Chemical and Pathway Proteomics

Abstract

In recent years mass spectrometry-based proteomics has moved beyond a mere quantitative description of protein expression levels and their possible correlation with disease or drug action. Impressive progress in LC-MS instrumentation together with the availability of new enabling tools and methods for quantitative proteome analysis and for identification of posttranslational modifications has triggered a surge of chemical and functional proteomics studies dissecting mechanisms of action of cancer drugs and molecular mechanisms that modulate signal transduction pathways. Despite the tremendous progress that has been made in the field, major challenges, relating to sensitivity, dynamic range, and throughput of the described methods, remain. In this review we summarize recent advances in LC-MS-based approaches and their application to cancer drug discovery and to studies of cancer-related pathways in cell culture models with particular emphasis on mechanistic studies of drug action in these systems. Moreover we highlight the emerging utility of pathway and chemical proteomics techniques for translational research in patient tissue. Molecular & Cellular Proteomics 7:1887-1901, 2008. LC-MS-BASED INVESTIGATION OF CANCER PATHWAYS AND ONCOLOGY DRUG ACTIONCancers share a restricted set of capabilities crucial for the development of the tumor phenotype: proliferation in the absence of growth factors, insensitivity to growth-suppressive mechanisms, avoidance of apoptosis, limitless replication, angiogenesis, tissue invasion, and metastasis. These characteristics have been referred to as the hallmarks of cancer (1). They are acquired by cancer cells over time and are caused by the accumulation of mostly somatic gene mutations and by overexpression of key causative "driver" proteins. These pivotal proteins, which are differentially expressed between cancer patients and healthy individuals, are being sought after as possible drug targets or biomarkers for early diagnosis of disease, for clinical trial management, and for personalized health care. Consequently in the classical expression proteomics paradigm these signature proteins are identified by LC-MS profiling methods in increasingly sophisticated ways that have recently been reviewed elsewhere (2).In addition to cellular changes in protein expression, it has been hypothesized that different peptidomes might be present in serum of cancer patients and healthy individuals as a result of cancer-associated changes in proteolytic processing. Based on this assumption proteomic peptide patterns (as opposed to identified peptide sequences), recorded by high resolution mass spectrometers and interpreted by suitable pattern analysis software, could serve as diagnostic tools (3). For example, proteomic MS patterns can distinguish between masked sets of serum samples from (known) ovarian cancer patients and those from healthy controls (4). Since this initial report, proteomics methods for exploiting the information content of the blood peptidome have evolved significantly (5). Recent...

Identification of plasma protein markers common to patients with malignant tumour and Abnormal Savda in Uighur medicine: a prospective clinical study

“…However, because of a lack of scientific interpretations, Uighur medicine has the same shortcomings as other traditional medicines [ 32 ]. The development of proteomics means there is the possibility that serum/plasma can eventually be established as a biomedium for the study of tumour aetiology, drug targets, and personalized cancer care in contemporary medicine [ 33 - 35 ]. In traditional Chinese medicine, many investigators have combined classical concepts with systems biology, in particular applying proteomics to studies of disease aetiology in association with syndromes and multi-target effects of prescriptions [ 32 , 36 - 37 ].…”

Mass Spectrometry-Based Proteomics in Molecular Diagnostics: Discovery of Cancer Biomarkers Using Tissue Culture

“…Therefore, their usage for candidate biomarker discovery is more relevant. Moreover, the field of drug discovery and disease prevention largely depends on the tissue culture-based model system, majorly relying on high-throughput proteomics techniques, because there is no scope for direct human trials of newly developed lead molecules [83, 84]. Recently, there have been a lot of reports where researchers have tried to find out the working mechanism of a drug through proteomic, genomic, and many other techniques [85, 86].…”

Off‐Target Decoding of a Multitarget Kinase Inhibitor by Chemical Proteomics

“…The Kinobeads TM approach is an advanced technology that quantitatively measures the competition of a free compound with an affinity matrix consisting of several immobilized tool compounds selected to capture a large portion of the expressed kinome. [20,29] However, by profiling compounds against a subset of proteins captured by tool compounds, the unbiased character in regard to potential off-targets, which is a particular advantage of chemical proteomics, partly gets lost. In fact, an unbiased off-target characterization during the lead optimization processes is highly desirable for gaining deeper insights into the biological activity and off-target profile of a drug.…”