Target Discovery and Validation Reviews and Protocols

4 Sioud
A more fruitful approach for discovering drug targets is to analyze pathways
known as genetic networks rather than individual genes. Once a pathway is
identified as being relevant for the disease, it is then possible to assess the individual
signaling proteins of the pathway for their potential druggability (8).
New bioinformatics tools are being developed that will allow the projection of
potential pathway alterations on the basis of the expression data. The analysis
of gene networks after gene disruption or drug treatment should play an important
role in identifying and validating drug target genes. In addition, this
approach allows for the identification of pathways that are directly or indirectly
affected by a drug in a cellular system. Chapter 3, Volume 1, provides an excellent
illustration of gene network analysis in living organisms and describes the
computer tools that can be used to analyze the data. Also, the identification of
families of gene targets that are affected by drug treatment would be of great
scientific interest as well as considerable pharmaceutical importance. When a
signaling protein family already contains known drug targets, algorithms can
define additional druggable family members. The advantage for searching for
sequence similarity would allow the identification of novel drug targets and the
design of selective drugs against only the target under investigation (8). It is
worth nothing that cancer cells do not invent new pathways; they use preexisting
pathways in different ways or they combine components of these pathways
in a new manner. DNA microarray studies should provide insight into the connectivity
of these connections.
Gene profiling and in silico analysis of expression databases to discover new
target genes also are evaluated for the discovery of tumor antigens (6). Ideally,
these new genomics approaches to antigen discovery in cancer should focus on
finding target genes overexpressed in cancer cells with a higher degree of tumor
specificity that are capable of inducing cellular immune responses in the host
immune system. However, for most antigens defined by genomics approach, it is
not yet known whether there is an endogenous immune response in patients. Thus,
any identified gene target requires validation to demonstrate immunogenicity.
The main goal of several studies is to identify variants in genes that might
affect disease outcome, drug response, or both. For example, human leukocyte
antigen (HLA) molecules are characterized by high degree of polymorphism,
and numerous allelic variants of both class I and class II molecules have been
described. Many immune diseases are associated with certain HLA genes (11).
However, the observed associations are far from absolute because some individuals
carrying a given HLA molecule will never develop the associated disease.
Therefore, for human diseases, it is important to understand how
nongenetic factors interact to influence the phenotype. In addition to genetic
changes, a set of human cancers is developed by de novo methylation in genes.
Mainly, tumor suppressor genes where promoter methylation diminishes or