Novel therapeutic targets in Waldenstrom macroglobulinemia

Best Pract Res Clin Haematol. 2016 Jun;29(2):216-228. doi: 10.1016/j.beha.2016.08.020. Epub 2016 Sep 7.

Abstract

Understanding of molecular mechanisms that drive Waldenstrom macroglobulinemia (WM) cell survival are rapidly evolving. This review briefly highlights emerging "WM-relevant" targets; for which therapeutic strategies are currently being investigated in preclinical and clinical studies. With the discovery of MYD88L265P signaling and remarkable activity of ibrutinib in WM, other targets within the B-cell receptor pathway are now being focused on for therapeutic intervention. Additional targets which play a role in WM cell survival include TLR7, 8 and 9, proteasome-associated deubiquitinating enzymes (USP14 and UCHL5), XPO1/CRM1 and AURKA. New drugs for established targets are also discussed. Lastly, we spotlight 3 highly innovative WM-specific therapies: MYD88 peptide inhibitors, MYD88L265P-directed immune activation and CD19-directed chimeric antigen receptor T-cell therapy, which are in various stages of development. Indeed, treatment of WM is poised to undergo a paradigm shift in the coming years towards highly disease-driven and more personalized therapeutic modalities with curative intent.

Keywords: Deubiquitinating enzymes; Ibrutinib; MYD88; Proteasome; Waldenstrom macroglobulinemia.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Antigens, CD19 / genetics
  • Antigens, CD19 / immunology
  • Antineoplastic Agents / therapeutic use*
  • Aurora Kinase A / antagonists & inhibitors
  • Aurora Kinase A / genetics
  • Aurora Kinase A / immunology
  • Cell- and Tissue-Based Therapy*
  • Deubiquitinating Enzymes / antagonists & inhibitors
  • Deubiquitinating Enzymes / genetics
  • Deubiquitinating Enzymes / immunology
  • Humans
  • Lymphocyte Transfusion*
  • Mutation, Missense
  • Myeloid Differentiation Factor 88 / antagonists & inhibitors
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / immunology
  • Receptors, Antigen, T-Cell*
  • Recombinant Fusion Proteins*
  • Toll-Like Receptors / antagonists & inhibitors
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / immunology
  • Waldenstrom Macroglobulinemia / genetics
  • Waldenstrom Macroglobulinemia / immunology
  • Waldenstrom Macroglobulinemia / therapy*

Substances

  • Antigens, CD19
  • Antineoplastic Agents
  • CD19 molecule, human
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • Toll-Like Receptors
  • AURKA protein, human
  • Aurora Kinase A
  • Deubiquitinating Enzymes