Validation of microRNAs as therapeutic targets in hematological malignancies

Summary

Principal Investigator: Natarajan Muthusamy
Abstract: DESCRIPTION (provided by applicant): Modulation of oncogene expression by DNA oligodeoxynucleotides (ODNs) that target messenger RNAs and result in translational inhibition and down-regulation of the corresponding specific target proteins has long been pursued as a therapeutic strategy in cancer. Both chronic and acute leukemia's have been regarded as suitable for this therapeutic approach because of the occurrence of non-random molecular abnormalities that de-regulate gene expression and directly contribute to leukemogenesis. To date mRNA targeted therapies have relied mostly on antisense or reverse complementary DNA ODN-based approaches. When administered in vivo, however, these molecules suffer from a variety of limitations that have recently been partially overcome by modifying the backbone structure of these compounds. Even then, the efficiency of ODNs for target downregulation remains overall low. The recent discovery of cellular endogenous microRNAs (miRs), short RNA sequences that by hybridizing to target RNAs regulate their translation rate, has offered a sound alternative to the antisense DNA oligonucleotides. This concept has been supported by the recent discovery that alterations in the levels of specific miRs are mechanistically relevant to malignant transformation through deregulation of target oncogene or tumor suppressor gene expression. MiRs offer the advantage of being normal counterparts to oncogene or tumor suppressor gene regulation and thereby appear to promote prolonged modulation of the relevant targets and more importantly to target simultaneously several genes involved in pathways regulating cell proliferation, differentiation and survival. These results have recently prompted the design of potential therapeutic applications of synthetically manufactured miRs in cancer. Here, we propose to investigate the clinical applicability of miR-based therapies in-vivo in mouse models where downregulation of specific miRs contributes to malignant transformation and/or aggressive phenotypes of the underlying leukemia. Our group has recently identified relevance of miR-29b in the pathogenesis of epigenetic progression in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) through modulation of DNA methyltransferases [DNMT1, DNMT3A and DNMT3B], DNA hypermethylation and gene silencing and miR-181a in tumor suppressor activity by modulating pathways involved in mechanisms of innate immunity, regulating Toll like receptor 4, IL-[unreadable] and miR155 expression in AML cell lines and primary blasts. Therefore, as proof of principle miR-based therapy is an applicable and effective therapeutic strategy. Hence, we propose to perform preclinical in-vivo pharmacokinetic (PK), pharmacodynamic (PD), and therapeutic evaluation of synthetic 2-OMemiR-29b and 2-OMemiR-181a with the goal to validate the pharmacokinetic, pharmacodynamic and therapeutic endpoints, using transgenic (CLL) and xenograft (AML) murine leukemia models. At completion of this project, we anticipate the beginning of initial phase I studies with miR based therapy using miR29b and miR-181 in cancer patients. PUBLIC HEALTH RELEVANCE: Only a fraction of patients with acute and chronic leukemia, types of cancer of the bone marrow and blood, survive following current standard chemotherapy treatments and therefore, new treatment approaches are urgently needed. Recently, we and others have discovered natural molecules called microRNAs that regulate expression of functionally relevant genes supporting proliferation, differentiation and death of normal cells and that are either abnormally low or abnormally high in cancer and leukemia cells, thereby initiating and maintaining malignant cell growth. Therefore, we propose here to replace the low levels of natural microRNAs in leukemia cells with synthetic microRNAs as novel therapeutic approach to leukemia patients.
Funding Period: 2011-03-01 - 2016-02-29
more information: NIH RePORT

Top Publications

  1. pmc Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia
    William Blum
    Division of Hematology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, B310 Starling Loving Hall, Columbus, OH 43210, USA
    Blood 119:6025-31. 2012
  2. pmc Synthetic microRNA cassette dosing: pharmacokinetics, tissue distribution and bioactivity
    Hongyan Wang
    Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States
    Mol Pharm 9:1638-44. 2012
  3. pmc Determination of cellular uptake and intracellular levels of Cenersen (Aezea(®), EL625), a p53 antisense oligonucleotide in acute myeloid leukemia cells
    Houda Alachkar
    Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
    J Pharm Biomed Anal 71:228-32. 2012
  4. pmc Targeted nanoparticle delivery overcomes off-target immunostimulatory effects of oligonucleotides and improves therapeutic efficacy in chronic lymphocytic leukemia
    Bo Yu
    Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA
    Blood 121:136-47. 2013
  5. pmc Milatuzumab-conjugated liposomes as targeted dexamethasone carriers for therapeutic delivery in CD74+ B-cell malignancies
    Yicheng Mao
    Division of Hematology, The Comprehensive Cancer Center, Division of Pharmaceutics and Medicinal Chemistry, College of Pharmacy, Ohio State University, Columbus, OH 43210, USA
    Clin Cancer Res 19:347-56. 2013
  6. pmc Antibody-based therapeutics for the treatment of human B cell malignancies
    Sivasubramanian Baskar
    Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
    Curr Allergy Asthma Rep 13:33-43. 2013
  7. pmc Targeted drug delivery and cross-linking induced apoptosis with anti-CD37 based dual-ligand immunoliposomes in B chronic lymphocytic leukemia cells
    Bo Yu
    Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA
    Biomaterials 34:6185-93. 2013
  8. pmc A novel liposomal formulation of FTY720 (fingolimod) for promising enhanced targeted delivery
    Yicheng Mao
    Center for Affordable Nanoengineering of Polymeric Biomedical Devices CANPBD, The Ohio State University, Columbus, OH, USA Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA
    Nanomedicine 10:393-400. 2014

Research Grants

Detail Information

Publications8

  1. pmc Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia
    William Blum
    Division of Hematology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, B310 Starling Loving Hall, Columbus, OH 43210, USA
    Blood 119:6025-31. 2012
    ..This study demonstrates the feasibility and preliminary clinical activity of decitabine plus bortezomib in AML and identifies FLT3 as a novel pharmacodynamic end point for future trials...
  2. pmc Synthetic microRNA cassette dosing: pharmacokinetics, tissue distribution and bioactivity
    Hongyan Wang
    Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States
    Mol Pharm 9:1638-44. 2012
    ..This study supports future exploration of miR-involved combination therapies...
  3. pmc Determination of cellular uptake and intracellular levels of Cenersen (Aezea(®), EL625), a p53 antisense oligonucleotide in acute myeloid leukemia cells
    Houda Alachkar
    Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
    J Pharm Biomed Anal 71:228-32. 2012
    ..Assessment of achievable concentration of Cenersen in different biologic matrices will be useful to elucidate the biological and clinical activity of this promising drug and define its recommended dose in future clinical trials...
  4. pmc Targeted nanoparticle delivery overcomes off-target immunostimulatory effects of oligonucleotides and improves therapeutic efficacy in chronic lymphocytic leukemia
    Bo Yu
    Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA
    Blood 121:136-47. 2013
    ..The broader implications of similar approaches in overcoming immunostimulatory properties of RNA-directed therapeutics in hematologic malignancies are also discussed...
  5. pmc Milatuzumab-conjugated liposomes as targeted dexamethasone carriers for therapeutic delivery in CD74+ B-cell malignancies
    Yicheng Mao
    Division of Hematology, The Comprehensive Cancer Center, Division of Pharmaceutics and Medicinal Chemistry, College of Pharmacy, Ohio State University, Columbus, OH 43210, USA
    Clin Cancer Res 19:347-56. 2013
    ..Herein, we developed novel milatuzumab-conjugated liposomes as a targeted dexamethasone carrier for therapeutic delivery in CD74(+) B-cell malignancies and explored its effect against the disease...
  6. pmc Antibody-based therapeutics for the treatment of human B cell malignancies
    Sivasubramanian Baskar
    Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
    Curr Allergy Asthma Rep 13:33-43. 2013
    ..This review describes recent advancements in some of these adoptive immunotherapeutic strategies targeting B cell malignancies...
  7. pmc Targeted drug delivery and cross-linking induced apoptosis with anti-CD37 based dual-ligand immunoliposomes in B chronic lymphocytic leukemia cells
    Bo Yu
    Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA
    Biomaterials 34:6185-93. 2013
    ..Our findings suggest that the dual-ligand ILs may provide a preferred strategy of personalized nanomedicine for the treatment of B-cell malignancies...
  8. pmc A novel liposomal formulation of FTY720 (fingolimod) for promising enhanced targeted delivery
    Yicheng Mao
    Center for Affordable Nanoengineering of Polymeric Biomedical Devices CANPBD, The Ohio State University, Columbus, OH, USA Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA
    Nanomedicine 10:393-400. 2014
    ....

Research Grants30

  1. Targeting aberrant epigenetics by nanomedicine
    Shujun Liu; Fiscal Year: 2013
    ..abstract_text> ..
  2. Role of 11q23 Chromosome Abnormalities in the Causation of Acute Leukemia
    Carlo M Croce; Fiscal Year: 2013
    ..abstract_text> ..
  3. Targeting the aberrant kinome-epigenome in AML
    Guido Marcucci; Fiscal Year: 2013
    ....
  4. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..