Y. Shaked

Publications (10)11.41 Total impact

• Article: Treatment-induced host-mediated mechanisms reducing the efficacy of antitumor therapies.

  L G M Daenen, J M Houthuijzen, G A Cirkel, J M L Roodhart, Y Shaked, E E Voest
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  ABSTRACT: In addition to its direct effects on tumor cells, chemotherapy can rapidly activate various host processes that contribute to therapy resistance and tumor regrowth. The host response to chemotherapy consists of changes in numerous cell types and cytokines. Examples include the acute mobilization and tumor homing of pro-angiogenic bone marrow-derived cells, activation of cells in the tumor microenvironment to produce systemic or paracrine factors, and tissue-specific responses that provide a protective niche for tumor cells. All of these factors reduce chemotherapy efficacy, and blocking the host response at various levels may therefore significantly improve treatment outcome. However, before the combination of conventional chemotherapy with agents blocking specific aspects of the host response can be implemented into clinical practice, a better understanding of the molecular mechanisms behind the host response is required.Oncogene advance online publication, 25 March 2013; doi:10.1038/onc.2013.94.
  Oncogene 03/2013; · 6.37 Impact Factor
• Article: On the clinical relevance of circulating endothelial cells and platelets in prostate cancer.

  F Bertolini, Y Shaked, P Mancuso
  British Journal of Cancer 02/2013; · 5.04 Impact Factor
• Chapter: Metronomic Low-Dose Antiangiogenic Chemotherapy in Mice and Man

  Robert S. Kerbel, U. Emmenegger, S. Man, R. Munoz, C. Folkins, Y. Shaked
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  ABSTRACT: Metronomic (antiangiogenic) chemotherapy refers to a form of dose dense chemotherapy involving close regular, even daily, administration of conventional chemotherapy drugs at relatively low doses over long periods in the absence of prolonged drug-free periods. Anti-tumor efficacy, which in some cases can be remarkably effective in various experimental mouse models of cancer, even in the absence of toxicity, is thought to be mediated mainly by antiangiogenic effects, either locally, by direct targeting of activated/dividing endothelial cells in the angiogenic tumor neovasculature, or systemically, by effects on circulating (bone marrow derived) endothelial progenitor cells (CEPs). However, additional mechanisms may also be involved, including stimulation of the immune system by targeting regulatory T cells, and possibly also direct effects on tumor cells—which could include the tumor stem cell(-like) subpopulation. Metronomic chemotherapy, because of its relatively nontoxic nature, is ideal for combination therapy using various targeted biologic agents, especially antiangiogenic drugs. Other promising combinatorial strategies include “doublet” metronomic chemotherapy using two different chemotherapy drugs, interspersing low-dose chemotherapy with higher bolus dose (BD) injections of the same drug, or short-course maximum tolerated dose (MTD) chemotherapy followed by long-term metronomic chemotherapy combined with a targeted biologic agent. Such combinations can sometimes have striking preclinical anti-tumor effects, even in models involving large primary tumors or widespread high-volume metastatic disease. A number of clinical trials and pilot studies testing various combinatorial metronomic chemotherapy regimens have been undertaken which, in aggregate, appear to confirm encouraging clinical activity in certain advanced-stage cancers, with only modest or minimal host toxicity being observed. Larger randomized phase III trials are thus warranted, especially considering some of the potential advantages of metronomic chemotherapy. These include increased convenience when using oral chemotherapeutic drugs, reduced costs when off-patent chemotherapeutic drugs are used, and reduced severity of toxic side effects. These features make metronomic chemotherapy-type regimens ideal for adjuvant chemotherapy of early-stage cancers, an example of which is long-term, nontoxic daily oral tegafur-uracil (UFT) (a 5-FU prodrug composed of uracil and tegafur) for treatment of early-stage non-small cell lung cancer (NSCLC).
  12/2007: pages 277-296;
• Article: Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis

  Y. Shaked, F. Bertolini, S. Man, M. S. Rogers, D. Cervi, T. Foutz, K. Rawn, D. Voskas, D. J. Dumont, Y. Ben-David, J. Lawler, J. Henkin, J. Huber, D. J. Hicklin, R. J. D'Amato, R. S. Kerbel
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  ABSTRACT: Development of antiangiogenic therapies would be significantly facilitated by quantitative surrogate pharmacodynamic markers. Circulating peripheral blood endothelial cells (CECs) and/or their putative progenitor subset (CEPs) have been proposed but not yet fully validated for this purpose. Herein, we provide such validation by showing a striking correlation between highly genetically heterogeneous bFGF- or VEGF-induced angiogenesis and intrinsic CEC or CEP levels measured by flow cytometry, among eight different inbred mouse strains. Moreover, studies using genetically altered mice showed that levels of these cells are affected by regulators of angiogenesis, including VEGF, Tie-2, and thrombospondin-1. Finally, treatment with a targeted VEGFR-2 antibody caused a dose-dependent reduction in viable CEPs that precisely paralleled its previously and empirically determined antitumor activity.
  Cancer Cell. 7(1):101-11.
• Article: Contribution of granulocyte colony-stimulating factor to the acute mobilization of endothelial precursor cells by vascular disrupting agents.

  Y. Shaked, T. Tang, J. Woloszynek, L.G.M. Daenen, S. de Man, P. Xu, S.R. Cai, J.M. Arbeit, E.E. Voest, D.J. Chaplin, J. Smythe, A. Harris, P. Nathan, I. Judson, G. Rustin, F Bertolini, D.C. Link, R S Kerbel
• Article: Bone marrow derived cells in tumor angiogenesis and growth: are they the good, the bad or the evil?

  Y. Shaked, E.E. Voest
• Article: Low-dose metronomic cyclophosphamide combined with vascular disrupting therapy induces potent antitumor activity in preclinical human tumor xenograft models.

  L.G.M. Daenen, Y. Shaked, S. de Man, P. Xu, E.E. Voest, R M Hoffman, D.J. Chaplin, R S Kerbel
• Article: Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents

  Y. Shaked, E Henke, J.M.L. Roodhart, P Mancuso, M.H.G. Langenberg, M Colleoni, L.G.M. Daenen, S. de Man, P. Xu, U. Emmenegger, T. Tang, Z Zhu, L. de Witte, R.M. Strieter, F Bertolini, E.E. Voest, R Benezra, R S Kerbel
• Article: Vascular disrupting agents (VDAs) in anticancer therapy

  L.G.M. Daenen, J.M.L. Roodhart, Y. Shaked, E.E. Voest
• Article: Liver surgery induces an immediate mobilization of progenitor cells in liver cancer patients: A potential role for G-CSF.

  M.H.G. Langenberg, M.W. Nijkamp, J.M.L. Roodhart, N. Snoeren, T. Tang, Y. Shaked, R. van Hillegersberg, P.O. Witteveen, J.S.P. Vermaat, O.W. Kranenburg, R S Kerbel, R.H. Medema, I.H.M. Borel Rinkes, E.E. Voest