Biology Reference
In-Depth Information
FIGURE 14.1
Anticancer treatments and their effects. Summary of various anticancer treatments, the types of DNA damage they cause, and
the DNA repair pathways that are activated under normal circumstances to generate repairs.
From Hosoya N, Miyagawa K. Clinical importance of
DNA repair inhibitors in cancer therapy,
Memo Magazine of European Medical Oncology
2009;
(1-2), p10, Figure 1; with permission from Springer
2
Science
Business Media.
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TH
E HUNT FOR BIOMARKE
RS
such an effort is to collect enough data to accurately
represent each population and tumor type. For example,
of all the similar efforts in progress in Japan, Europe, and
the United Kingdom, none of them contains samples
from a substantial number of patients of African-Amer-
ican ethnicity; only Gene-PARE (a joint US/France/
Switzerland/Israel effort) does.
14
In addition to identifying mutations that might
be associated with radiosensitivity, Gene-PARE is
attempting to quantify how a small difference in cellular
survival translates to increased radiosensitivity and
potentially increased severity of radiation response. By
identifying genetic predictors of radiosensitivity and
quantifying these differences, Gene-PARE may help
cancer patients avoid serious complications that can
arise secondary to radiotherapy.
14
Similar large-scale
efforts are needed to determine chemosensitivity.
Just as we have much to learn about DNA repair
pathways and tumor transformation, we have an equal
amount of work to do in understanding the complexities
of replication networks. Cancer cells can overcome gen-
otoxic effects in at least three ways: (1) by reversal of
a genetic or epigenetic defect; (2) through emergence
of a compensatory mechanism; or (3) via development
of a tolerance mechanism. Researchers have already
identified that the PARP1 synthetic lethal interaction
can be overridden by additional mutations,
5
so it
is safe to assume that more scenarios like that may occur.
This underscores the importance of (1) detecting
and treating cancers early before they canaccumulate
such mutations and (2) elucidating how tumor response
to inhibitors can vary in a cell
Finding biomarkers that accurately demonstrate
cancer-specific altered protein function is a critical
element in developing truly personalized cancer medi-
cine. Biomarkers must be (1) reliable, (2) easily detected
by existing laboratory technology, and (3) readily avail-
able (Chapter 12). However, according to that definition,
few “good” biomarkers currently exist.
Several other wrinkles complicate the hunt for clini-
cally significant biomarkers. First, variant alleles may
create different effects for different
tumor types at
different stages of illness
and during different treat-
ment regimens or in different patient populations. All
these influences contribute to a needle-in-a-haystack
hunt for biomarkers. Second, variant alleles from both
germline mutations as well as single-nucleotide poly-
morphisms (SNPs) must be scrutinized. SNPs were
considered functionally and clinically insignificant until
recently; today's research indicates otherwise
14
(Chapter
12). Third, the collective effect of several variant alleles
e
e
not just one
likely causes many DNA repair miscues.
Screening for yet-unidentified variants as well as finding
clinically significant combinations are enormous chal-
lenges. Fourth, altered protein expression may not
always equate to altered functionality that is clinically
significant for tumors.
Thus, large-scale projects such as Gene-PARE
(Genetic Predictors of Adverse Radiotherapy Project)
are needed. Gene-PARE and its global counterparts
collect prospective samples of genomic DNA to help
determine how SNPs of DNA repair may affect clinical
response to radiotherapy. One challenge inherent in
e
type-dependent man-
ner. The latter is particularly true with checkpoint
e
