The global study of proteins has many unique difficulties that set it apart from comprehensive studies of genes and transcripts. One difficulty is that the behavior of proteins is determined by the tertiary structure of the molecule. Any assay based on protein binding depends on maintaining the native conformation of the protein. This puts constraints on the systems used to capture protein targets in affinity-based assays. Another difficulty is that the detection of low-abundance proteins poses a particular challenge, given that the dynamic ranges of proteins in biological systems can reach parts per million or lower. An amplification system analogous to the PCR has yet to be developed for protein studies. Protein regulation is often based not on synthesis and degradation, but on reversible modifications such as phosphorylation and glycosylation. In addition, RNA splicing can produce splice variants that are highly homologous but differ in function. The proteomics revolution hopefully will advance to overcome many of these hurdles and provide us with information and biomarkers that can aid in intervention and the prevention of cancer.
Now that the draft of the human genome has been completed, the field of proteomics is ramping up to tackle the vast protein networks that both control and are controlled by the information encoded by the genome. The study of proteomics should yield an unparalleled understanding of cancer as well as invaluable new targets for therapeutic intervention and markers for early detection. This rapidly expanding field attempts to track the protein interactions responsible for all cellular processes. Through careful analysis of these systems, a detailed understanding of the molecular causes and consequences of cancer could emerge. Soon, cellular protein networks will be understood at a level that will permit a totally new paradigm of diagnosis and will allow therapy tailored to individual patients and situations.
As new protein biomarkers are discovered through proteomic approaches, the necessity to validate and ultimately use them in a clinical setting increases. This can be done only as a collaborative effort among the research communities. The National Cancer Institute (US) has taken a lead role in this regard by creating the Early Detection Research Network (EDRN). This network brings together national and international experts from academia and industry to promote biomarker discovery and validation and to help translation into clinical practice. The EDRN thus serves as an integrated platform designed to accelerate translation of discovery into tools for early detection and risk assessment. A five-phase criterion for the development and evaluation of biomarkers has been established by the network. The first phase is a preclinical exploratory phase to help identify promising directions. Next is a clinical assay and validation phase necessary to evaluate the ability of the assay to detect established disease. The third is a retrospective/longitudinal phase to determine the putative biomarker's ability to detect preclinical disease and to define a screen positive rule. In the fourth phase, prospective screening is developed to identify the extent and characteristics of disease detected by the test and the false-positive rate. In the last phase, a definitive trial is designed (prospective randomized trial) to determine the impact of screening on reducing the burden of disease in the general population.
Diverse methodologies and approaches are in use by the EDRN investigators in their pursuit of novel biomarkers. Investigations are in progress on the epigenetic mechanisms of hypermethylation, using a panel of genes as a marker for early disease in lung and other cancers. Efforts are also underway to detect membrane and secreted proteins in breast cancer through novel signal sequence trapping approaches. Studies are also underway to determine the utility of mitochondrial DNA mutations as markers of early detection. There is also an effort to build a two-dimensional gel database of lung-specific proteins from human lung samples to help in the detection of lung cancer. EDRN investigators are also involved in the search for prostate-specific markers, through the use of the SELDI platform, to help in the early detection of prostate cancer. Through the use of microarray analysis, investigators within the network have identified osteopontin as a potential diagnostic biomarker for ovarian cancer. Exciting information is expected to emerge from the EDRN's collaborative effort that can ultimately be applied to population screening for risk assessment, early detection, and diagnosis of cancer.
Source: Pother R. Srinivas, Mukesh Verma, Yinming Zhao, Sudhir Srivastava
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