Myeloma
New treatment modalities for multiple myeloma (Morbus Kahler)
@
Andries Bloem
Multiple myeloma (MM) is a so far incurable neoplastic disease of B-cell lineage, characterized by the presence of monoclonal plasma cells in the bone marrow (BM). Treatment with standard chemotherapy generally results in a temporary indolent state of the tumor. After relapse, the tumor is invariably more aggressive and resistant to chemotherapy. Alternative treatment strategies include transplantation with allogeneic stem cells. These patients may benefit from an infusion with leukocytes from the original stem cell donor resulting in a demise of the myeloma tumor. This phenomenon is called graft versus myeloma effect and implies that T cells in the graft are capable to destroy tumor cells.
Research on multiple myeloma performed in close collaboration with dr. H.Lokhorst and dr. T. Mutis (
Department of Hematology).
The research focuses on drug-resistance in MM and cellular and molecular identification of target antigens on myeloma tumor cells for future immuno-therapy (for more information contact dr. T.Mutis).
Drug-resistance in MM. Several proteins have been implicated in drug-resistance. Such proteins in general prevent drugs from entering cells or finding their biochemical targets. Many of these MDR factors may co-exist and co-operate in MM plasma cells. Agents that make tumor cells sensitive for drugs (chemosensitization) offer a new approach for the treatment of drug resistant disease.
Simvastatin is a well-known drug that lowers cholesterol levels. Recently we have found and described that inhibition of protein isoprenylation by lovastatin or simvastatin inhibits cell proliferation, induces cell death and chemosensitizes myeloma tumor cells and tumor cells from patients with B-cell non-Hodgkin lymphoma in vitro. The biochemical mechanisms underlying these processes are under investigation. The in vivo effectiveness of a combined simvastatin/chemotherapy treatment in multidrug resistant myeloma is tested in a phase II.
New treatment strategy for multiple myeloma by targeting Bcl-2 and the mevalonate pathway.Van de Donk NW, Bloem AC, van der Spek E and Lokhorst HM.
Curr Pharm Des, 2006,12:327-40.
A novel anti-apoptotic mechanism based on interference of Fas signaling by CD44 variant isoforms.Mielgo A, van Driel M, Bloem AC, Landmann L, Gunthert U.
Cell Death and Apoptosis, 2006, 13:465-77.
Immunoglobulin gene analysis in polyneuropathy associated with IgM monoclonal gammopathy.Eurelings M, Notermans NC, Lokhorst HM, van Kessel B, Jacobs BC, Wokke JH, Sahota SS, Bloem AC.
J Neuroimmunol. 2006, 175:152-9.
Dose-finding study of high-dose simvastatin combined with standard chemotherapy in patients with relapsed or refractory myeloma or lymphoma.Van der Spek E, Bloem AC, van de Donk NW, Bogers LH, van der Griend R, Kramer MH, de Weerdt O, Wittebol S, Lokhorst HM.Haematologica. 2006, 91:542-5.
A bioluminescence imaging based in vivo model for preclinical testing of novel cellular immunotherapy strategies to improve the graft-versus-myeloma effect.
Rozemuller H, van der Spek E, Bogers-Boer LH, Zwart MC, Verweij V, Emmelot M, Groen RW, Spaapen R, Bloem AC, Lokhorst HM, Mutis T, Martens AC.
Haematologica. 2008 Jul;93(7):1049-57.
High dose simvastatin does not reverse resistance to vincristine, adriamycin, and dexamethasone (VAD) in myeloma.
van der Spek E, Bloem AC, Sinnige HA, Lokhorst HM.
Haematologica. 2007 Dec;92(12):e130-1.
Rebuilding human leukocyte antigen class II-restricted minor histocompatibility antigen specificity in recall antigen-specific T cells by adoptive T cell receptor transfer: implications for adoptive immunotherapy.Spaapen R, van den Oudenalder K, Ivanov R, Bloem A, Lokhorst H, Mutis T.
Clin Cancer Res. 2007 Jul 1;13(13):4009-15.
Inhibition of the mevalonate pathway potentiates the effects of lenalidomide in myeloma.van der Spek E, Bloem AC, Lokhorst HM, van Kessel B, Bogers-Boer L, van de Donk NW.
Leuk Res. 2008 Jul 11.