Novel biologically based therapies for myeloma.
Recent advances in our understanding of the molecular regulation of myeloma cells suggest novel strategies for treating multiple myeloma. Some myeloma cells express a 69 kD variant of Ku86, a heterodimer subunit that is essential for double-stranded DNA break repair. Presence of the variant impairs DNA repair; therefore normal Ku86 in myeloma cells confers resistance to therapy and may represent a therapeutic target. The upregulation of NF-kappaB-dependent interleukin-6 (IL-6) transcription and secretion that occurs following adhesion of myeloma cells to bone marrow stromal cells (BMSCs) may serve as a potential therapeutic target, as IL-6 is a growth and survival factor for myeloma cells. Accordingly, proteasome inhibitors inhibit activation of NF-kappaB and induce apoptosis of myeloma cells; they also inhibit the NF-kappaB-dependent up-regulation of IL-6 in BMSCs and related paracrine growth of adherent tumor cells. Therapeutic strategies may also target the mitogen-activated protein kinase (MAPK) pathway that is thought to mediate the IL-6-induced proliferation of myeloma cells. Vascular endothelial growth factor (VEGF) is also upregulated by adhesion of myeloma cells to BMSCs and may serve as a growth and/or survival factor for myeloma cells; preliminary studies suggest that VEGF receptor inhibitors may block proliferation of tumor cells. Thalidomide was recently used successfully to treat myeloma in patients whose disease was refractory to conventional treatment. An enhanced understanding of the mechanisms of action of thalidomide may result in the development of analogues with enhanced potency and fewer side effects. The potential mechanisms of action of thalidomide are reviewed, including antiangiogenic effects; direct effects of thalidomide on the growth and survival of myeloma cells and BMSCs; modulation of adhesive interactions; and regulation of secretion and bioactivity of cytokines. Immune-based strategies for treating multiple myeloma are also reviewed. Therapeutic obstacles include excessive toxicity after allografting, contaminating tumor cells in autografts, and the persistence of minimal residual disease (MRD) after high-dose therapy followed by allogenic or autologous stem cell transplantation. Allografting can be performed safely in myeloma, donor lymphocyte infusions (DLI) may effectively treat relapsed myeloma post allografting; and use of CD4+ T cell-enriched DLI may reduce the risk of graft-versus-host disease. Treatment with autografting is frequently compromised by MRD in the autograft and in the patient post myeloablative therapy. Adenoviral purging prior to autotransplantation and in vivo and ex vivo stimulation of autoimmune cells are discussed as potential approaches to address these problems.
Anderson
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KC
Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D034961:Antigens, Nuclear; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D000072200:Ku Autoantigen; D008222:Lymphokines / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013792:Thalidomide / Q000627:therapeutic use*; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D015850:Interleukin-6; D008222:Lymphokines; D009687:Nuclear Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D013792:Thalidomide; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen