“Application of Proteomic Technology in Drug Development

“Application of Proteomic Technology in Drug Development & Discovery “-aMini
Review
‘Proteomics ‘is the study of the proteome. Proteome, also known as protein
profile is used as the technology to identify the functionality of the proteins expressed
in certain conditions or diseases. The proteomic technology also enables us to
understand the underlying effect of the protein-protein and protein-nucleic acid
interactions as well as the post-translational modifications (Hewick et al., 2003).
Recent proteomic technologies have evolved from avery conventional two
dimensional electrophoresis,found by O'Farrell and Klos ein 1975 ,to computational
methods coupled with other complementary techniques. These recent upgrades of
proteomic technology enables the researchers to identify the potential proteins that is
clinically significant.The recent tool of proteomic technology, Mass spectrometry
techniques such as nanoflow liquid chromatography-tandem mass
spectrometry (nanoLC-MS/MS) and matrix-assisted laser desorption/ionization
time-of-flight mass spectrometry (MALDI-TOF MS) along with other techniques
such as immunocapture platforms have enabled high-throughput analysis of a
proteome or functional subsets of the proteome. Protein array technology are
also used to study the interaction of pr oteins with standardized antibodies
specific for total and activated protein targets allowing for investigation of
pre-selected functional signaling outputs .These tools enables the discovery of
novel biomarkers, identify drug targets, design effective drugs, assess drug efficacy
and patient response to the therapy nshort understanding the underlying activity of
proteins by the means of proteomic permits us to intensify the discovery and
development of drugs (Walgen et al, 2004).
Traditionally, drug discovery and development has been sculptu red based on
“one drug for all “.These method target sthe disease condition rather than individual
patient management. However, the clinical prognosis manifest different profiles for
majority of patients. These opens anew paradigm on target therapy which required
development and discovery of new target therapy drugs.In conclusion, proteome
analysis during preclinical or clinical development may allow the discovery of
candidate markers for the prediction of drugs efficacy (Kelloff et al., 2005). Table 1
shows examples of afew disease related biomarkers.
Disease Clinical Biomarker
Alzheimer's Disease Sulfatide, amyloid precursor, glycerophosphocholine and
Tau proteins in CSF; Cystatin C and peptic fragment of the
neurosecretory protein VGF Protein kinase C in red blood
cells
Multiple Sclerosis CSF cystatin C and matrix metalloproteinases in serum
Breast Cancers HER-2/neu oncoprotein and tumor-specific glycoproteins
Gefitinib Resistance Hypoxia-inducible factor-1 in head and
neck cancer, epithelial membrane protein-1
Traumatic Brain Injury C-tau, hyperphosphorylated axonal neuro-filment protein
and serum S100B
Advanced Breast
Cancer
Cdk6 and serum CA 15-3 for prognosis
Metastasic Breast
Cancer
Protein kinase C
Stroke Lipoprotein associated phospholipase-A2, intracellular
adhesion molecule 1, PARK7 and nucleoside diphosphate
kinase-A
Gliomas Receptor protein tyrosine phosphatase-B

Ischemic Heart
Disease
Troponin, natriuretic peptide, creatine kinase, myoglobin
and fatty acid binding protein
Congestive Heart
Failure
G protein-coupled receptor kinase-2
Table. 1: List of biomarkers identified for diagnosis of several diseases (Chen et
al., 2004; Meuwis et al., 2007; Ornstein et al., 2006; Sinha et al., 2007).
Examples of studies conducted to prove the co-relation of drug development with
biomarkers are well establishedd. Carey et al examined 80 validated proteins from
signaling pathways in advanced-stage ovarian carcinoma cases using the Reverse
Phase Protein Array to identify express ion of proteins associated with response to
primary chemotherapy drug .Normalization of CA125, an established biomarker, by
the 3rd cycle of platinum-based chemotherapy was chosen as the primary outcome
measure of response .The outcome of the study indicates the secretion of cytokine
Tumour Growth Factor -?pathway signaling strongly with chemoresistance .These
indications are crucial for individual patient target and asses better therapeutic
prognosis.
Another example would be HER2 .HER2 is asuccessful target for three
FDA-approved agents, trastuzumab, pertuzumab, and lapatinib. These targets have
been proved to fulfil all 4FDA criteria; identification of target, activation of the target,
alteration of target by intervention and lastly target alteration associated with the
clinical outcome (refer table 2). He nc e, itis proven that when HER2 is amplified in
most cases, italso is activated. The agents inhibit this activation and have been
shown to be clinically valuable. A few trials are being conducted to evaluate selective
targets using proteomic profiling to develop the knowledge required to optimally direct
biomarker and therapeutic development.HER2 is regarded as one of the the most
successful molecular targets .
Table 2: Four criteria and examples for credentialing therapeutic targets.
Criteria Examples
The target was present. Rheumatoid arthritis
TNF ?overexpression was present and was
etiologic in driving local inflammation and tissue
destruction
The target was activated. Crohn ‘sdisease
TNF ?overexpression was adriving event.
The target was altered by the
intervention.
Ovarian cancer
Ras/Raf/ERK pathway was altered by sorafenib, a
c-RAF kinase inhibitor.
The target alteration was
associated with the clinical
outcome.
Breast cancer
HER2 amplification was associated with improved
survival by trastuzumab, an anti-HER2 neutralizing
antibody.