Proteomics in Clinical Trials and Practice

Azad, Nilofer S.; Rasool, Nabila; Annunziata, Christina M.; Minasian, Lori M.; Whiteley, Gordon; Kohn, Elise C.

doi:10.1074/mcp.r600008-mcp200

Cited by 75 publications

(42 citation statements)

References 60 publications

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“…Newer semiquantitative and quantitative techniques are being developed to facilitate this important endpoint. 31 The current results indicated that EGFR is present in EOC and is activated in most patients SEM indicates standard error of the mean; EGFR, epidermal growth factor receptor; AKT, protein kinase B; p-ERK, phosphorylated extracellular regulated kinase; GI, gastrointestinal; p-AKT, phosphorylated AKT; pY1148-EGFR, pY1173-EGFR, and pY992-EGFR, phosphorylated forms of epidermal growth factor receptor. * Exact Jonckheere-Terpstra trend test.…”

Section: Discussionmentioning

confidence: 99%

A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer

Posadas

Liel

Kwitkowski

et al. 2007

Cancer

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130

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BACKGROUNDThe primary objective of this study was to evaluate the biochemical effects of gefitinib on its target signal‐transduction pathways in patients with recurrent epithelial ovarian cancer (EOC). The secondary objectives included assessing clinical activity and toxicity and determining the association between biochemical and clinical outcomes.METHODSTwenty‐four heavily pretreated patients with EOC who had good end‐organ function and performance status and who had measurable disease received gefitinib 500 mg daily. Prospectively planned core‐needle tumor biopsies were obtained before treatment and after 4 weeks. Protein expression of total and phosphorylated (p) epidermal growth factor receptor (EGFR), protein kinase B (AKT), and extracellular regulated kinase (ERK) was quantified in microdissected tumor cells using tissue lysate array proteomics.RESULTSAll tumor samples had detectable levels of EGFR and p‐EGFR. A decrease in the quantity of both EGFR and p‐EGFR was observed with gefitinib therapy in >50% of patients. This was not associated with clinical benefit, nor were responses observed. However, trends for increased gastrointestinal and skin toxicity were observed with greater phosphorylation or quantities of EGFR, ERK, and AKT in tumor samples (P ≤ .05). Gefitinib had limited clinical activity as monotherapy despite documented target inhibition.CONCLUSIONSThe results from this study demonstrated that gefitinib inhibited the phosphorylation of EGFR in EOC tumor cells, providing proof of target in a clinical setting. Combinatorial therapy with molecular therapeutics against complementary targets may prove successful. Cancer 2007. Published 2007 by the American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer

Posadas

Liel

Kwitkowski

et al. 2007

Cancer

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130

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“…Accordingly, detection of early stage disease offers an opportunity to reduce mortality. Unfortunately, to date, no screening protocol for ovarian cancer has been shown to achieve this aim, and only 19% of ovarian cancer cases are diagnosed at local stage (9,10) Despite advances in molecular biology, surgery, and chemotherapy, survival rates have changed very little in the last three decades. The glycoprotein CA-125 is the most thoroughly investigated biomarker for ovarian cancer screening and is currently the only marker used in combination with transvaginal ultrasound to detect a significant proportion of ovarian cancer (8,(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Ovarian and Prostate Cancer Peptidome for Candidate Early Detection Markers Using a Novel Nanoparticle Biomarker Capture Technology

Fredolini

Meani

Luchini

et al. 2010

AAPS J

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Abstract. Current efforts to identify protein biomarkers of disease use mainly mass spectrometry (MS) to analyze tissue and blood specimens. The low-molecular-weight "peptidome" is an attractive information archive because of the facile nature by which the low-molecular-weight information freely crosses the endothelial cell barrier of the vasculature, which provides opportunity to measure disease microenvironmentassociated protein analytes secreted or shed into the extracellular interstitium and from there into the circulation. However, identifying useful protein biomarkers (peptidomic or not) which could be useful to detect early detection/monitoring of disease, toxicity, doping, or drug abuse has been severely hampered because even the most sophisticated, high-resolution MS technologies have lower sensitivities than those of the immunoassays technologies now routinely used in clinical practice. Identification of novel low abundance biomarkers that are indicative of early-stage events that likely exist in the sub-nanogram per milliliter concentration range of known markers, such as prostate-specific antigen, cannot be readily detected by current MS technologies. We have developed a new nanoparticle technology that can, in one step, capture, concentrate, and separate the peptidome from high-abundance blood proteins. Herein, we describe an initial pilot study whereby the peptidome content of ovarian and prostate cancer patients is investigated with this method. Differentially abundant candidate peptidome biomarkers that appear to be specific for early-stage ovarian and prostate cancer have been identified and reveal the potential utility for this new methodology

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“…Invariably these RPA studies utilized specific antibodies directed against phosphorylation sites that had been associated with disease before (10). In an RPA format, each position in the array represents a complex protein test sample, such as a serum sample or a tissue lysate, and hundreds of patient samples can be combined on a single array slide.…”

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confidence: 99%

Chemical and Pathway Proteomics

Kruse¹,

Bantscheff²,

Drewes³

et al. 2008

Molecular & Cellular Proteomics

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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...

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Proteomics in Clinical Trials and Practice

Cited by 75 publications

References 60 publications

A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer

A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer

Investigation of the Ovarian and Prostate Cancer Peptidome for Candidate Early Detection Markers Using a Novel Nanoparticle Biomarker Capture Technology

Chemical and Pathway Proteomics

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