Sylvester Comprehensive Cancer Center

Arthur Zelent, Ph.D.

Arthur Zelent, Ph.D.

Research Professor of Medicine

Description of Research

Dr. Zelent has had a long standing interest in the mechanisms of transcriptional regulation of gene expression and the roles that its deregulation contributes to cancer pathogenesis. Although initially more basic in nature, the current work in Dr. Zelent’s laboratory has become highly translational with the overall goal being the development of novel and more effective therapeutic approaches to acute myeloid leukemia (AML) and other hematopoietic neoplasms through elucidation of the basic molecular mechanisms underlying their pathogenesis. Therefore, Dr. Zelent strives to maintain highly integrated basic and translational activities in his laboratory with an emphasis on successful use of retinoid-based therapies for non-acute promyelocytic leukemia (non-APL) AML.

Dr. Zelent utilizes, two key model systems – regulation of gene expression by retinoic acid receptors (RARs) and epigenetic modifications. From a clinical perspective, the reversible nature of pathologic epigenetic changes mark out these processes as attractive therapeutic targets. RARs, which have been demonstrated to play a role in the pathogenesis of human cancer (including AML) and are highly susceptible to pharmacological manipulation with small molecules (retinoids), represent important and validated targets for the development of anticancer therapies. Dr. Zelent also has a strong background in studying abnormal epigenetics in AML and interest in rational development of agents (“epi-drugs”) that target aberrant epigenetic changes and may prove therapeutic alone, or combination with retinoids. Given cross-talks between the retinoid and cytokine receptors signaling pathways, Dr. Zelent has also set out to identify specific kinase and/or phosphatase inhibitors that would optimisme retinoid induced AML cell differentiation and could add to the development of the most effective combinatorial anti-AML therapies..

One of the key hypotheses, which was based on published and unpublished results from the laboratory, was that inhibition of LSD1 and EZH2 (histone H3 lysine 4 mono/di-methyl demethylase and lysine 27 methyltransferase, respectively) would unlock the therapeutic potential of retinoids in AML. This hypothesis has proved to be correct and the studies describing therapeutic effect of LSD1 inhibitor tranylcypromine (clinically available antidepressant) and all-trans-retinoic acid in AML have been published in Nature Medicine. Although this work has focused on hematopoitic malignancies, conceptually it can be translated to many other cancers.

Highlights

  • Retinoic acid receptor gamma
  • Retinoic acid receptor isoforms
  • Variant t(11;17) translocation in APL and PLZF-RARalpha fusion protein
  • Role of nuclear receptor co-repressors and histone deacetylases in APL
  • Histone deacetylase 9
  • LSD1 as a therapeutic target in AML
  • Selected Cancer-Related Publications

    • Kaluza D, Kroll J, Gesierich S, Manavsky Y, Boeckel J-N, Doebele C, Zelent A, Roessig L, Zeiher AM, Augustin HG, Urbich C, and Dimmeler S. Histone Deacetylase 9 Promotes Angiogenesis by Targetting the Antiangiogenic MicroRNA-17-92 Cluster in Endothelial Cells. Arterioscler Thromb Vasc Biol 33(3):533-+, 2013 Read more »
    • Schenk T, Howell L, Göllner S, Woster P, Marton L, Casero Jr R, Dick J, Mills K, Burnett A, Müller-Tidow C, Petrie K and Zelent A. Inhibition of the LSD1/KDM1 histone demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med 18(4):605-11, 2012. Read more »
    • Kotian S, Liyanarachchi S, Zelent A, Parvin JD. Histone deacetylases 9 and 10 are required for homologous recombination. J Biol Chem 286(10):7722-6, 2011 Read more »
    • Farias E, Petrie K, Leibovitch B, Murtagh J, Boix-Chornet M, Schenk T, Zelent A and Waxman S. Interference with Sin3 function induces epigenetic reprogramming, and differentiation in breast cancer cells. Proc Natl Acad Sci USA 107:11811-11816, 2010. Read more »

    Programs

    Collaborating in the Multidisciplinary Research Program(s):

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