Discovery of a functional protein complex of netrin-4, laminin 1 chain, and integrin 6 1 in mouse neural stem cells (original) (raw)
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Vascular ligand-receptor mapping by direct combinatorial selection in cancer patients
Proceedings of the National Academy of Sciences, 2011
Molecules differentially expressed in blood vessels among organs or between damaged and normal tissues, are attractive therapy targets; however, their identification within the human vasculature is challenging. Here we screened a peptide library in cancer patients to uncover ligand-receptors common or specific to certain vascular beds. Surveying ∼2.35 × 10 6 motifs recovered from biopsies yielded a nonrandom distribution, indicating that systemic tissue targeting is feasible. High-throughput analysis by similarity search, protein arrays, and affinity chromatography revealed four native ligand-receptors, three of which were previously unrecognized. Two are shared among multiple tissues (integrin α4/annexin A4 and cathepsin B/apolipoprotein E3) and the other two have a restricted and specific distribution in normal tissue (prohibitin/ annexin A2 in white adipose tissue) or cancer (RAGE/leukocyte proteinase-3 in bone metastases). These findings provide vascular molecular markers for biotechnology and medical applications.
European Journal of Cancer, 2007
Vasculature Viral vectors Targeting therapeutic agents A B S T R A C T The structural and molecular diversity of vascular endothelium may depend on the functional state and tissue localisation of its cells. Tumour vasculature expresses a number of molecular markers that distinguish it from normal vasculature. In cancer, the determinant of specific tumour vasculature heterogeneity is, in part, dictated by dysregulated expression of tumour-derived angiogenic factors. The identification of molecular 'addresses' on the surface of tumour vasculature has significantly contributed to the selection of targets, which have been used for delivering therapeutic and imaging agents in cancer. Cytotoxic drug, pro-apoptotic peptides, protease inhibitors, and gene therapy vectors have been successfully linked to peptides and delivered to tumour sites with an improved experimental therapy. Different diagnostic and therapeutic compounds can be efficiently targeted to specific receptors on vascular endothelial cells; the development of liganddirected vector tools may promote systemic targeted gene delivery.
Combinatorial vascular targeting in translational medicine
PROTEOMICS - Clinical Applications, 2010
In the post-genomic era, the phage display technology surfaces as an alternative approach for large-scale study of tissue-specific protein interactions with direct clinical and therapeutic applications. The unbiased identification of molecular complexes expressed on the surface of cells and blood vessels of organs and tissues may eventually lead to a considerably improved understanding of cellular and vascular proteomics. The ultimate value of this technology consists in the conception of a new ligand-directed pharmacology, with broad implications for both treatment and molecular imaging of cancer patients. In this review, we describe the use and applications of phage display for efficient development of targeted drug discovery and design.
Steps toward mapping the human vasculature by phage display
Nature Medicine, 2002
The molecular diversity of receptors in human blood vessels remains largely unexplored. We developed a selection method in which peptides that home to specific vascular beds are identified after administration of a peptide library. Here we report the first in vivo screening of a peptide library in a patient. We surveyed 47,160 motifs that localized to different organs. This largescale screening indicates that the tissue distribution of circulating peptides is nonrandom. Highthroughput analysis of the motifs revealed similarities to ligands for differentially expressed cell-surface proteins, and a candidate ligand-receptor pair was validated. These data represent a step toward the construction of a molecular map of human vasculature and may have broad implications for the development of targeted therapies.
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2014
The vasculature of each organ expresses distinct molecular signatures critically influenced by the pathological status. The heterogeneous profile of the vascular beds has been successfully unveiled by the in vivo phage display, a high-throughput tool for mapping normal, diseased, and tumor vasculature. Specific challenges of this growing field are targeted therapies against cancer and cardiovascular diseases, as well as novel bioimaging diagnostic tools. Tumor vasculature-homing peptides have been extensively evaluated in several preclinical and clinical studies both as targeted-therapy and diagnosis. To date, results from several Phase I and II trials have been reported and many other trials are currently ongoing or recruiting patients. In this review, advances in the identification of novel peptide ligands and their corresponding receptors on tumor endothelium through the in vivo phage display technology are discussed. Emphasis is given to recent findings in the clinical setting of vascular-homing peptides selected by in vivo phage display for the treatment of advanced malignancies and their altered vascular beds.
From Combinatorial Chemistry to Cancer-Targeting Peptides
Molecular Pharmaceutics, 2007
Several monoclonal antibodies that target cell surface receptors have gained approval by the U.S. Food and Drug Administration and are widely used in the treatment of some cancers. These include but are not limited to the anti-CD20 antibody Rituximab, used in lymphoma treatment, as well as anti-HER-2 antibody for breast cancer therapy. The efficacy of this cancer immunotherapy modality is, however, limited by the large size of the antibody (160 kd) and its relatively nonspecific binding to the reticuloendothelial system. This latter property is particularly problematic if the antibody is used as a vehicle to deliver radionuclides, cytotoxic drugs, or toxins to the tumor site. Peptides, peptidomimetic, or small molecules are thus attractive as alternative cell surface targeting agents for cancer imaging and therapy. Cancer cell surface targeting peptides can be derived from known native peptide hormones such as somatostatin and bombesin, or they can be identified through screening combinatorial peptide libraries against unknown cell surface receptor targets. Phage-display peptide library and one-bead onecompound (OBOC) combinatorial library methods have been successfully used to discover peptides that target cancer cells or tumor blood vessel endothelial cells. The phage-display peptide library method, because of its biological nature, can only display L-amino acid peptides. In contrast, the OBOC combinatorial library method allows for bead-surface display of peptides that contain L-amino acids, D-amino acids, unnatural amino acids, or other organic moieties. We have successfully used the OBOC method to discover and optimize ligands against unique cell surface receptors of prostate cancer, T-and B-cell lymphoma, as well as ovarian and lung cancers, and we have used some of these peptides to image xenografts in nude mice with high specificity. Here, we (i) review the literature on the use of phage-display and OBOC combinatorial library methods to discover cancer and tumor blood vessel targeting ligands, and (ii) report on the use of an ovarian cancer targeting ligand, OA02, as an in vivo PET imaging probe in a xenograft model in nude mice.
Proceedings of the …, 2010
The epidermal growth factor receptor (EGFR), a tyrosine kinase, is central to human tumorigenesis. Typically, three classes of drugs inhibit tyrosine kinase pathways: blocking antibodies, small kinase inhibitors, and soluble ligand receptor traps/decoys. Only the first two types of EGFR-binding inhibitory drugs are clinically available; notably, no EGFR decoy has yet been developed. Here we identify small molecules mimicking EGFR and that functionally behave as soluble decoys for EGF and TGFα, ligands that would otherwise activate downstream signaling. After combinatorial library selection on EGFR ligands, a panel of binding peptides was narrowed by structure-function analysis. The most active motif was CVRAC (EGFR 283-287), which is necessary and sufficient for specific EGFR ligand binding. Finally, a synthetic retro-inverted derivative, D (CARVC), became our preclinical prototype of choice. This study reveals an EGFR-decoy drug candidate with translational potential. peptide | cancer | EGFR | cetuximab | phage display T he epidermal growth factor receptor (EGFR) is a member of the ErbB family of tyrosine kinase receptors (1, 2). Several lines of evidence indicate that the EGFR is abnormally activated in many types of epithelial tumors. The first therapeutic agent targeted to the EGFR is a monoclonal antibody, cetuximab, which blocks ligand binding and thus inhibits tyrosine kinase activity (3). In the past few years, it has become clear that specific somatic EGFR mutations present in non-small-cell lung cancer potentiate responses to certain low molecular weight tyrosine kinase inhibitors and monoclonal antibodies (1, 4-8); mutation of the K-ras gene also has been associated with survival in patients with advanced colon cancer treated with cetuximab (9). These agents, both antibodies and tyrosine kinase inhibitors, prevent ligand-induced receptor activation and downstream signaling and result in cell cycle arrest, promotion of apoptosis, and inhibition of angiogenesis (10, 11).
Towards high-throughput functional target discovery in angiogenesis research
Trends in molecular medicine, 2006
Angiogenesis is a hallmark of malignancies and other proliferative diseases, and inhibition of this process is considered to be a promising treatment strategy. Classical gene-expression analyses performed during the past decade have generated vast lists of genes associated with disease but have so far yielded only limited novel therapeutic targets for clinical applications. Recently, the focus has shifted from target identification, based on gene-expression analysis, to identification of genes, based on the function of the encoded protein. Disease-target genes can now be identified in a high-throughput fashion based on functional properties that are directly related to the disease phenotype. This new approach significantly shortens the time span for the development of therapeutic applications from the laboratory bench to the hospital bedside.