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

76 Applying Pharmacogenomics in Therapeutics
INTRODUCTION
Over 90% of the new drug applications (NDAs) fail to receive approval from the US
Food and Drug Administration (FDA) due to lack of efficacy or unacceptable levels
of toxicity. 1–3 This high failure rate is widely believed to be one of the main reasons
why drug development costs are so high and why there has been a steady decline
in the number of NDAs in recent years. 4,5 More importantly, this high failure rate
implies that many clinical trial participants receive treatment that is not of benefit
to them and that may, in fact, cause more harm than standard of care treatment.
This chapter will discuss how pharmacogenomics can be used in drug discovery and
development to maximize the likelihood that a new drug will have high efficacy and
low toxicity in patients, bringing the new drug to market quickly and safely, and also
benefiting all stakeholders.
USE OF PHARMACOGENOMICS TO IDENTIFY DRUG TARGETS
It is well known that some genetic alterations can drive disease initiation and progression
as well as resistance to drug therapies. Targeting these genetic alterations
through the design and usage of drugs that “hit” the genetic alteration (target) can
help slow, halt, or even reverse the disease process as well as minimize the likelihood
of drug-related toxicity. 6 Many new anticancer drugs are targeted therapies.
For example, trastuzumab (Herceptin ® ), a drug used to treat metastatic breast cancer,
negates the effects of genetic alterations (typically gene amplification) that mediate
HER2/Neu receptor overexpression by binding to the HER2/Neu receptor and preventing
activation of downstream pathways that drive cell proliferation. 7 Treatment
regimens that include trastuzumab have been shown to significantly improve overall
survival rates in patients who harbor this genetic alteration. 8 Genomic analyses
can be used to identify genetic alterations that are associated with a particular disease
and thereby serve as a starting point for drug target identification and subsequent
drug development. There are two main genomic-based approaches that can
be used to identify genetic alterations that are associated with a disease: target gene
analysis and genomic profiling. For target gene analysis, potential drug targets are
identified based on our existing understanding of disease pathophysiology. This
approach focuses on identifying genetic alterations that occur in components of
specific molecular pathways known to be responsible for disease initiation and/or
progression. An advantage of this approach is that the number of analyses needed
are limited, thus reducing time and cost. Also because it is based on the existing
understanding of disease process, it is more likely to identify a genetic alteration
that is causative in the disease process. A disadvantage is that the likelihood of
identifying a potential target is largely reduced if the underlying pathophysiology
for a disease is not well understood or if prior studies have failed to identify good
targets based on existing knowledge of the disease process. In contrast, genomic
profiling allows for drug targets to be identified in an unbiased way; the presence
of genetic alterations is assessed in all known genes, not only those that have been
associated with a particular disease and/or molecular pathway. 9 The genomic profiling
approach therefore not only has greater potential to identify drug targets,