Biology Reference
In-Depth Information
I. Introduction
A. Targeting Cancer Genes in the Context of DNA
Damage
Genomic instability is a critical component of tumor development and
progression from in situ lesions to invasive cancers. As a consequence, cancer
cells acquire the ability to tolerate an increased amount of DNA damage
compared to noncancer cells. This is often achieved by dampening one or
more DNA damage repair pathways combined with suppression of DNA
damage signaling networks that control cell cycle arrest in the presence of
genotoxic stress.
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These mutated or partially compromised DNA damage
pathways, while directly contributing to cancer development, also furnish an
''Achilles' heel'' for anticancer therapy.
Many cytotoxic chemotherapies as well as ionizing radiation therapy used
in anticancer treatment target rapidly growing cells by introducing lesions into
their chromosomal DNA, or by inhibiting DNA replication. Even though
cancer cells show an enhanced sensitivity to these agents, the targets of these
conventional cancer drugs are present in both normal and cancer cells. It is well
accepted that the off-target effects of DNA damage in nontumor cells (the so-
called bystander effect) is responsible for most dose-limiting toxicities.
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As
therapeutic success in killing cancer cells depends on separating tumor toxicity
from normal tissue toxicity, the use of additional agents that specifically affect
other signaling or repair pathways that may be compromised in tumors can be
exploited to achieve synthetic lethal effects. These synthetic lethal effects can
be due to inherent underlying mutations within the cancer cells, or they can be
induced by specifically targeting pathways which tumor cells have become
dependent on (i.e., poly(ADP-ribose) polymerase (PARP) in BRCA1/2-defective
tumors). Thus, novel targeted anticancer therapies can be developed by focusing
on the oncogenic context of cancer cells, and making use of unique tumor
properties that are not shared by normal tissue.
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Current clinical problems
such as the limited success of specific chemotherapeutic agents in only a small
subset of cancer types and the evolution of drug resistance highlight the need for
treatments with wider therapeutic windows.
During tumor development, cancer cells accumulate a variety of genetic
lesions. As a consequence of these dynamic changes in the genome and the
consequent rewiring of their signaling networks, cancer cells acquire proper-
ties such as unlimited replicative potential, self-sufficiency in growth signals,
insensitivity to antiproliferative and apoptotic signals, and the potential to
sustain angiogenesis as well as to invade tissue and metastasize.
4
These typical
cancer phenotypes are often caused, at least in part, by either the gain of
function of tumor oncogenes or by the loss of tumor suppressor genes.
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