Biomedical Engineering Reference
In-Depth Information
Moreover, drugs that target the base excision repair (BER)
pathway by inhibitors of poly-ADP ribose polymerase (PARP), an
enzyme critical to BER, have shown promising activity in patients
with
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Both BRCA1 and BRCA2,
which are involved in the process of homologous recombination
(HR) that mediates the repair of double-stranded DNA breaks, are
not the direct targets of PARP inhibitors. The incurred killing by
PARP inhibitors in cells with BRCA dysfunctions is largely ascribed
to a mechanism of synthetic lethality, a type of genetic interaction
that one (or more) mutation or defect is not lethal, but two (or more)
are lethal to a cell.
BRCA
mutations (Chapter 15).
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Anti-tumor activity of PARP inhibitors has been
observed in advanced breast cancer and ovarian cancer patients
with BRCA deficiencies.
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In this scenario, BRCA deficiency is
considered to be a surrogate therapeutic biomarker for anti-PARP
agents. It, however, remains to be determined if pretreatment
levels of poly-ADP ribose (PAR) and expression levels of the PARP
enzymes―direct targets of PARP inhibitors―have significant impacts
on efficacy or treatment outcome.
28
Moreover, PARP inhibitors' anti-
tumor activity has also been observed in BRCA-wild-type tumors.
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The variability in responses suggests that the mechanisms of activity
of PARP inhibitors are not yet fully understood. Further preclinical
and clinical research is needed to elucidate the mechanisms of anti-
tumor activity of PARP inhibitors.
1.4.3.3
Anti-angiogenesis therapy and biomarkers
During the past decade, agents targeting the processes that lead to
new blood vessel formation—angiogenesis, and drugs that disrupt
the existing tumor vasculature have evolved as an effective cancer
treatment when combined with conventional chemotherapy.
Bevacizumab, a humanized antibody to vascular endothelial growth
factor-A (VEGF-A), and other anti-angiogenic agents have been
integrated into standard management of several tumor types over
the past decade. However, a significant number of patients do not
benefit from anti-angiogenesis therapy and/or in combination with
chemotherapy, the search for biomarkers for appropriate selection of
patients has been challenging and is an intense area of translational
and clinical research.
6,73
