Biology Reference
In-Depth Information
As researchers are finding, not all forays into DNA
repair inhibition are equally fruitful
DNA synthesis inhibitors
(DNA polymerase inhibitors; ribonucleotide
reductase inhibitors)
￿
but even apparent
“failures” often yield useful serendipities. Some exam-
ples follow:
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￿
Antimetabolites
(inhibit nucleotide metabolism pathways)
Developing an MGMT inhibitor has not been nearly as
successful as exploiting MGMT defects. For example,
patients with acute myeloid leukemia (AML) and an
MGMT defect respond well to temozolomide,
whereas other AML patients do not. 8
￿
￿
Topoisomerase inhibitors
(prevent DNA from resealing breaks that occur due
to supercoiling or uncoiling of DNA)
Ionizing radiation (IR) and radiomimetic agents (e.g.,
bleomycin)
(cause replication-independent DSBs)
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￿
With few exceptions, concomitant administration of
a DNA repair inhibitor with a chemotherapeutic has
required downward adjustments of chemotherapy
dosing. However, some DNA repair inhibitors work
well as single agents.
Cell-cycle checkpoint inhibitors
(arrest the cell cycle)
￿
Chromatin modification inhibitors
(HDAC inhibitors)
￿
Sometimes a counterintuitive approach to rational
combinations with inhibitors can work. Because
PARP inhibitors influence vasoactivity, the addition
of a PARPi may facilitate more effective drug
delivery. 11
￿
Drugs that covalently bind to DNA directly or after
being metabolized
(e.g., alkylating agents)
￿
Crosslinking agents
(e.g., platinating drugs, mitomycin-C)
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The stage of cancer may influence the optimal choice
of inhibitor. For example, as cancer progresses, it
creates a hypoxic microenvironment. This causes
replicative stress, disrupting DNA synthesis and
downregulating DNA repair, 5 which makes cancer
cells even more prone to DNA mutations. Thus, in
advanced cancers, checkpoint inhibitors may be more
effective than DNA repair inhibitors. Interestingly,
chronic hypoxia often makes tumors more sensitive to
radiotherapy. This may be due to downregulation of
genes in the MMR and HR pathways. 2
￿
DNA repair inhibitors
(e.g., PARP1 inhibitors, APE1 inhibitors,
polymerase inhibitors, etc.) (see also Figure 14.1 )
￿
The concept of using targeted agents, particularly DNA
repair inhibitors, to “treat a weakness” or create
a synthetic lethality, is still in its infancy. 13 While the
development of PARP inhibitors is a highly significant
stride in this arena, it likely represents the tip of the
iceberg. Many more repair defects associated with
cancers are waiting to be discovered. 8 The challenge is
threefold: (1) to find clinically significant proteins with
altered expression that contribute to dysfunctional
DNA repair response only in cancers; (2) to determine
the collective contributions of multiple proteins that
contribute to a mutagenic phenotype; and (3) to deter-
mine the right inhibitor activity that will confer the
greatest therapeutic value while sparing normal tissues
from cytotoxic side effects. Researchers may find that
the elegant lethal combination of PARP inhibition plus
an HR repair deficiency is an exception rather than
a rule.
It is well established that DNA repair deficiency
and its ensuing genome instability is a major contrib-
utor to cancer pathogenesis. But researchers continue
to discover DNA damage response and repair
proteins
In addition to capitalizing on genetic alterations that are
unique to cancers, scientists are starting to investigate
epigenetic mechanisms to modulate expression of
DNA repair proteins. Examples include methylating
the BRCA1 gene promoter to silence DNA repair
and amplifying the EMSY gene to silence BRCA2
transcription. 2
Cancer is an epic tug-of-war: cells fighting for
survival versus anticancer agents inflicting damage to
the cells. Regardless of the target or method, the ultimate
goal of cancer treatment is to halt cellular replication at
all costs, 12 while limiting peripheral effects as much as
possible. That is why most anticancer agents either
damage DNA directly so that replication is obviated
and apoptosis is triggered, or they work to arrest cell
cycle progression so that lethal levels of damage accu-
mulate before mitosis can occur. Such treatments
include the following: 5,7
more than 130 to date and still counting.
Thus, the forward-looking excitement of being able
to assess DNA repair capacity as a predictor of
patient response to cytotoxic agents is tempered
with the difficult task of isolating the most clinically
relevant proteins and developing selective inhibitors
of them. Biomarkers are crucial in this hunt for tar-
geted and personalized DNA repair therapies (see
Chapter 12).
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Growth signal inhibitors
(hormone receptors, monoclonal antibodies, other
signaling inhibitors)
￿
Mitotic spindle inhibitors
(microtubule inhibitors)
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