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Molekularbiologie maligner Lymphome

Neue Ziele, neue Therapien?

Molecular biology of malignant lymphoma

New targets, new therapies?

  • Leitthema
  • Published:
Der Onkologe Aims and scope

Zusammenfassung

Hintergrund

Die Behandlung maligner Lymphome ist im Umbruch. Zahlreiche neue Wirkstoffe, die spezifische Signalwege inhibieren, sind momentan in der klinischen Testung bzw. bereits für die Therapie einzelner Subtypen zugelassen.

Material und Methoden

Diese Arbeit basiert auf einer systematischen Literaturrecherche in der Datenbank Pubmed zum Thema „Molekulare Therapien bei aggressiven Lymphomen“.

Ergebnisse

Der Brutons-Tyrosinkinase-Inhibitor Ibrutinib ist für die Behandlung der chronisch-lymphatischen Leukämie und des Mantelzelllymphoms zugelassen, während der PI3K-Inhibitor Idelalisib für die Behandlung der chronisch-lymphatischen Leukämie und des follikulären Lymphoms zur Verfügung steht. Die bislang publizierten klinischen Daten legen jedoch nahe, dass nicht alle Patienten gleich gut auf die Behandlung mit diesen spezifischen Inhibitoren ansprechen und weiterhin, dass diese Wirkstoffe aller Wahrscheinlichkeit nach nicht kurativ sind. Zuletzt sind diese Substanzen auch nicht bei allen malignen Lymphomsubtypen wirksam. Aus diesem Grund ist ein besseres Verständnis der molekularen Pathogenese maligner Lymphome unabdingbar, um einerseits das Therapieansprechen auf momentan verfügbare Inhibitoren besser zu verstehen und andererseits neue therapeutische Zielstrukturen zu identifizieren, damit die Prognose betroffener Patienten weiter verbessert werden kann.

Abstract

Background

The therapy of malignant lymphoma is currently in a state of flux. Various novel compounds that target specific signaling pathways are currently being tested in clinical trials, while some of the novel inhibitors have just been approved for the treatment of certain lymphoma subtypes.

Material and methods

This study is based on a systematic literature search in PubMed on the topic of molecular therapies for aggressive lymphoma.

Results

The Bruton’s tyrosine kinase inhibitor ibrutinib has been approved for the therapy of chronic lymphocytic leukemia and mantle cell lymphoma, whereas the PI3K inhibitor idelalisib can be utilized in chronic lymphocytic leukemia and follicular lymphoma patients. However, the currently available data suggest that not all patients respond equally to these agents and furthermore it seems that these compounds are most likely not curative. Finally, these compounds are not equally effective in all lymphoma subtypes. Thus, a significantly better understanding of the molecular pathogenesis of these entities is critically important to understand the responses observed in treated patients and furthermore to identify novel targets for future therapies in order to improve the prognosis for affected patients.

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Literatur

  1. Advani RH, Buggy JJ, Sharman JP et al (2013) Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 31:88–94

    Article  CAS  PubMed  Google Scholar 

  2. Alizadeh AA, Eisen MB, Davis RE et al (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503–511

    Article  CAS  PubMed  Google Scholar 

  3. Chen L, Monti S, Juszczynski P et al (2013) SYK inhibition modulates distinct PI3K/AKT- dependent survival pathways and cholesterol biosynthesis in diffuse large B cell lymphomas. Cancer Cell 23:826–838

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Compagno M, Lim WK, Grunn A et al (2009) Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature 459:717–721

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Davids MS, Roberts AW, Anderson MA (2012) The BCL-2-Specific BH3-Mimetic ABT-199 (GDC-0199) Is active and well-tolerated in patients with relapsed non-hodgkin lymphoma: interim results of a phase I study [abstract]. Blood 120

  6. Davis RE, Brown KD, Siebenlist U et al (2001) Constitutive nuclear factor kappaB activity Is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 194:1861–1874

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Davis RE, Ngo VN, Lenz G et al (2010) Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463:88–92

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Dreyling M, Hiddemann W (2009) Current treatment standards and emerging strategies in mantle cell lymphoma. Hematol Am Soc Hematol Educ Program 542–551

  9. Dunleavy K, Pittaluga S, Czuczman MS et al (2009) Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood 113:6069–6076

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Field-Smith A, Morgan GJ, Davies FE (2006) Bortezomib (Velcadetrade mark) in the treatment of multiple myeloma. Ther Clin Risk Manag 2:271–279

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Gisselbrecht C, Glass B, Mounier N et al (2010) Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 28:4184–4190

    Article  PubMed Central  PubMed  Google Scholar 

  12. Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL et al (2011) Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer 117:5058–5066

    Article  CAS  PubMed  Google Scholar 

  13. Honigberg LA, Smith AM, Sirisawad M et al (2010) The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A 107:13075–13080

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Kahl BS, Spurgeon SE, Furman RR et al (2014) A phase 1 study of the PI3Kdelta inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood 123:3398–3405

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Kato M, Sanada M, Kato I et al (2009) Frequent inactivation of A20 in B-cell lymphomas. Nature 459:712–716

    Article  CAS  PubMed  Google Scholar 

  16. Lenz G, Davis RE, Ngo VN et al (2008) Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319:1676–1679

    Article  CAS  PubMed  Google Scholar 

  17. Lenz G, Wright G, Dave SS et al (2008) Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 359:2313–2323

    Article  CAS  PubMed  Google Scholar 

  18. Leonard JP, Lacasce AS, Smith MR et al (2012) Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 119:4597–4607

    Article  CAS  PubMed  Google Scholar 

  19. Mussetti A, Kumar A, Dahi PB et al (2014) Lifting the mantle: Unveiling new treatment approaches in relapsed or refractory mantle cell lymphoma. Blood Rev

  20. Ngo VN, Young RM, Schmitz R et al (2011) Oncogenically active MYD88 mutations in human lymphoma. Nature 470:115–119

    Article  CAS  PubMed  Google Scholar 

  21. Nogai H, Dorken B, Lenz G (2011) Pathogenesis of Non-Hodgkin’s Lymphoma. J Clin Oncol 29:1803–1811

    Article  CAS  PubMed  Google Scholar 

  22. Nowakowski GS, Laplant B, Macon WR et al (2015) Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell lymphoma: a phase II study. J Clin Oncol 33:251–257

    Article  CAS  PubMed  Google Scholar 

  23. Pfeifer M, Grau M, Lenze D et al (2013) PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A 110(30):12420–12425

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Pfeifer M, Zheng B, Erdmann T et al (2015) Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia 29(7):1578–1586

    Article  CAS  PubMed  Google Scholar 

  25. Rahal R, Frick M, Romero R et al (2014) Pharmacological and genomic profiling identifies NF-kappaB-targeted treatment strategies for mantle cell lymphoma. Nat Med 20:87–92

    Article  CAS  PubMed  Google Scholar 

  26. Rizzatti EG, Falcao RP, Panepucci RA et al (2005) Gene expression profiling of mantle cell lymphoma cells reveals aberrant expression of genes from the PI3K-AKT, WNT and TGFbeta signalling pathways. Br J Haematol 130:516–526

    Article  CAS  PubMed  Google Scholar 

  27. Rosenwald A, Wright G, Chan WC et al (2002) The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346:1937–1947

    Article  PubMed  Google Scholar 

  28. Rosenwald A, Wright G, Leroy K et al (2003) Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 198:851–862

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Savage KJ, Monti S, Kutok JL et al (2003) The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102:3871–3879

    Article  CAS  PubMed  Google Scholar 

  30. Smith SM, Van Besien K, Karrison T et al (2010) Temsirolimus has activity in non-mantle cell non-Hodgkin’s lymphoma subtypes: the University of Chicago phase II consortium. J Clin Oncol 28:4740–4746

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Wang ML, Rule S, Martin P et al (2013) Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 369:507–516

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Wilson WH, Young RM, Schmitz R et al (2015) Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med 21:922–992

    Article  CAS  PubMed  Google Scholar 

  33. Witzig TE, Reeder CB, Laplant BR et al (2011) A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia 25:341–347

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Yang Y, Shaffer AL III, Emre NC et al (2012) Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell 21:723–737

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Einhaltung ethischer Richtlinien

Interessenkonflikt. G. Lenz weist auf folgende Beziehungen hin: wissenschaftliche Advisory Boards: Celgene, Janssen, Gilead, Roche, Bayer, Pfizer. Finanzielle Unterstützung präklinischer wissenschaftlicher Projekte: Genentech, Janssen. T. Erdmann gibt an, dass kein Interessenkonflikt besteht.

Der Beitrag enthält keine Studien an Menschen oder Tieren.

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Authors and Affiliations

  1. Translationale Onkologie, Medizinische Klinik A, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude D3, 48149, Münster, Deutschland

    T. Erdmann &  G. Lenz

  2. Excellenzcluster EXC1003, Cells in Motion, Münster, Deutschland

    T. Erdmann &  G. Lenz

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  1. T. Erdmann
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  2. G. Lenz
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Correspondence to G. Lenz.

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Erdmann, T., Lenz, G. Molekularbiologie maligner Lymphome. Onkologe 21, 905–912 (2015). https://doi.org/10.1007/s00761-015-2963-8

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  • DOI: https://doi.org/10.1007/s00761-015-2963-8

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