Novel therapeutic targets in Waldenstrom macroglobulinemia.
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 MYD88L265Psignaling 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.
Mayo Clinic Jacksonville, Department of Cancer Biology and Division of Hematology and Oncology, United States. Electronic address: Paulus.aneel@mayo.edu.
Aneel
A
Paulus
Mayo Clinic Jacksonville, Division of Hematology and Oncology, United States. Electronic address: Ailawadhi.sikander@mayo.edu.
Sikander
S
Ailawadhi
Mayo Clinic Jacksonville, Division of Hematology and Oncology, United States. Electronic address: Chanan-Khan.asher@mayo.edu.
Asher
A
Chanan-Khan
D019943:Amino Acid Substitution; D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D064987:Cell- and Tissue-Based Therapy; D000072017:Deubiquitinating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D006801:Humans; D017710:Lymphocyte Transfusion; D020125:Mutation, Missense; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics / Q000276:immunology / Q000628:therapy*
D018941:Antigens, CD19; D000970:Antineoplastic Agents; C000604811:CD19 molecule, human; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D051193:Toll-Like Receptors; C576917:AURKA protein, human; D064096:Aurora Kinase A; D000072017:Deubiquitinating Enzymes
Deubiquitinating enzymes; Ibrutinib; MYD88; Proteasome; Waldenstrom macroglobulinemia