Biology Reference
In-Depth Information
temozolomide was recently reported.
129
INO-101 is an
intravenous PARP inhibitor given 12 hourly via a central
venous catheter. This study established the MTD in
combination with full dose temozolomide (200 mg/m
2
daily times 5q 4 weekly) as 200 mg/m
2
. Dose-limiting
toxicities were myelosuppression and liver enzyme
elevations (transaminitis). No pharmacodynamic data
are reported so it is not clear what degree of PARP inhi-
bition is achieved. A total of 12 patients with metastatic
melanoma were treated across the dose ranges and it is
not possible to comment of any improved efficacy.
Phase I chemotherapy combination studies of a range
of other PARP inhibitors have also been performed
(
www.clinicaltrials.gov
) and some have been reported in
abstract
form. A common theme that is emerging, particu-
larly with the oral PARP inhibitors which are dosed
continuously, is that enhancednormal tissue toxicity, espe-
cially myelosuppression, is a predictable but common
dose-limiting problem. An NCI sponsored combination
study of olaparib (KU59436, AZD2281; KuDos/AstraZe-
neca) with cisplatin and gemcitabine reported dose-
limiting toxicity ofmyelosuppression at the first dose level
explored. The investigators de-escalated to establish an
MTD of a PARP inhibitory does of olaparib with gemcita-
bine 400 mg/m
2
cisplatin 40 mg/m
2
as tolerable in non-
heavily pre-treated patients.
130,131
Likewise ABT-888
(Abbott) in combination with topotecan was also investi-
gated by the NCI, dose limiting myelosuppression was
again observed at the first dose level and the MTD estab-
lished with the PARP inhibitory dose was topotecan
0.6 mg/m
2
days 1
a different mechanism of action from the other PARP
inhibitors and PARP is only one of its targets (as
described above) and this may explain its different spec-
trum of activity and lack of toxicity compared to the
other PARP catalytic inhibitors.
SYNTHETIC LETHALITY IN HR
DEFICIENCY
Cellular DNA is subject to a variety of insults from
endogenous (e.g. oxygen radicals formed as part of
normal metabolism) and exogenous (e.g. UV) sources
on a continuous basis. Therefore, all living organisms
have, of necessity, evolved a variety of unique and over-
lapping or complementary pathways to signal and
repair the damage. Cancer cells are characterized by
genomic instability and one cause of this instability is
an imbalance of DNA damage signalling and repair.
For example, inherited defects in mismatch repair
predispose carriers to hereditary non-polyposis colon
cancer
135
and inherited defects in BRCA1 and BRCA2,
which are important in HR, predispose carriers to
breast and ovarian. Defects in one pathway may be
compensated by upregulation of a complementary
pathway. The upregulated pathways can form a mecha-
nism of resistance to anticancer DNA damaging therapy,
justifying targeting them to selectively sensitize cancer
cells. In addition, if one pathway is lost the cell becomes
totally dependent on the complementary pathway
such that inhibition of the complementary pathway
will have devastating consequences. The term
“synthetic lethality” has been used to describe this
concept, a term borrowed from bacterial genetics where
mutation of two genes together results in cell death but
the mutation of either one alone does not
5.
132
A fascinating contradiction to this trend of enhanced
normal tissue toxicity is the intravenous PARP inhibitor
BSI-201 (BiPar, Sanofi Aventis). Clinical trials with this
agent have explored an intermittent twice-weekly
schedule and no increase in normal tissue toxicity has
been reported.
88,133
What is most interesting is that
evidence of a dramatic improvement in anti-tumor
activity was reported in a randomized phase II study
of a total 120 triple negative breast cancer patients where
treatment with BSI-201 on the biweekly schedule (days
1, 4, 8, 11) combined with carboplatin (AUC2) and gem-
citabine 1000 mg/m
2
days 1 and 8 was compared to
treatment with carboplatin and gemcitabine alone.
This study showed an increased objective response
rate (48 vs. 16%, p
e
impair
viability.
Thomas Helleday's group had demonstrated the
complementarity between DNA SSBR and HR, noting
that cells defective in SSBR components (e.g. PARP
and XRCC1) formed recombinogenic lesions (ref) that
required HR for their repair. This group, in collaboration
with the Newcastle group, determined the synthetic
lethality of the more potent PARPi in cells defective
in HR. These studies showed that AG014361 was
selectively cytotoxic to Chinese hamster cells with
mutant BRCA2 or XRCC3, causing the regression of
BRCA2-mutant tumors, and also to both p53 wild
type and mutant human breast cancer cells in
which BRCA2 was depleted by siRNA.
136
Parallel inde-
pendent studies in the Ashworth lab demonstrated
that another potent PARPi, KU0058948, was selectively
toxic to BRCA1 and 2 defective mouse embryonic
stem (ES) cells and tumors derived from them.
137
The
hypothesis underlying this selective cytotoxicity is that
0.002), median progression free
survival (6.9 vs. 3.3 months, p
¼
0.0001) and overall
<
survival (9.6 vs. 7.5 months, p
0.0005), and a phase III
study in this indication is on-going with results expected
in 2011.
134
It is possible that the intermittent dosing
regimen gives protection from enhanced myelosuppres-
sion and explains the lack of normal tissue toxicity.
However, it is intriguing that this intermittent schedule
provides apparent protection from enhanced normal
tissue toxicity but an increase in efficacy. BSI-201 has
¼
