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      Small Molecule MYC Inhibitor Conjugated to Integrin-Targeted Nanoparticles Extends Survival in a Mouse Model of Disseminated Multiple Myeloma.

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          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.

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          Author and article information

          Journal
          Mol. Cancer Ther.
          Molecular cancer therapeutics
          American Association for Cancer Research (AACR)
          1538-8514
          1535-7163
          Jun 2015
          : 14
          : 6
          Affiliations
          [1 ] Division of Oncology, Department of Medicine, Washington University Medical School, St. Louis, Missouri.
          [2 ] Department of Bioengineering, University of Illinois, Urbana-Champaign, Illinois.
          [3 ] Division of Cardiology, Department of Medicine, Washington University Medical School, St. Louis, Missouri.
          [4 ] Division of Pediatric Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburg, Pennsylvania.
          [5 ] Division of Oncology, Department of Medicine, Washington University Medical School, St. Louis, Missouri. Tomasson@dom.wustl.edu.
          Article
          1535-7163.MCT-14-0774-T NIHMS699807
          10.1158/1535-7163.MCT-14-0774-T
          4571491
          25824336

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