title: Molecular target characterization and antimyeloma activity of the novel, insulin-like growth factor 1 receptor inhibitor, GTx-134.
abstract: OBJECTIVE
  Therapeutic strategies that target insulin-like growth factor 1 receptor (IGF-1R) hold promise in a wide variety of cancers including multiple myeloma (MM). In this study, we describe GTx-134, a novel small-molecule inhibitor of IGF-1R and insulin receptor (IR) and characterized its antitumor activity in preclinical models of MM.
  
  
  METHODS
  The activity of GTx-134 as a single agent and in combination was tested in MM cell lines and primary patient samples. Downstream effector proteins and correlation with apoptosis was evaluated. Cytotoxcity in bone marrow stroma coculture experiments was assessed. Finally, the in vivo efficacy was evaluated in a human myeloma xenograft model.
  
  
  RESULTS
  GTx-134 inhibited the growth of 10 of 14 myeloma cell lines (<5 μmol/L) and induced apoptosis. Sensitivity to GTx-134 correlated with IGF-1R signal inhibition. Expression of MDR-1 and CD45 were associated with resistance to GTx-134. Coculture with insulin-growth factor-1 (IGF-1) or adherence to bone marrow stroma conferred modest resistance, but did not overcome GTx-134-induced cytotoxicity. GTx-134 showed in vitro synergies when combined with dexamethasone or lenalidomide. Further, GTx-134 enhanced the activity of PD173074, a fibroblast growth factor receptor 3 (FGFR3) inhibitor, against t(4;14) myeloma cells. Therapeutic efficacy of GTx-134 was shown against primary cells and xenograft tumors. Although dysregulation of glucose homeostasis was observed in GTx-134-treated mice, impairment of glucose tolerance was modest.
  
  
  CONCLUSIONS
  These studies support the potential therapeutic efficacy of GTx-134 in MM. Further, they provide a rationale for clinical application in combination with established antimyeloma treatments and novel targeted therapies.
authors.affiliation: Department of Medical Oncology-Hematology, Princess Margaret Hospital, McLaughlin Centre for Molecular Medicine, Toronto, Ontario, Canada.
authors.forename: Sheng-Ben
authors.initials: SB
authors.lastname: Liang
authors.forename: Xiu-Zhi
authors.initials: XZ
authors.lastname: Yang
authors.forename: Young
authors.initials: Y
authors.lastname: Trieu
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.forename: Jessica
authors.initials: J
authors.lastname: Zive
authors.forename: Chungyee
authors.initials: C
authors.lastname: Leung-Hagesteijn
authors.forename: Ellen
authors.initials: E
authors.lastname: Wei
authors.forename: Sergey
authors.initials: S
authors.lastname: Zozulya
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Coss
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
authors.forename: Ivan George
authors.initials: IG
authors.lastname: Fantus
authors.forename: Suzanne
authors.initials: S
authors.lastname: Trudel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C568615:GTx 134; D006575:Heterocyclic Compounds, 3-Ring; D013450:Sulfones; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt