title: Small Molecule MYC Inhibitor Conjugated to Integrin-Targeted Nanoparticles Extends Survival in a Mouse Model of Disseminated Multiple Myeloma.
abstract: Multiple myeloma pathogenesis is driven by the MYC oncoprotein, its dimerization with MAX, and the binding of this heterodimer to E-Boxes in the vicinity of target genes. The systemic utility of potent small molecule inhibitors of MYC-MAX dimerization was limited by poor bioavailability, rapid metabolism, and inadequate target site penetration. We hypothesized that new lipid-based MYC-MAX dimerization inhibitor prodrugs delivered via integrin-targeted nanoparticles (NP) would overcome prior shortcomings of MYC inhibitor approaches and prolong survival in a mouse model of cancer. An Sn 2 lipase-labile prodrug inhibitor of MYC-MAX dimerization (MI1-PD) was developed which decreased cell proliferation and induced apoptosis in cultured multiple myeloma cell lines alone (P < 0.05) and when incorporated into integrin-targeted lipid-encapsulated NPs (P < 0.05). Binding and efficacy of NPs closely correlated with integrin expression of the target multiple myeloma cells. Using a KaLwRij metastatic multiple myeloma mouse model, VLA-4-targeted NPs (20 nm and 200 nm) incorporating MI1-PD (D) NPs conferred significant survival benefits compared with respective NP controls, targeted (T) no-drug (ND), and untargeted (NT) control NPs (T/D 200: 46 days vs.
  28 days, P < 0.05 and T/D 20: 52 days vs.
  29 days, P = 0.001). The smaller particles performed better of the two sizes. Neither MI1 nor MI1-PD provided survival benefit when administered systemically as free compounds. These results demonstrate for the first time that a small molecule inhibitor of the MYC transcription factor can be an effective anticancer agent when delivered using a targeted nanotherapy approach.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University Medical School, St. Louis, Missouri.
authors.forename: Deepti
authors.initials: D
authors.lastname: Soodgupta
authors.affiliation: Department of Bioengineering, University of Illinois, Urbana-Champaign, Illinois.
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Pan
authors.affiliation: Division of Cardiology, Department of Medicine, Washington University Medical School, St. Louis, Missouri.
authors.forename: Grace
authors.initials: G
authors.lastname: Cui
authors.affiliation: Division of Cardiology, Department of Medicine, Washington University Medical School, St. Louis, Missouri.
authors.forename: Angana
authors.initials: A
authors.lastname: Senpan
authors.affiliation: Division of Cardiology, Department of Medicine, Washington University Medical School, St. Louis, Missouri.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Division of Oncology, Department of Medicine, Washington University Medical School, St. Louis, Missouri.
authors.forename: Lan
authors.initials: L
authors.lastname: Lu
authors.affiliation: Division of Oncology, Department of Medicine, Washington University Medical School, St. Louis, Missouri.
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Weilbaecher
authors.affiliation: Division of Pediatric Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburg, Pennsylvania.
authors.forename: Edward V
authors.initials: EV
authors.lastname: Prochownik
authors.affiliation: Division of Cardiology, Department of Medicine, Washington University Medical School, St. Louis, Missouri.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Lanza
authors.affiliation: Division of Oncology, Department of Medicine, Washington University Medical School, St. Louis, Missouri.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Tomasson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000737:chemistry / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry*; D011355:Prodrugs / Q000494:pharmacology; D055503:Protein Multimerization / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D039041:Integrin alpha4beta1; D039302:Integrin alphaVbeta3; C499330:MAX protein, human; D011355:Prodrugs; D016271:Proto-Oncogene Proteins c-myc; D054852:Small Molecule Libraries
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