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

Deepti Soodgupta; Dipanjan Pan; Grace Cui; Angana Senpan; Xiaoxia Yang; Lan Lu; Katherine N Weilbaecher; Edward V Prochownik; Gregory M Lanza; Michael H Tomasson

doi:10.1158/1535-7163.MCT-14-0774-T

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

Deepti Soodgupta, Dipanjan Pan, Grace Cui, Angana Senpan, Xiaoxia Yang, Lan Lu, Katherine N Weilbaecher, Edward V Prochownik, Gregory M Lanza and Michael H Tomasson

Molecular cancer therapeutics, Vol.14(6), pp.1286-1294

06/2015

DOI: 10.1158/1535-7163.MCT-14-0774-T

PMCID: PMC4571491

PMID: 25824336

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https://doi.org/10.1158/1535-7163.MCT-14-0774-TView

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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. 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.

Small Molecule Libraries - pharmacology

Integrin alpha4beta1 - metabolism

Nanoparticles - chemistry

Apoptosis - drug effects

Humans

Small Molecule Libraries - metabolism

Integrin alphaVbeta3 - metabolism

Dose-Response Relationship, Drug

Multiple Myeloma - drug therapy

Disease Models, Animal

Integrin alphaVbeta3 - antagonists & inhibitors

Cell Survival - drug effects

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - chemistry

Proto-Oncogene Proteins c-myc - metabolism

Blotting, Western

Small Molecule Libraries - chemistry

Multiple Myeloma - pathology

Animals

Tumor Burden - drug effects

Integrin alpha4beta1 - antagonists & inhibitors

Proto-Oncogene Proteins c-myc - antagonists & inhibitors

Survival Analysis

Cell Line, Tumor

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism

Mice

Proto-Oncogene Proteins c-myc - chemistry

Prodrugs - pharmacology

Protein Multimerization - drug effects

Details

Title: Subtitle: Small Molecule MYC Inhibitor Conjugated to Integrin-Targeted Nanoparticles Extends Survival in a Mouse Model of Disseminated Multiple Myeloma
Creators: Deepti Soodgupta - Division of Oncology, Department of Medicine, Washington University Medical School, St. Louis, Missouri
Dipanjan Pan - Department of Bioengineering, University of Illinois, Urbana-Champaign, Illinois
Grace Cui - Division of Cardiology, Department of Medicine, Washington University Medical School, St. Louis, Missouri
Angana Senpan - Division of Cardiology, Department of Medicine, Washington University Medical School, St. Louis, Missouri
Xiaoxia Yang - Division of Cardiology, Department of Medicine, Washington University Medical School, St. Louis, Missouri
Lan Lu - Division of Oncology, Department of Medicine, Washington University Medical School, St. Louis, Missouri
Katherine N Weilbaecher - Division of Oncology, Department of Medicine, Washington University Medical School, St. Louis, Missouri
Edward V Prochownik - Division of Pediatric Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburg, Pennsylvania
Gregory M Lanza - Division of Cardiology, Department of Medicine, Washington University Medical School, St. Louis, Missouri
Michael H Tomasson - Division of Oncology, Department of Medicine, Washington University Medical School, St. Louis, Missouri
Resource Type: Journal article
Publication Details: Molecular cancer therapeutics, Vol.14(6), pp.1286-1294
DOI: 10.1158/1535-7163.MCT-14-0774-T
PMID: 25824336
PMCID: PMC4571491
ISSN: 1535-7163
eISSN: 1538-8514
Grant note: CA100623 / NCI NIH HHS HL113392 / NHLBI NIH HHS R21 CA100623 / NCI NIH HHS U54 CA199092 / NCI NIH HHS CA154737 / NCI NIH HHS R01 CA154737 / NCI NIH HHS P01 CA100730 / NCI NIH HHS R01 HL113392 / NHLBI NIH HHS
Language: English
Date published: 06/2015
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094542702771

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