FKBPL and Peptide Derivatives: Novel Biological AgentsThat Inhibit Angiogenesis by a CD44-Dependent Mechanism

A. Valentine, M O'Rourke, A Yakkundi, Jenny Worthington, M Hookham, R Bicknall, HO McCarthy, K McClelland, L McCallum, H Dyer, H McKeen, DJ Waugh, J Roberts, J McGregor, G Cotton, I James, T Harrison, DG Hirst, T Robson

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    Abstract

    Purpose: Antiangiogenic therapies can be an important adjunct to the management of many malignancies. Here we investigated a novel protein, FKBPL, and peptide derivative for their antiangiogenic activity and mechanism of action.Experimental Design: Recombinant FKBPL (rFKBPL) and its peptide derivative were assessed in a range of human microvascular endothelial cell (HMEC-1) assays in vitro. Their ability to inhibit proliferation, migration, and Matrigel-dependent tubule formation was determined. They were further evaluated in an ex vivo rat model of neovascularization and in two in vivo mouse models of angiogenesis, that is, the sponge implantation and the intravital microscopy models. Antitumor efficacy was determined in two human tumor xenograft models grown in severe compromised immunodeficient (SCID) mice. Finally, the dependence of peptide on CD44 was determined using a CD44-targeted siRNA approach or in cell lines of differing CD44 status.Results: rFKBPL inhibited endothelial cell migration, tubule formation, and microvessel formation in vitro and in vivo. The region responsible for FKBPL’s antiangiogenic activity was identified, and a 24-amino acid peptide (AD-01) spanning this sequence was synthesized. It was potently antiangiogenic and inhibited growth in two human tumor xenograft models (DU145 and MDA-231) when administered systemically, either on its own or in combination with docetaxel. The antiangiogenic activity of FKBPL and AD-01 was dependent on the cell-surface receptor CD44, and signaling downstream of this receptor promoted an antimigratory phenotype.Conclusion: FKBPL and its peptide derivative AD-01 have potent antiangiogenic activity. Thus, these agents offer the potential of an attractive new approach to antiangiogenic therapy.
    LanguageEnglish
    Pages1044-1056
    JournalClinical Cancer Research
    Volume17
    Issue number5
    Publication statusPublished - 1 Mar 2011

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    docetaxel
    Heterografts
    Peptides
    Endothelial Cells
    Neoplasms
    Cell Surface Receptors
    Porifera
    Microvessels
    Small Interfering RNA
    Cell Movement
    Research Design
    Phenotype
    Amino Acids
    Cell Line
    Therapeutics
    Growth
    Proteins
    In Vitro Techniques
    AD-01 peptide
    matrigel

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    Valentine, A., O'Rourke, M., Yakkundi, A., Worthington, J., Hookham, M., Bicknall, R., ... Robson, T. (2011). FKBPL and Peptide Derivatives: Novel Biological AgentsThat Inhibit Angiogenesis by a CD44-Dependent Mechanism. Clinical Cancer Research, 17(5), 1044-1056.
    Valentine, A. ; O'Rourke, M ; Yakkundi, A ; Worthington, Jenny ; Hookham, M ; Bicknall, R ; McCarthy, HO ; McClelland, K ; McCallum, L ; Dyer, H ; McKeen, H ; Waugh, DJ ; Roberts, J ; McGregor, J ; Cotton, G ; James, I ; Harrison, T ; Hirst, DG ; Robson, T. / FKBPL and Peptide Derivatives: Novel Biological AgentsThat Inhibit Angiogenesis by a CD44-Dependent Mechanism. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 5. pp. 1044-1056.
    @article{810dbe69d05a4b9291957a4811bc851f,
    title = "FKBPL and Peptide Derivatives: Novel Biological AgentsThat Inhibit Angiogenesis by a CD44-Dependent Mechanism",
    abstract = "Purpose: Antiangiogenic therapies can be an important adjunct to the management of many malignancies. Here we investigated a novel protein, FKBPL, and peptide derivative for their antiangiogenic activity and mechanism of action.Experimental Design: Recombinant FKBPL (rFKBPL) and its peptide derivative were assessed in a range of human microvascular endothelial cell (HMEC-1) assays in vitro. Their ability to inhibit proliferation, migration, and Matrigel-dependent tubule formation was determined. They were further evaluated in an ex vivo rat model of neovascularization and in two in vivo mouse models of angiogenesis, that is, the sponge implantation and the intravital microscopy models. Antitumor efficacy was determined in two human tumor xenograft models grown in severe compromised immunodeficient (SCID) mice. Finally, the dependence of peptide on CD44 was determined using a CD44-targeted siRNA approach or in cell lines of differing CD44 status.Results: rFKBPL inhibited endothelial cell migration, tubule formation, and microvessel formation in vitro and in vivo. The region responsible for FKBPL’s antiangiogenic activity was identified, and a 24-amino acid peptide (AD-01) spanning this sequence was synthesized. It was potently antiangiogenic and inhibited growth in two human tumor xenograft models (DU145 and MDA-231) when administered systemically, either on its own or in combination with docetaxel. The antiangiogenic activity of FKBPL and AD-01 was dependent on the cell-surface receptor CD44, and signaling downstream of this receptor promoted an antimigratory phenotype.Conclusion: FKBPL and its peptide derivative AD-01 have potent antiangiogenic activity. Thus, these agents offer the potential of an attractive new approach to antiangiogenic therapy.",
    author = "A. Valentine and M O'Rourke and A Yakkundi and Jenny Worthington and M Hookham and R Bicknall and HO McCarthy and K McClelland and L McCallum and H Dyer and H McKeen and DJ Waugh and J Roberts and J McGregor and G Cotton and I James and T Harrison and DG Hirst and T Robson",
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    Valentine, A, O'Rourke, M, Yakkundi, A, Worthington, J, Hookham, M, Bicknall, R, McCarthy, HO, McClelland, K, McCallum, L, Dyer, H, McKeen, H, Waugh, DJ, Roberts, J, McGregor, J, Cotton, G, James, I, Harrison, T, Hirst, DG & Robson, T 2011, 'FKBPL and Peptide Derivatives: Novel Biological AgentsThat Inhibit Angiogenesis by a CD44-Dependent Mechanism', Clinical Cancer Research, vol. 17, no. 5, pp. 1044-1056.

    FKBPL and Peptide Derivatives: Novel Biological AgentsThat Inhibit Angiogenesis by a CD44-Dependent Mechanism. / Valentine, A.; O'Rourke, M; Yakkundi, A; Worthington, Jenny; Hookham, M; Bicknall, R; McCarthy, HO; McClelland, K; McCallum, L; Dyer, H; McKeen, H; Waugh, DJ; Roberts, J; McGregor, J; Cotton, G; James, I; Harrison, T; Hirst, DG; Robson, T.

    In: Clinical Cancer Research, Vol. 17, No. 5, 01.03.2011, p. 1044-1056.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - FKBPL and Peptide Derivatives: Novel Biological AgentsThat Inhibit Angiogenesis by a CD44-Dependent Mechanism

    AU - Valentine, A.

    AU - O'Rourke, M

    AU - Yakkundi, A

    AU - Worthington, Jenny

    AU - Hookham, M

    AU - Bicknall, R

    AU - McCarthy, HO

    AU - McClelland, K

    AU - McCallum, L

    AU - Dyer, H

    AU - McKeen, H

    AU - Waugh, DJ

    AU - Roberts, J

    AU - McGregor, J

    AU - Cotton, G

    AU - James, I

    AU - Harrison, T

    AU - Hirst, DG

    AU - Robson, T

    PY - 2011/3/1

    Y1 - 2011/3/1

    N2 - Purpose: Antiangiogenic therapies can be an important adjunct to the management of many malignancies. Here we investigated a novel protein, FKBPL, and peptide derivative for their antiangiogenic activity and mechanism of action.Experimental Design: Recombinant FKBPL (rFKBPL) and its peptide derivative were assessed in a range of human microvascular endothelial cell (HMEC-1) assays in vitro. Their ability to inhibit proliferation, migration, and Matrigel-dependent tubule formation was determined. They were further evaluated in an ex vivo rat model of neovascularization and in two in vivo mouse models of angiogenesis, that is, the sponge implantation and the intravital microscopy models. Antitumor efficacy was determined in two human tumor xenograft models grown in severe compromised immunodeficient (SCID) mice. Finally, the dependence of peptide on CD44 was determined using a CD44-targeted siRNA approach or in cell lines of differing CD44 status.Results: rFKBPL inhibited endothelial cell migration, tubule formation, and microvessel formation in vitro and in vivo. The region responsible for FKBPL’s antiangiogenic activity was identified, and a 24-amino acid peptide (AD-01) spanning this sequence was synthesized. It was potently antiangiogenic and inhibited growth in two human tumor xenograft models (DU145 and MDA-231) when administered systemically, either on its own or in combination with docetaxel. The antiangiogenic activity of FKBPL and AD-01 was dependent on the cell-surface receptor CD44, and signaling downstream of this receptor promoted an antimigratory phenotype.Conclusion: FKBPL and its peptide derivative AD-01 have potent antiangiogenic activity. Thus, these agents offer the potential of an attractive new approach to antiangiogenic therapy.

    AB - Purpose: Antiangiogenic therapies can be an important adjunct to the management of many malignancies. Here we investigated a novel protein, FKBPL, and peptide derivative for their antiangiogenic activity and mechanism of action.Experimental Design: Recombinant FKBPL (rFKBPL) and its peptide derivative were assessed in a range of human microvascular endothelial cell (HMEC-1) assays in vitro. Their ability to inhibit proliferation, migration, and Matrigel-dependent tubule formation was determined. They were further evaluated in an ex vivo rat model of neovascularization and in two in vivo mouse models of angiogenesis, that is, the sponge implantation and the intravital microscopy models. Antitumor efficacy was determined in two human tumor xenograft models grown in severe compromised immunodeficient (SCID) mice. Finally, the dependence of peptide on CD44 was determined using a CD44-targeted siRNA approach or in cell lines of differing CD44 status.Results: rFKBPL inhibited endothelial cell migration, tubule formation, and microvessel formation in vitro and in vivo. The region responsible for FKBPL’s antiangiogenic activity was identified, and a 24-amino acid peptide (AD-01) spanning this sequence was synthesized. It was potently antiangiogenic and inhibited growth in two human tumor xenograft models (DU145 and MDA-231) when administered systemically, either on its own or in combination with docetaxel. The antiangiogenic activity of FKBPL and AD-01 was dependent on the cell-surface receptor CD44, and signaling downstream of this receptor promoted an antimigratory phenotype.Conclusion: FKBPL and its peptide derivative AD-01 have potent antiangiogenic activity. Thus, these agents offer the potential of an attractive new approach to antiangiogenic therapy.

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    VL - 17

    SP - 1044

    EP - 1056

    JO - Clinical Cancer Research

    T2 - Clinical Cancer Research

    JF - Clinical Cancer Research

    SN - 1078-0432

    IS - 5

    ER -

    Valentine A, O'Rourke M, Yakkundi A, Worthington J, Hookham M, Bicknall R et al. FKBPL and Peptide Derivatives: Novel Biological AgentsThat Inhibit Angiogenesis by a CD44-Dependent Mechanism. Clinical Cancer Research. 2011 Mar 1;17(5):1044-1056.