95%
confidence
interval:
40.6%,
81.2%)
inhibitor-naive
24).
median
duration
6.9
months.
progression-free
survival
8.1
months
5.5,
12.3).
As
exploratory
objective,
observed
decline
variant
allele
frequency
identified
acquired
genomic
alterations
disease
progression
that
may
be
resistance.
manageable
encouraging
support
the
further
investigation
ClinicalTrials.gov
identifier:
NCT04449874
Cancers,
Journal Year:
2022,
Volume and Issue:
14(7), P. 1732 - 1732
Published: March 29, 2022
Colorectal
cancer
(CRC)
is
the
second
most
deadly
cancer.
Global
incidence
and
mortality
are
likely
to
be
increased
in
coming
decades.
Although
deaths
associated
with
CRC
very
high
high-income
countries,
fatalities
related
growing
developing
countries
too.
detected
early
entirely
curable
by
surgery
subsequent
medications.
However,
recurrence
rate
high,
drug
resistance
increases
treatment
failure
rate.
Access
diagnosis
of
for
survival
somewhat
possible
developed
countries.
these
facilities
rarely
available
Highlighting
current
status
CRC,
its
development,
risk
factors,
management
crucial
creating
public
awareness.
Therefore,
this
review,
we
have
comprehensively
discussed
global
epidemiology,
resistance,
challenges,
preventive
strategies
CRC.
Additionally,
there
a
brief
discussion
on
development
pathways
recommendations
preventing
treating
Signal Transduction and Targeted Therapy,
Journal Year:
2020,
Volume and Issue:
5(1)
Published: Oct. 7, 2020
Abstract
Esophageal
cancer
(EC)
is
one
of
the
most
lethal
cancers
in
world,
and
its
morbidity
mortality
rates
rank
among
top
ten
China.
Currently,
surgical
resection,
radiotherapy
chemotherapy
are
primary
clinical
treatments
for
esophageal
cancer.
However,
outcomes
still
unsatisfactory
due
to
limited
efficacy
severe
adverse
effects
conventional
treatments.
As
a
new
type
approach,
targeted
therapies
have
been
confirmed
play
an
important
role
treatment
cancer;
these
include
cetuximab
bevacizumab,
which
target
epidermal
growth
factor
receptor
(EGFR)
vascular
endothelial
(VEGF),
respectively.
In
addition,
other
drugs
targeting
surface
antigens
signaling
pathways
or
acting
on
immune
checkpoints
continuously
developed.
For
example,
trastuzumab,
monoclonal
antibody
human
2
(HER-2),
has
approved
by
Food
Drug
Administration
(FDA)
as
first-line
HER-2-positive
Moreover,
PD-L1
inhibitor
pembrolizumab
highly
efficient
drug
patients
with
PD-L1-positive
advanced
squamous
cell
carcinoma
(ESCC).
These
novel
can
be
used
alone
combination
strategies
further
improve
prognosis
patients.
Nevertheless,
events,
optimal
dosages
effective
combinations
need
investigation.
this
review,
we
expound
outline
latest
advances
mechanisms
relevant
drugs,
discuss
their
safety,
provide
rationale
precision
medicine
Genes & Development,
Journal Year:
2021,
Volume and Issue:
35(11-12), P. 787 - 820
Published: June 1, 2021
Colorectal
cancer
has
served
as
a
genetic
and
biological
paradigm
for
the
evolution
of
solid
tumors,
these
insights
have
illuminated
early
detection,
risk
stratification,
prevention,
treatment
principles.
Employing
hallmarks
framework,
we
provide
conceptual
framework
to
understand
how
alterations
in
colorectal
drive
cell
biology
properties
shape
heterotypic
interactions
across
cells
tumor
microenvironment.
This
review
details
research
advances
pertaining
genetics
cancer,
emerging
concepts
gleaned
from
immune
single-cell
profiling,
critical
remaining
knowledge
gaps
influencing
development
effective
therapies
this
that
remains
major
public
health
burden.
New England Journal of Medicine,
Journal Year:
2022,
Volume and Issue:
388(1), P. 44 - 54
Published: Dec. 21, 2022
Adagrasib,
an
oral
small-molecule
inhibitor
of
mutant
KRAS
G12C
protein,
has
shown
clinical
activity
in
pretreated
patients
with
several
tumor
types,
including
colorectal
cancer.
Preclinical
studies
suggest
that
combining
a
epidermal
growth
factor
receptor
antibody
could
be
effective
strategy.In
this
phase
1-2,
open-label,
nonrandomized
trial,
we
assigned
heavily
metastatic
cancer
to
receive
adagrasib
monotherapy
(600
mg
orally
twice
daily)
or
(at
the
same
dose)
combination
intravenous
cetuximab
once
week
(with
initial
loading
dose
400
per
square
meter
body-surface
area,
followed
by
250
meter)
every
2
weeks
500
meter).
The
primary
end
points
were
objective
response
(complete
partial
response)
and
safety.As
June
16,
2022,
total
44
had
received
adagrasib,
32
therapy
cetuximab,
median
follow-up
20.1
months
17.5
months,
respectively.
In
group
(43
evaluable
patients),
was
reported
19%
(95%
confidence
interval
[CI],
8
33).
duration
4.3
CI,
2.3
8.3),
progression-free
survival
5.6
4.1
8.3).
combination-therapy
(28
46%
28
66).
7.6
5.7
not
estimable),
6.9
5.4
8.1).
percentage
grade
3
4
treatment-related
adverse
events
34%
16%
group.
No
5
observed.Adagrasib
antitumor
G12C,
both
as
cetuximab.
more
than
6
Reversible
common
two
groups.
(Funded
Mirati
Therapeutics;
KRYSTAL-1
ClinicalTrials.gov
number,
NCT03785249.).
International Journal of Molecular Sciences,
Journal Year:
2020,
Volume and Issue:
22(1), P. 130 - 130
Published: Dec. 24, 2020
Colorectal
cancer
(CRC),
the
third
most
common
type
of
cancer,
is
second
leading
cause
cancer-related
mortality
rates
worldwide.
Although
modern
research
was
able
to
shed
light
on
pathogenesis
CRC
and
provide
enhanced
screening
strategies,
prevalence
still
rise.
Studies
showed
several
cellular
signaling
pathways
dysregulated
in
CRC,
onset
malignant
phenotypes.
Therefore,
analyzing
involved
metastasis
necessary
elucidate
underlying
mechanism
progression
pharmacotherapy.
This
review
focused
target
genes
as
well
various
including
Wnt/β-catenin,
p53,
TGF-β/SMAD,
NF-κB,
Notch,
VEGF,
JAKs/STAT3,
which
are
associated
with
metastasis.
Additionally,
alternations
methylation
patterns
relation
regulating
mechanisms
such
cell
cycle,
transcription,
apoptosis,
angiogenesis
invasion
were
also
reviewed.
To
date,
understanding
genomic
epigenomic
instability
has
identified
candidate
biomarkers
that
validated
for
routine
clinical
use
management.
Nevertheless,
better
can
aid
development
early
detection
molecular
markers
risk
stratification
methods
improve
care
patients.
Frontiers in Microbiology,
Journal Year:
2023,
Volume and Issue:
13
Published: Jan. 12, 2023
Gut-microbial
butyrate
is
a
short-chain
fatty
acid
(SCFA)
of
significant
physiological
importance
than
the
other
major
SCFAs
(acetate
and
propionate).
Most
producers
belong
to
Clostridium
cluster
phylum
Firmicutes,
such
as
Faecalibacterium
,
Roseburia
Eubacterium
Anaerostipes
Coprococcus
Subdoligranulum
Anaerobutyricum
.
They
metabolize
carbohydrates
via
butyryl-CoA:
acetate
CoA-transferase
pathway
kinase
terminal
enzymes
produce
most
butyrate.
Although,
in
minor
fractions,
amino
acids
can
also
be
utilized
generate
glutamate
lysine
pathways.
Butyrogenic
microbes
play
vital
role
various
gut-associated
metabolisms.
Butyrate
used
by
colonocytes
energy,
stabilizes
hypoxia-inducible
factor
maintain
anaerobic
environment
gut,
maintains
gut
barrier
integrity
regulating
Claudin-1
synaptopodin
expression,
limits
pro-inflammatory
cytokines
(IL-6,
IL-12),
inhibits
oncogenic
pathways
(Akt/ERK,
Wnt,
TGF-β
signaling).
Colonic
shape
microbial
community
secreting
anti-microbial
substances,
cathelicidins,
reuterin,
β-defensin-1,
homeostasis
releasing
anti-inflammatory
molecules,
IgA,
vitamin
B,
molecules.
Additionally,
producers,
anti-carcinogenic
metabolites,
shikimic
precursor
conjugated
linoleic
acid.
In
this
review,
we
summarized
significance
butyrate,
critically
examined
relevance
contextualized
their
therapeutics.
International Journal of Molecular Sciences,
Journal Year:
2020,
Volume and Issue:
21(15), P. 5311 - 5311
Published: July 27, 2020
Colorectal
cancer
(CRC)
is
a
leading
cause
of
death
worldwide,
despite
progress
made
in
detection
and
management
through
surgery,
chemotherapy,
radiotherapy,
immunotherapy.
Novel
therapeutic
agents
have
improved
survival
both
the
adjuvant
advanced
disease
settings,
albeit
with
an
increased
risk
toxicity
cost.
However,
metastatic
continues
to
poor
long-term
prognosis
significant
challenges
remain
due
late
stage
diagnosis
treatment
failure.
Biomarkers
are
key
tool
early
detection,
prognostication,
survival,
predicting
response.
The
past
three
decades
seen
advances
genomics
molecular
pathology
biomarkers,
allowing
for
greater
individualization
therapy
positive
impact
on
outcomes.
Clinically
useful
predictive
biomarkers
aid
clinical
decision
making,
such
as
presence
KRAS
gene
mutations
benefit
from
epidermal
growth
factor
receptor
(EGFR)
inhibiting
antibodies.
few
been
translated
into
practice
highlighting
need
further
investigation.
We
review
range
protein,
DNA
RNA-based
under
investigation
diagnostic,
predictive,
prognostic
properties
CRC.
In
particular,
long
non-coding
RNAs
(lncRNA),
investigated
cancers
including
colorectal
cancer.
Specifically,
we
evaluate
potential
role
lncRNA
plasmacytoma
variant
translocation
1
(PVT1),
oncogene,
prognostic,
biomarker
Journal of Hematology & Oncology,
Journal Year:
2022,
Volume and Issue:
15(1)
Published: Nov. 1, 2022
Colorectal
cancer
(CRC)
is
the
third
most
common
and
second
leading
cause
of
cancer-related
death
worldwide.
Countless
CRC
patients
undergo
disease
progression.
As
a
hallmark
cancer,
Warburg
effect
promotes
metastasis
remodels
tumor
microenvironment,
including
promoting
angiogenesis,
immune
suppression,
cancer-associated
fibroblasts
formation
drug
resistance.
Targeting
metabolism
would
be
promising
method
for
treatment
CRC.
In
this
review,
we
summarize
information
about
roles
in
microenvironment
to
elucidate
mechanisms
governing
identify
novel
targets
therapy.