Biology Reference
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improving therapy in the fight against cancer.” 12 That
knowledge should help researchers know how to more
effectively “tip the scales” from repair to apoptosis in
developing new anticancer treatments as single agents
or combination therapies. Similarly, aberrant expres-
sions of DNA repair proteins can be exploited to create
more synthetic lethalities.
signaling inhibitors (e.g., Chk1 and Chk2) during
replication. 5
GLOBAL CONCERNS ASSOCIATED
WITH U SE OF DNA REPAIR INHI BITORS
While the field of DNA damage response and repair
inhibition is a burgeoning one, it is not without its
concerns. Chief among these is enhanced cytotoxicity,
particularly in the form of myelosuppression, that
occurs when an inhibitor is given with a DNA-
damaging drug. 15 To minimize this, numerous strategies
are currently being tested: (1) administering the inhib-
itor intermittently during therapy; (2) alternating it
with other therapies; (3) using inhibitors with highly
localized radiotherapy to minimize collateral damage; 7
(4) using inhibitors as single agents; 16 and (5) creating
more effective carriers to ensure targeted, deep-pene-
trating drug delivery. Examples of carriers that show
promise for delivering their payloads deeper into
tumors include nanoparticles,
PREPARING FOR TOMORROW'S
CHALLENGES
Developing DNA repair inhibitors is challenging on
many fronts. As already mentioned, investigators are
still identifying and characterizing DNA lesions
produced during neoplastic transformation and
progression. That information drives the development
of protein inhibitors to exploit for selective therapy. 5
Inhibitors need to disrupt their targeted protein-
protein interactions in a potent, specific, reproducible
manner. 7 Researchers must demonstrate not only that
inhibitors are safe as single agents, but also that they
augment DNA damage when given with chemotherapy
or radiotherapy
liposomes, and folate-
receptor carriers. 12
Another concern related to use of DNA inhibitors
is their potential to predispose patients to secondary
cancers. For example, evidence is emerging that targeting
certain deficiencies of the HR pathway may increase the
likelihood of additional mutations; as already mentioned,
in BRCA-deficient cancers, additional mutations can
restore the open reading frame and thus recoup
BRCA function. 2,15 e 17
Yet another fear relates to targeting one gene. In the
quest to find synthetic lethal combinations, single-
knockout or -knockdown gene therapy may be toxic to
healthy cells. In addition, misgivings exist that the selec-
tivity of such treatment will actually “select out” resis-
tant cell populations.
With the notable exception of how PARP inhibition
affects “BRCAness,” researchers and clinicians still
have considerable work to do in identifying the types
of lesions that occur during tumor transformation, 5
the biomarkers that can predict what treatments will
be most effective against those tumors, 15 and the
best treatment or treatment combinations to exploit
such weaknesses in tumors. Thus, the goal of targeted,
individualized treatment
which underscores the need to fast-
track combination trials. 8
Researchers must prove that development of inhibi-
tors is better, more effective stewardship of R&D
resources and patient expenses. As Aziz noted, “Ineffec-
tive or non-specific treatments consume a large portion
of patient care expenditures. Researchers are starting
to think about the amount of funding being injected
towards drug discovery and that patient treatment
would be utilized more efficiently if their use was tar-
geted according to the particular patient's mutation
profile, after genome sequencing
e
Dissecting these
subsets of cancer cells and tumors according to gene
and pathway defects are therefore important for tar-
geted cancer therapy. Moreover because of age, sex,
diet and organ function differences between patients,
drug metabolism is not uniform. The problem is
increased when there is a mutation in the gene encoding
a drug metabolizing enzyme, transporter, or target
molecule, perhaps a polymorphism. This may affect
their expression, activity or affinity to drugs therefore
influencing
.
the
drug's
pharmacokinetics
and
pharmacodynamics. 12
is still more a goal
than
a reality
butitisanecessity.
The goal of targeting DNA repair pathways with
selective inhibitors is to increase the therapeutic ratio
for cancer treatment while selectively killing cancer
cells. As Aziz et al. have noted, “A thorough under-
standing of DNA repair pathways dysregulated during
carcinogenesis and neoplastic progression, as well as
types of DNA damage induced during cancer develop-
ment, may hold the key to the breakthrough in
e
OTHER PROGRESS TO DATE: DNA
REPAIR AS A PREDICTIVE MEASURE
OF TR EATMENT TYPE AND RES PONSE
Knowledge of repair proteins' overexpression or
underexpression in cancers is helping predict and guide
development of treatments will likely yield the greatest
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