Biology Reference
In-Depth Information
need to carefully examine dosing schedules as this can
potentially aid in maintaining tolerability.
Although as described above, both the checkpoint
kinase inhibitors and MK1775 can be given in combina-
tion with DNA damaging agents at doses that are both
efficacious and well tolerated, at least in animal models,
translation of a good therapeutic index to the clinic has
not yet been proven. While emerging data from the early
clinical studies is somewhat encouraging, and seems to
indicate that additional or enhanced toxicities are not
dramatic
,
an acceptable risk/benefit ratio remains
to be demonstrated.
97,116,120,123,126
The long-term risk of
secondary cancer formation also remains, and this will
clearly take longer studies to be understood.
For other therapeutic approaches using Chk and
Wee1 inhibitors, such as the identification of patient
populations that may respond to monotherapy, or
combination strategies other than those with DNA
damaging therapies, there is early promise. On the
basis of this, there will likely be future clinical investi-
gation of these agents to address additional hypotheses.
Assuming this is the case, there will also be an
increased emphasis on the parallel identification and
development of biomarkers (both for patient selection
and as PD markers) will also be necessary, depending
on the precise hypothesis to be tested.
Although only agents currently in clinical trials are
discussed here, there is considerable effort and interest
in bringing additional agents forward. Many groups are
actively seeking alternative inhibitors for these targets
and it is likely that in the near future more compounds
will progress to join those already in clinical trials.
FUTURE DIRECTIONS AND
CHALLENGES
The preclinical and emerging clinical data from
studies of Chk and Wee1 inhibitors both suggest that
their clinical impact in combination with DNA
damaging agents will have clinical utility, and may
enhance the efficacy of many established DNA-
damaging therapies across a wide range of tumor types.
While much more has been learned about the various
Chk inhibitors than Wee1 inhibitors, data so far suggest
that both ways of targeting G2 checkpoint abrogation
may result in an increase in efficacy from DNA-
damaging agents. From emerging clinical data it seems
likely that validation of the potentiation hypothesis
will soon be achieved. Ultimately, this approach could
achieve equal or greater efficacy than is possible today,
and possibly even with a lower dose of chemothera-
peutic agent, thereby greatly improving patient well-
being and providing a significant step forward in
oncology treatment. Deriving maximum patient benefit,
however, will be complex as there are many possible
combination and dose-scheduling strategies and select-
ing optimal regimens will not be straightforward. In
addition, there are remaining questions regarding the
potential for side effects in normal tissues, as well as
the possibility of exaggerated toxicity from the combina-
tion of these agents with existing chemotherapeutics.
In addition, it seems clear that additional therapeutic
strategies are likely to emerge as the biological roles of
Chk1, Chk2, and Wee1 are better understood. There
are already some suggestions that there may be addi-
tional opportunities for Chk1 inhibitors in specific
patient populations, for example, in the case of Chk1-
driven drug resistance, and this notion has some prelim-
inary support in the early clinical data from trials of
SCH-900776 where two partial responses were observed
in patients whose disease had previously progressed
during treatment with gemcitabine alone.
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