title: Inhibition of P-Selectin and PSGL-1 Using Humanized Monoclonal Antibodies Increases the Sensitivity of Multiple Myeloma Cells to Bortezomib.
abstract: Multiple myeloma (MM) is a plasma cell malignancy localized in the bone marrow. Despite the introduction of novel therapies majority of MM patients relapse. We have previously shown that inhibition of P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) play a key role in proliferation of MM and using small-molecule inhibitors of P-selectin/PSGL-1 sensitized MM cells to therapy. However, these small-molecule inhibitors had low specificity to P-selectin and showed poor pharmacokinetics. Therefore, we tested blocking of P-selectin and PSGL-1 using functional monoclonal antibodies in order to sensitize MM cells to therapy. We have demonstrated that inhibiting the interaction between MM cells and endothelial and stromal cells decreased proliferation in MM cells and in parallel induced loose-adhesion to the primary tumor site to facilitate egress. At the same time, blocking this interaction in vivo led to MM cells retention in the circulation and delayed homing to the bone marrow, thus exposing MM cells to bortezomib which contributed to reduced tumor growth and better mice survival. This study provides a better understanding of the biology of P-selectin and PSGL-1 and their roles in dissemination and resensitization of MM to treatment.
authors.affiliation: Cancer Biology Division, Department of Radiation Oncology, Washington University in Saint Louis School of Medicine, Saint Louis, MO 63108, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Muz
authors.affiliation: Cancer Biology Division, Department of Radiation Oncology, Washington University in Saint Louis School of Medicine, Saint Louis, MO 63108, USA.
authors.forename: Feda
authors.initials: F
authors.lastname: Azab
authors.affiliation: Cancer Biology Division, Department of Radiation Oncology, Washington University in Saint Louis School of Medicine, Saint Louis, MO 63108, USA.
authors.forename: Pilar
authors.initials: P
authors.lastname: de la Puente
authors.affiliation: Selexys Pharmaceuticals, 840 Research Parkway, Suite 510, Oklahoma City, OK 73104, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Rollins
authors.affiliation: Selexys Pharmaceuticals, 840 Research Parkway, Suite 510, Oklahoma City, OK 73104, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Alvarez
authors.affiliation: Selexys Pharmaceuticals, 840 Research Parkway, Suite 510, Oklahoma City, OK 73104, USA.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Kawar
authors.affiliation: Cancer Biology Division, Department of Radiation Oncology, Washington University in Saint Louis School of Medicine, Saint Louis, MO 63108, USA.
authors.forename: Abdel Kareem
authors.initials: AK
authors.lastname: Azab
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000069286:Bortezomib / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000276:immunology; D004727:Endothelium / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D019007:P-Selectin / Q000037:antagonists & inhibitors* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; C546937:SELP protein, human; D000069286:Bortezomib