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Adhesion Molecules, Stem Cells, and the Microenvironment in Acute
Myeloid Leukemia
In patients with relapsed or refractory
acute myeloid leukemia (AML), blocking
immature leukemia cells from migrating to the bone marrow increased the
cancer-killing effect of chemotherapy
in a recent phase Ib/IIa trial. “Homing
of leukemia cells to the bone marrow
depends on CXCR4, a chemokine receptor, which the drug BL-8040 blocked,”
said Gautam Borthakur, M.D., associate
professor in the department of leukemia
at the University of Texas MD Anderson
Cancer Center in Houston. Blocking
CXCR4, which is involved in cell migration and adhesion, prevented immature
leukemia cells from hiding in the bone
marrow, where they can cause recurrence, said Borthakur, lead researcher of
the study that he presented in Orlando,
Fla.at the 58th annual meeting of the
American Society of Hematology (ASH)
in December 2015 (abstr. 2546; https;/
ash.confex.com/ash/2015/webprogram/
Paper82437.html). The composite complete remission rate in 22 patients was
38% at the three highest doses.
“The idea is that if we can disrupt
cancer cell adhesion to the bone marrow, we can flush out cancer cells hiding there,” Borthakur said. BL-8040 also
increased cancer cell death by mobilizing immature AML cells to move into
peripheral blood, where cytarabine,
given later, killed them. Two days after
taking BL-8040, patients showed a 40.2fold mobilization of immature AML
cells, as well as substantial apoptosis
(programmed cell death) of immature
progenitors remaining in the bone marrow. Granulocytes, a type of white blood
cell, increased 3.1-fold on day 3, and
blood cells began differentiating into
mature cells. A maintenance trial with
BL-8040 and cytarabine is being planned,
Borthakur said.
In AML the bone marrow overproduces immature, dysfunctional blood
cells, or blasts, that do not develop
into normal, functional blood cells.
Chemotherapy kills cancer cells in the
peripheral blood. But chemotherapy
does not kill immature cells sheltered by
the bone marrow and its microenvironment, which is thought to be a reason for
high rates of minimally residual disease
after treatment and eventual disease
recurrence. In recent years researchers
have begun focusing on the bone marrow and the microenvironment, progenitor and stem cells, and adhesion
molecules like CXCR4 to target the disease at its roots. “The microenvironment
has long been considered a target in solid
tumors, but only recently have researchers focused on it for blood cancers,” said
Craig Jordan, Ph.D., Nancy Carroll Allen
Professor and chief of the division of
hematology at the University of Colorado
in Aurora. Researchers debate whether
the immature cells must leave the bone
marrow to be killed or whether cells are
more vulnerable while residing in it,
Borthakur said.
“The idea is that if we
can disrupt cancer cell
adhesion to the bone
marrow, we can flush out
cancer cells hiding there.”
Targeting the microenvironment and
stem cells is somewhat controversial,
since many researchers believe that it is
more effective to target mutations, said
Michael Andreeff, M.D., Ph.D., professor
of medicine in the departments of leukemia and stem cell transplantation at
MDAnderson. “Mutations are necessary
for cancer development and progression,
but they are not sufficient,” he said. “To
target AML in particular, it is necessary
to target the stroma and bone marrow
microenvironment, where blood cells
differentiate,” Andreeff said. If immature
cells can be induced to differentiate, cure
may be possible. “The microenvironment, which has a different set of signaling pathways, can mimic mutations
and must be targeted to prevent relapse,”
Andreeff said.
Another inhibitor of CXCR4 in trials
for AML and other blood cancers is plerixafor. In a phase II trial with 69 patients,
combining plerixafor with the hypomethylating agent decitabine in newly
diagnosed older AML patients resulted in
an overall response rate of 43%. Median
overall survival for responders was
18 months, compared with 5 months
for decitabine alone (ASH 2013abstr.
621;
https://ash.confex.com/ash/2013/
webprogram/Paper62535.html).
Prior
treatment with hypomethylating drugs
was the strongest independent predictor of overall survival: 52% of drug-naïve
patients achieved complete responses,
compared with only 14% of those previously treated with these drugs. Leukemia
stem cells (LSCs) and progenitor cells
were mobilized in a subset of patients as
a result of CXCR4 blockade.
CXCL4 acts through several pathways
to promote leukemia progression and activates the PI3K–Akt and mitogen-activated
protein kinase signaling pathways, which
directs leukemia cell survival and proliferation. Higher
levels of CXCR4
are found in
these AML cells,
and interaction between
CXCR4 and the
microenvironment can occur
in response to
cancer therapies and is
involved in drug
Gautam Borthakur, M.D.
resistance. “The
highest levels of CXCR4 are found in in
FLT3-mutated AML, one of the most difficult types of AML to treat, and a good reason to target CXCR4,” Andreeff said.
Eradicating Stem Cells,
Targeting Stroma, and
Microenvironment
“Treatments that kill bulk disease do not
target leukemic stem cells,” Jordan said.
Using drugs to treat AML and other stem
cell–derived cancers without targeting
stem cells is like mowing a lawn full of
dandelions,” Jordan said. It kills visible
weeds, but without reaching the roots,
it’s only a temporary solution, he said.
Progenitor and LSCs have different properties, such as quiescence, from most
AML cells, which makes them difficult to
eradicate with chemotherapy but easy to
identify and target.
AML was one of the first cancers
in which the existence of cancer stem
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cells was proven, and consequently,
they are among the best-characterized cancer stem cell population, said
Daniel Pollyea, M.D., clinical director of
leukemia services at the University of
Colorado at Aurora. “We know properties in these cells, from lab studies, that
represent a true Achilles’ heel,” Pollyea
said. Although treating chronic myeloid
leukemia without targeting stem cells
is possible because one determinative
mutation is responsible for that cancer,
that is not the case in AML, he said.
Another advantage in targeting LSCs
is that disease regression can occur
even after clonal evolution has happened, Pollyea said. The self-renewing
properties of LSCs depend on activating
signaling pathways, including WNT–βcatenin, NOTCH, and Hedgehog, all of
which are good LSC targets. In addition, therapies that inhibit antigens
more highly expressed on LSCs than on
hematopoietic stem cells, such as CD123
and CD47, and kinases such as c-Kit
and Src kinases are also good strategies
for eradicating cancerous stem cells.
Clinical trials are under way for AML
with all these targets.
A related issue is the bone marrow
microenvironment and stroma’s relationship to LSCs and leukemia cells.
The microenvironment was a prominent topic of discussion among scientists this year at ASH. Scientists from
the German Cancer Research Center in
Munich sought to disrupt the protective interaction of stroma in a line of
AML cells that is particularly resistant to
treatment (abstr. 676; https://ash.confex.
com/ash/2015/webprogram/Paper84991.
html). Combining azacytidine with a
new kinase inhibitor, crenolanib, of the
resistant FLT-3 mutation, interfered with
stromal protection of CD34 leukemiainitiating cells. They hypothesized that
when the cells lost their quiescence disease cells became more susceptible to
therapy with tyrosine kinase inhibitors.
Another strategy for understanding
microenvironment-mediated
signaling is proteomic profiling, said Marina
Konopleva, M.D., Ph.D., associate professor in the department of leukemia of
the division of cancer medicine at MD
Anderson. Konopleva and colleagues
studied stroma-mediated paths of resistance to targeted drugs that come with
relapse in order to identify effective combinations to kill residual disease (abstr.
1398; https://ash.confex.com/ash/2015/
webprogram/Paper85339.html).
They
profiled 53 key molecules in 11 signaling pathways in 20 samples treated with
several drugs. Changes in the stromaregulated network responsible for cell
survival are specific to each AML therapy.
They found, for example, that activation
of the PI3K–AKT–mTOR pathway was a
common survival mechanism mediated
by stroma in response to inhibition of
two cancer-related molecules. By protein
profiling, the team found mechanismbased drug combinations to address drug
resistance in each case.
Focusing on Apoptosis
The Bcl-2 antiapoptosis protein is found
in high levels in AML cells and plays a
large role in disease pathogenesis, stem
and cancer cell survival, and chemotherapy resistance. Having higher levels of
Bcl-2 in CD34+ hematopoietic stem cells
confers a survival advantage to diseased
cells and resistance to chemotherapy
and helps maintain a favorable antiapoptotic microenvironment for the survival
of AML blasts.
An anti-Bcl2 drug discussed extensively at ASH is venetoclax, or ABT-199.
In a phase Ib study of with decitabine
or azacytidine in 22 treatment-naïve
patients aged 65 years or older and ineligible for standard induction therapy, the
overall response rate was 75% (abstr.
327;
https://ash.confex.com/ash/2015/
webprogram/Paper84265.html).
Three
patients who did not experience objective
responses still had beneficial decreases
in bone marrow blast counts. “While
still early, the responses were rapid and
very encouraging, much better than
with hypomethylating agents alone,”
said lead investigator Courtney DiNardo,
M.D., assistant professor in the department of leukemia at MD Anderson. Many
patients had stable disease at 6 months
and were no longer transfusion dependent. A phase II is ongoing in 125 patients.
Resistance to venetoclax is an
important issue. Researchers from the
University of Helsinki in Finland reported
that combining venetoclax with ruxolitinib, a JAK1/2 inhibitor, was synergistic
in combating stromal resistance to venetoclax (abstr. 867; https://ash.confex.
com/ash/2015/webprogram/Paper84426.
html). Stroma-derived cytokines induce
JAK–STAT signaling in AML cells, which
increases Bcl-2 expression and creates
venetoclax resistance. Blocking JAK1/2
with ruxolitinib restored sensitivity of
AML cells to venetoclax.
Additional studies to tackle venetoclax
resistance by using inhibitors of other
signaling pathways were discussed. Lina
Han, Ph.D., a postdoctoral student at MD
Anderson combined it with cobimetinib, a
mitogen-activated protein kinase inhibitor, in mice, and found synergistic activity
in blocking both pathways, which overcame venetoclax resistance (abstr. 2544;
https://ash.confex.com/ash/2015/webprogram/Paper81612.html).
Combining
venetoclax with idasanutlin, which
activates p53 and produced synergistic apoptosis, also overcame venetoclax
resistance (abstr. 673; https://ash.confex.
com/ash/2015/webprogram/Paper85569.
html). The hope is that by targeting AML
at its roots it will be possible to raise what
remains a dismal 5-year survival rate.
© Oxford University Press 2016.
First published online April 2, 2016
DOI:10.1093/jnci/djw113
Unraveling How Obesity Fuels Cancer
By Anna Azvolinsky
“We are getting more and more precise about the different risk factors for
the various subtypes of cancer,” said
Stephen Hursting, Ph.D., M.P.H., professor in the department of nutrition at the
University of North Carolina at Chapel
Hill. One established factor is obesity,
now well linked to at least ten cancers,
including pancreatic, colorectal, endometrial, and hormone receptor–positive,
postmenopausal breast cancer. “The
connections between [cancer and obesity] seem to be getting stronger in part
because the quality and quantity of data
has increased, particularly data from