title: The Novel Pan-PIM Kinase Inhibitor, PIM447, Displays Dual Antimyeloma and Bone-Protective Effects, and Potently Synergizes with Current Standards of Care.
abstract: OBJECTIVE
  PIM kinases are a family of serine/threonine kinases recently proposed as therapeutic targets in oncology. In the present work, we have investigated the effects of the novel pan-PIM kinase inhibitor, PIM447, on myeloma cells and myeloma-associated bone disease using different preclinical models.
  
  
  METHODS
  In vitro/ex vivo cytotoxicity of PIM447 was evaluated on myeloma cell lines and patient samples. Synergistic combinations with standard treatments were analyzed with Calcusyn Software. PIM447 effects on bone cells were assessed on osteogenic and osteoclastogenic cultures. The mechanisms of PIM447 were explored by immunoblotting, qPCR, and immunofluorescence. A murine model of disseminated multiple myeloma was employed for in vivo studies.
  
  
  RESULTS
  PIM447 is cytotoxic for myeloma cells due to cell-cycle disruption and induction of apoptosis mediated by a decrease in phospho-Bad (Ser112) and c-Myc levels and the inhibition of mTORC1 pathway. Importantly, PIM447 demonstrates a very strong synergy with different standard treatments such as bortezomib + dexamethasone (combination index, CI = 0.002), lenalidomide + dexamethasone (CI = 0.065), and pomalidomide + dexamethasone (CI = 0.077). PIM447 also inhibits in vitro osteoclast formation and resorption, downregulates key molecules involved in these processes, and partially disrupts the F-actin ring, while increasing osteoblast activity and mineralization. Finally, PIM447 significantly reduced the tumor burden and prevented tumor-associated bone loss in a disseminated murine model of human myeloma.
  
  
  CONCLUSIONS
  Our results demonstrate dual antitumoral and bone-protective effects of PIM447. This fact, together with the very strong synergy exhibited with standard-of-care treatments, supports the future clinical development of this drug in multiple myeloma. Clin Cancer Res; 23(1); 225-38. ©2016 AACR.
authors.affiliation: Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain.|Complejo Asistencial Universitario de Salamanca-IBSAL, Salamanca, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Paíno
authors.affiliation: Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain.|Complejo Asistencial Universitario de Salamanca-IBSAL, Salamanca, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Garcia-Gomez
authors.affiliation: Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain.|Complejo Asistencial Universitario de Salamanca-IBSAL, Salamanca, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: González-Méndez
authors.affiliation: Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain.|Complejo Asistencial Universitario de Salamanca-IBSAL, Salamanca, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: San-Segundo
authors.affiliation: Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain.|Complejo Asistencial Universitario de Salamanca-IBSAL, Salamanca, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Hernández-García
authors.affiliation: Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain.|Complejo Asistencial Universitario de Salamanca-IBSAL, Salamanca, Spain.
authors.forename: Ana-Alicia
authors.initials: AA
authors.lastname: López-Iglesias
authors.affiliation: Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain.|Complejo Asistencial Universitario de Salamanca-IBSAL, Salamanca, Spain.
authors.forename: Esperanza M
authors.initials: EM
authors.lastname: Algarín
authors.affiliation: Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain.|Complejo Asistencial Universitario de Salamanca-IBSAL, Salamanca, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Martín-Sánchez
authors.affiliation: Program in Solid Tumors and Biomarkers, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra; Navarra's Health Research Institute (IDISNA), Pamplona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Corbacho
authors.affiliation: Program in Solid Tumors and Biomarkers, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra; Navarra's Health Research Institute (IDISNA), Pamplona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Ortiz-de-Solorzano
authors.affiliation: Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain.|Complejo Asistencial Universitario de Salamanca-IBSAL, Salamanca, Spain.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Corchete
authors.affiliation: Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain.|Complejo Asistencial Universitario de Salamanca-IBSAL, Salamanca, Spain.
authors.forename: Norma C
authors.initials: NC
authors.lastname: Gutiérrez
authors.affiliation: Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain.|Complejo Asistencial Universitario de Salamanca-IBSAL, Salamanca, Spain.
authors.forename: María-Victoria
authors.initials: MV
authors.lastname: Maetos
authors.affiliation: Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain.|Complejo Asistencial Universitario de Salamanca-IBSAL, Salamanca, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Garayoa
authors.affiliation: Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain. emocio@usal.es.|Complejo Asistencial Universitario de Salamanca-IBSAL, Salamanca, Spain.
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Ocio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D059039:Standard of Care; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D020011:Protective Agents; D047428:Protein Kinase Inhibitors; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim