Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

112 Applying Pharmacogenomics in Therapeutics
and Cys19/Arg16/Gln27. In a study by Cagliani et al. (2009), dominant clades
were identified: Gly16/Gln27 Ha, Arg16Gln27 Hb, Arg16Gln27 Hc1, and Gly16/
Glu27 Hc2. Drysdale et al. (2000) described 12 haplotypes and 5 pairs of haplotypes.
These haplotypes have been shown to be responsible for genetic variability in 90%
of the population studied. While any effect was observed for single polymorphisms
in this study, only haplotype analysis brought some conclusion. The ADRB2 gene is
highly polymorphic and the allele prevalence differs among different ethnic groups.
It has been studied in multiple populations and more than 80 polymorphisms have
been identified. Four known SNPs are nonsynonymous polymorphisms: Val34Met,
Arg16Gly, Gln27Glu, and Thr164Ile. Two of these SNPs (Arg16Gly and Gln27Glu)
are common with minor allele frequencies (MAFs) of 40–50%. Thr164Ile occurs
with MAFs of 1–3%. The rarely occurring Val34Met has MAFs of less than 1%. The
genetic analysis also showed that the 3′-UTR of the gene contains a poly-C repeat of
variable length that is interrupted by two polymorphisms. It was suggested that these
polymorphisms could be responsible for the variable response to β-adrenergic therapy.
However, a clinical study concerning therapy with a long-acting beta-agonist
(LABA) plus inhaled corticosteroid did not show any association with this genotype.
PHARMACOGENOMICS OF TARGETED CANCER THERAPIES
In the past decade, advances in cancer biology, genetics, pharmacology, and biotechnology
made novel cancer-targeted therapy possible. Targeted anticancer drugs have
been designed to act on selected molecular targets/pathways to provide stratified
treatment with the benefit of better antitumor efficacy and lower host toxicity based
on a patient’s unique germline (inherited) or cancer (somatic) genomic profile. These
cancer-targeted treatment agents can be antibodies, small chemical molecules, natural
or engineered peptides, proteins, or synthetic nucleic acids such as antisense
oligonucleotides or ribozymes. Pharmacogenomics, particularly genomic-based
diagnostics, plays a critical role in cancer-targeted treatment. Currently, the US FDA
has recommended pharmacogenomic consideration or package-insert labeling for
more than 120 drugs involving more than 50 genes (FDA Biomarker). These drugs
are used for treatments of cancer, cardiovascular diseases, infectious and psychiatric
diseases. In particular, anticancer pharmacogenomics is the most active area with
24 biomarkers available in the drug labels for 30 FDA-approved anticancer agents
(FDA Biomarker). The US FDA defines a genomic biomarker as “a measurable
DNA and/or RNA characteristic that is an indicator of normal biologic processes,
pathogenic processes, and/or response to therapeutic or other interventions” (FDA
Definition). Such genomic biomarkers can be gene variants, copy-number changes,
chromosomal abnormalities, functional deficiencies, expression changes, and more.
Drug labeling for genomic biomarkers can include description of drug exposure and
clinical response variability, risk for adverse events, genotype-specific dosing, mechanisms
of drug action, and polymorphic drug target and disposition genes.
This chapter will use BCR-ABL in CML, HER2 amplification in breast cancer,
EGFR mutation, and ALK rearrangement in lung cancer as examples to discuss
genomic-based diagnostics. For more information regarding biomarkers, refer to
Chapter 4.