ASH News Daily 2012 - Monday, December 10, 2012 - (Page A-4)
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LEUKEMIA
Don’t Forget to Check the ‘Back Doors’ of Cancer Cells
BY MATTHEW HSIEH, MD
or some time now, isolating
the molecular defect in malignant
cells meant not only
understanding the process of cancer
development, but also providing
the molecular target to treat the
disease. Mutations like BCR-ABL in
chronic myeloid leukemia and JAK2
in myeloproliferative disorders are a
couple of excellent examples of this
concept. But for a growing number
of cancers, the identifying molecular
defect, or the “front door” only
explains the phenotype or how the
cancer cells got there in the first
place. Checking the “back doors,”
or studying the alternate pathways
by which cancer cells survive, may
prove to be equivalent targets.
Robert A. Hromas, MD, University
of Florida College of Medicine,
Gainesville, FL, introduced this
Plenary abstract #3 presentation by
discussing the concept of synthetic
lethality. Cancer cells accumulate a
series of genetic mutations that al-
F
APL
«« From Page A-1
that results from induction of both
differentiation and apoptosis. A reluctance
to omit chemotherapy persisted,
however, until pilot studies
of ATRA and arsenic trioxide, completed
a few years ago, suggested
that durable remissions could be
achieved without either anthracyclines
or cytarabine, and without
their attendant toxicities.
Yesterday, another milestone was
reached at the Plenary session with
the report of the results of a European
multi-center trial comparing
standard therapy with idarubicin
plus ATRA to arsenic trioxide (ATO)
plus ATRA in patients with low- or
intermediate-risk APL (abstract
6). Francesco Lo-Coco, MD, of the
University Tor Vergata, Rome, Italy,
presented the results of Intergroup
APL-0406 for a consortium of Italian
and German cooperative groups.
Investigators from more than 60 institutions
accrued 154 evaluable APL
patients over a three-year period. Patients
with WBC greater than 10,000
were excluded. About two-thirds
of patients were intermediate-risk
(platelet counts < 40,000), while the
remainder were low-risk (platelets >
40,000). The study was designed to
demonstrate non-inferiority, by demonstrating
that at least 80 percent patients
in the experimental arm were
alive and event-free at two years of
follow-up, compared with those in
the standard arm.
low them to escape from normal
cell cycle checkpoints. Some of
these mutations, e.g., in BRCA 1 or
2 (whose normal function is DNA
repair), force the cancer cells to rely
on alternate pathway(s) for survival.
In essence, he explains, “Cancer
cells are addicted to the back-up
DNA repair pathway.” Thus, inhibiting
the alternate pathway should
deliver a lethal blow to cancer cells,
but spare normal cells – this is the
central premise of synthetic lethality.
One of these alternate pathways
is PARP, which cancer cells depend
on to repair double-stranded DNA
breaks, and targeting PARP is on
everyone’s radar screen. PARP inhibitors
have been developed by
all the major pharmaceutical companies,
and phase 1 and 2 trials are
currently underway. Other alternate
pathways for DNA repair include
CHK, ATM, RAD51, and RAD52,
and more.
Kimberly Cramer, PhD, Temple
University School of Medicine,
Philadelphia, PA, and her labora-
The non-inferiority goals of the
study were achieved and according
to Dr. Lo-Coco, “The combination
of ATO and ATRA represents a
new standard therapy option for the
first-line treatment of non-high-risk
patients with acute promyelocytic
leukemia.” Given the encouraging
results
in
non-high-risk APL pa-
tients, Dr. Lo-Coco suggested that
the combination of ATO plus ATRA
should be studied in patients with
high-risk disease.
The overwhelming majority of
patients in both arms entered a
complete molecular remission upon
completion of therapy. After a median
follow-up of 34 months, the twoyear
event-free survival was no different.
One death and two relapses
were observed in the ATO arm, compared
with seven deaths and five relapses
in the chemotherapy arm.
Differences were noted with respect
to toxicities. Patients enrolled
on the chemotherapy-containing arm
experienced a significantly higher incidence
of febrile events and severe,
prolonged cytopenias. One of 79 patients
in the ATO arm required cessation
of therapy because of prolongation
of the QTc interval. Elevations of
liver enzymes and development of
hyperleukocytosis during treatment
were more frequent in patients receiving
ATO, although in no instance
did these side effects lead to treatment
withdrawal. Other adverse effects,
including differentiation syndrome,
appeared to be no different
in either arm.
tory focus on RAD51 and RAD52 in
the CML model. While tyrosine kinase
inhibitors can induce molecular
remission, the stem cell clone is
not eliminated, evidenced by the
need to chronically administer these
drugs. She showed that CML stem
and progenitor cells, with BRCA1/
RAD51 defect, have many doublestranded
DNA breaks and rely
heavily on RAD52 to repair. RAD52
is a critical binding domain to single-stranded
DNA before the repair
begins. In a series of proof-of-concept
experiments, RAD52 mutants
(which prevent binding to DNA)
induced apoptosis and reduced the
stem cell clones in a murine CML
model while sparing normal cells.
She next used a specific peptide
aptamer, which blocks the binding
of normal RAD52 to DNA, and obtained
the same inhibitory results
in CML cells. When the peptide aptamer
is given in combination with
imatinib, an enhanced anti-CML
effect was demonstrated, again
sparing normal hematopoiesis and
prompt
Dr. Lo-Coco emphasized that
diagnosis,
appropriate
treatment, and meticulous attention
to supportive care is critical in
APL management. Most deaths in
APL occur before or during induction,
suggesting that early recognition
and proper management of its
many unique complications – including
coagulopathy, differentiation
syndrome, hyperleukocytosis,
intracranial bleeding, and infec-
demonstrating the synthetic lethality
idea. This inhibitory effect, using
the peptide aptamer, was extended
in CML cells in chronic or accelerated
phase, and many others: primary
AML, B-ALL, and solid tumors with
BRCA1/2 defects (breast, ovarian,
and pancreatic cancer cells). Looking
ahead, Dr. Cramer hopes “to
use epigenetic profiling to analyze
the potential responsiveness of patients
to RAD52 inhibition by profiling
genes involved in homologous
recombination.”
In police work (at least from what
I’ve seen on television shows), securing
the front door is important,
but providing coverage for the back
door is equally crucial, as it is a commonly
used escape route. In our understanding
of cancer pathogenesis
and planning of cancer treatment, it
looks like the parallel strategy is being
used – to ultimately capture and
bring cancer cells to their knees.
Dr. Hsieh indicated no relevant conflicts
of interest.
tion – often determine successful
outcomes. He pointed to the work
of the International Consortium on
Acute Promyelocytic Leukemia –
established by ASH in 2004 to optimize
the care of APL patients in
Brazil, Peru, Mexico, Uruguay, and
Chile – as a model of effective intervention.
Dr. Bufill indicated no relevant conflicts
of interest.
ASH NEWS DAILY
Monday, December 10, 2012
Dr. Paula Bockenstedt, left, of Ann Arbor, MI, talks to Dr. Alvin Schmaier, of
Cleveland, OH, during the Hematology Course Directors Workshop on Sunday
morning.
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