title: The selective adhesion molecule inhibitor Natalizumab decreases multiple myeloma cell growth in the bone marrow microenvironment: therapeutic implications.
abstract: Recent advances regarding the introduction of anti-adhesion strategies as a novel therapeutic concept in oncology hold great promise. Here we evaluated the therapeutic potential of the new-in-class-molecule selective-adhesion-molecule (SAM) inhibitor Natalizumab, a recombinant humanized IgG4 monoclonal antibody, which binds integrin-α4, in multiple myeloma (MM). Natalizumab, but not a control antibody, inhibited adhesion of MM cells to non-cellular and cellular components of the microenvironment as well as disrupted the binding of already adherent MM cells. Consequently, Natalizumab blocked both the proliferative effect of MM-bone marrow (BM) stromal cell interaction on tumour cells, and vascular endothelial growth factor (VEGF)-induced angiogenesis in the BM milieu. Moreover, Natalizumab also blocked VEGF- and insulin-like growth factor 1 (IGF-1)-induced signalling sequelae triggering MM cell migration. In agreement with our in vitro results, Natalizumab inhibited tumour growth, VEGF secretion, and angiogenesis in a human severe combined immunodeficiency murine model of human MM in the human BM microenvironment. Importantly, Natalizumab not only blocked tumour cell adhesion, but also chemosensitized MM cells to bortezomib, in an in vitro therapeutically representative human MM-stroma cell co-culture system model. Our data therefore provide the rationale for the clinical evaluation of Natalizumab, preferably in combination with novel agents (e.g. bortezomib) to enhance MM cytotoxicity and improve patient outcome.
authors.affiliation: Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics, Boston, MA 02115, USA. klaus_podar@dfci.harvard.edu
authors.forename: Klaus
authors.initials: K
authors.lastname: Podar
authors.forename: Alexander
authors.initials: A
authors.lastname: Zimmerhackl
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Fulciniti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
authors.forename: Ursula
authors.initials: U
authors.lastname: Hainz
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Sonia
authors.initials: S
authors.lastname: Vallet
authors.forename: Niels
authors.initials: N
authors.lastname: Halama
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.forename: Dian L
authors.initials: DL
authors.lastname: Olson
authors.forename: Martin
authors.initials: M
authors.lastname: Sattler
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D039441:Integrin alpha4 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000069442:Natalizumab; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D005353:Fibronectins; D000069442:Natalizumab; D042461:Vascular Endothelial Growth Factor A; D039441:Integrin alpha4