Page 10 The Skanner October 11, 2017
News
Treatment
cont’d from pg 9
course.
This is called “preci-
sion medicine,” and it has
had some successes in
breast cancer treatment.
Many biomarker-based,
or precision, therapies
are now standard of care.
But this field needs to
be expanded further to
improve overall patient
outcomes.
Not only are tumors
are different from one
another, but there can
even be genetic differ-
ences within a single
tumor. These differenc-
es between tumors and
within them are called
tumor heterogeneity.
Our lab at Michigan
State University, under
the direction of Eran An-
drechek, is studying how
best to define the tumor
heterogeneity and the
effect that these differ-
ences have on a patient’s
Jonathan Rennhack, pictured here, is part of a team of researchers
focusing on identifying biomarkers in breast cancer tumors.
response to therapy. In
particular, we are using
next-generation technol-
ogies to understand tu-
mor heterogeneity and
define better treatment
strategies for patients.
Tumor diversity makes
treatment
complexTo
devise a better treat-
ment strategy we have
to understand how het-
erogeneity within and
between tumors arise in
the first place.
Tumors are a result of
uncontrolled division of
a single cell. However,
a tumor is not the same
throughout. Even though
it starts with a single cell,
the cells that make up the
tumor are not all identi-
cal.
As a tumor cell divides,
each daughter cell has
mutations not present
in the parent cell. This is
called genetic instability.
This multitude of muta-
tions leads to a surviv-
al-of-the-fittest scenario
within the tumor (this
is called selective pres-
sure).
Some of these muta-
tions give cells an edge
over other cells. Selec-
tive pressure means
that cells with certain
characteristics “win” the
survival of fittest battle
within the tumor. The
result is that different
“neighborhoods” of the
tumor will be populated
with clones of the fittest
cells. Perhaps one region
of the tumor is low in
nutrients; it will contain
cells that have picked up
mutations to survive in
a low nutrient environ-
ment. Another region
might be under constant
exposure to the body’s
immune system; it will
contain cells with im-
mune evasion mutations.
This is how differences
within tumors emerge,
and this diversity is also
one reason why each pa-
tient’s tumor is unique,
and subsequently why
their tumor’s vulnera-
bility to therapy is differ-
ent, too.
This genomic instabili-
ty also exists between pa-
tients. A combination of
random chance and dif-
ferences in the genome
lead to unique tumors to
develop in each patient.
Let’s say, for example,
that we are looking at a
group of breast cancer
patients whose tumors
all have the same bio-
marker.
Some patients have a
complete response to a
particular treatment tai-
lored to that biomarker,
meaning that the tumor
shrinks and the patient
is in remission.
“
[Precision
medicine]
needs to
be expand-
ed further
to improve
overall
patient
outcomes.
But one treatment does
not fit all patients with
the same biomarker. For
instance, other patients
with that same biomark-
er may respond to the
same treatment at first,
but then their tumor
grows back because it
has become resistant to
the original therapy. This
is due to what is called in-
tra-tumor heterogeneity,
which refers to genetic
differences within the
tumor, thanks to the ge-
netic instability and sur-
vival of the fittest that we
described earlier. One
region of a tumor may
have one genetic change,
while other regions of
the tumor have a differ-
ent change. This leads to
one region of a tumor re-
sponding to a treatment
while another region of
the tumor will not.
Other patients may
have little or no response
to the treatment that led
to remission in patients
with the same biomarker,
or at least worked initial-
ly in other patients. For
instance, we have found
that the same genes give
the tumor different char-
acteristics in two differ-
ent subtypes of breast
cancer (basal and HER2
positive). The difference
between tumors from
one patient to another,
inter-tumor heterogene-
ity, is a complicating fac-
tor in our current cancer
treatment therapy based
upon biomarkers.
Therefore, the genetic
heterogeneity both be-
tween tumors and within
tumors is a critical factor
to be considered in de-
veloping suitable treat-
ments.
Sequencing tumors to
find better treatmentsIn
the Andrechek lab we
have used whole genome
sequencing and microar-
ray technology chip for
examining gene expres-
sion data, to understand
what the genomic profile
of different regions of
the tumor look like.
We can look at mu-
tations, changes in the
number of copies of
certain genes or trans-
location, which is when
genes aren’t in the place
they should be.
Perhaps more impor-
tantly, we have worked
to understand the impact
of those mutations on all
of the genes produced by
a tumor cell, called the
transcriptome.
This is important be-
cause the transcriptome
contains the majority of
the instructions the tu-
mor needs to grow and
survive.
We noted that disrup-
tion of the expression
of one particular gene
promotes the forma-
tion of tumors as well as
slows the tumor growth
in a model of breast can-
cer. The combination of
genes that a tumor takes
advantage of to grow are
referred to as key onco-
genic pathways.
If we can profile these
pathways and identify
which ones are active in
a tumor, that could let
us design individualized
therapies to target them.
Our results showed that
through the use of target-
ed genomic therapy, we
inhibited tumor growth
in each group. Then we
expanded our study to
analyze more than 1,000
tumors from breast
cancer patients, and
we noticed significant
shrinkage of tumors. In
these trials, we are also
able to understand in-
tra-tumor heterogeneity
through profiling the
genetic changes after
treatments. This showed
the selective pressures a
treatment creates on the
different types of cells in
a tumor.