Biology Reference
In-Depth Information
malignant but also in normal cells, thereby causing
toxicity not only in combination with DNA damaging
therapies but also in mono-therapy. For example, an
unexpected complication of the ERBB2/HER2-directed
monoclonal antibody trastuzumuab was the occurrence
of cardiac failure in a subset of patients treated with
drug in conjunction with anthracycline chemotherapeu-
tics, which are also cardiotoxic.
359
Imatinib, directed
against oncogenic kinases such as BCR/ABL, also
proved to be cardiotoxic,
360
while small molecular inhib-
itors of the EGFR tyrosine kinase can cause severe and
fatal interstitial lung disease in ~1% of lung cancer
patients or augment the pulmonary toxicity of radiation
therapy in individual patients.
361,362
Even PARP inhibi-
tors, which are well tolerated in mono-therapy,
363
have
demonstrated unexpected severe myelosuppression
when combined with temozolomide or DNA damaging
chemotherapeutics.
364
FIGURE 7.9
Illustration of therapeutic ratio when targeting HRR
in cancer. Any tumor effect needs to be carefully balanced against
normal tissue toxicity in order to maximize therapeutic gain.
adverse effects, also known as toxicity, safety, or adverse
event profiles.
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Early side effects are those that are
observed either during or right after a course of cancer
therapy. These side effects are typically expressed in
tissues or organs with a hierarchical proliferative struc-
ture, such as skin, mucosa, or the bone marrow. To this
end, common side effects of radiation therapy include
fatigue, dermatitis, and mucositis leading to sore throat,
difficulty swallowing or diarrhea depending on the
anatomical site being irradiated. Typical side effects of
chemotherapeutics may involve bone marrow suppres-
sion, nausea, diarrhea, hair loss, infertility, as well as
fatigue. Late side effects are a particular concern after
radiation therapy and can manifest themselves months,
years, and even decades after treatment. These include
fibrosis, atrophy, vascular damage, neural damage, and
a range of endocrine and growth-related effects. Radia-
tion-induced second malignancies are also a concern.
Late effects are often persistent or even progressive in
severity and may affect the long-term quality of life of
a cancer survivor or compromise the survival benefit
from therapy.
358
Late side effects after chemotherapeutic
agents have been less well studied, compared to radia-
tion therapy. Generally, chemotherapy causes more
early than late toxicity, although neuropathies, cardiac
injury, and second cancers among other complications
have been documented. Any increase in the efficacy of
radiation or chemotherapy with regard to tumor kill
upon combination with novel anticancer agents has to
be thus carefully evaluated for any worsening of estab-
lished or the occurrence of new normal tissue toxicity.
Over the past several years, a new era of targeted
molecular therapeutics has emerged for treating cancer,
and consequently, the prospects for more effective and
less toxic treatments have greatly improved. However,
molecular targeted agents have the potential to disrupt
signal transduction and DDR pathways not only in
Therapeutic Benefits of Targeting HRR
Thus, the demonstration of increased tumor cell kill
upon targeting of HRR pathways in preclinical
in vitro
and
in vivo
models may not always translate into thera-
peutic gain in patients. Successful clinical translation
may be guided by carefully defining the window of ther-
apeutic gain in preclinical studies. Below we outline the
main theoretical considerations regarding the potential
of therapeutic gain when targeting HRR pathways in
different settings.
1. DISRUPTING PROFICIENT HRR PATHWAYS
THAT HAVE SIMILAR ACTIVITY IN TUMORS
AND NORMAL TISSUES
In this setting, relatively little therapeutic gain can be
expected. While therapy may be toxic to proliferating
tumor cells that rely on HRR to cope with exogenously
induced replication-fork blocking lesions, the same will
apply to proliferating normal tissue and organs such as
the bone marrow, which would lead to early-occurring
toxicity. However, if early effects are manageable, thera-
peutic gain might be realized in combination with radi-
ation. The total radiation dose that can be administered
is typically limited by the development of late occurring
normal tissue complications which are expressed in non-
or slowly proliferating tissues. Thus, in its simplest
conception, targeting HRR could achieve therapeutic
gain by the following mechanism: A novel combination
of IR and a drug that disrupts HRR would preferentially
kill proliferating tumor cells that are in S- or G2-phase
and thus repair DSBs predominantly by HRR. Thera-
peutic gain will result especially in relation to non- or
slowly proliferating normal cells, which are largely in
the G0- or G1-phase and repair DSB mainly via NHEJ.
However, tumor cells that are quiescent and non-
proliferating (such as hypoxic cells) may not be hit.
