Der Internist

, Volume 46, Issue 8, pp 835–846 | Cite as

Grundlagen der molekularen Diagnostik und Therapie maligner Tumoren

Schwerpunkt: Molekulare Ziele der Therapie


Neue Einblicke in Tumorpathogenese und Mechanismen der Therapieresistenz maligner Tumoren sind rationale Basis für die Entwicklung neuer Therapieansätze, die gezielt genetische Defekte und deregulierte Signalwege in malignen Tumoren nutzen. Im Gegensatz zu konventionellen Therapien ermöglicht hierbei der Einsatz niedermolekularer Inhibitoren oder monoklonaler Antikörper eine wesentlich selektivere, „gezielte“ Therapie solcher Tumoren, die den entsprechenden Gendefekt oder ein entsprechendes Genexpressionsprofil tragen. Molekulare Therapiemodalitäten erfordern daher auch den klinischen Einsatz neuer genetischer Diagnostik zur Identifikation der Patienten, die von den neuen, gezielten Therapeutika profitieren können.


Molekulare Therapie Signalwegtherapie Pharmakogenetik Molekulare Diagnostik Maligne Tumoren Onkogene 

Basics of molecular diagnostics and therapy of malignant tumors


Recent insights in disease pathogenesis and mechanisms of resistance to therapy of malignant tumors provide a rational basis for the development of novel therapeutic strategies that target genetic defects and deregulated signaling events in malignant tumors. In contrast to conventional therapeutics, small molecule inhibitors or monoclonal antibodies allow for a far more selective, targeted therapy of tumors that carry a corresponding target structure or gene expression profile. Molecular therapeutics therefore necessitate clinical deployment of genetic diagnostics for the identification of those patients who have a chance to benefit from these novel targeted therapies.


Molecular therapy Targeted therapy Pharmacogenetics Malignant tumors Molecular diagnostics Oncogene 



Der korrespondierende Autor versichert, dass keine Verbindungen mit einer Firma, deren Produkt in dem Artikel genannt ist, oder einer Firma, die ein Konkurrenzprodukt vertreibt, bestehen.


  1. 1.
    Herbst RS, Fukuoka M, Baselga J (2004) Gefitinib — a novel targeted approach to treating cancer. Nat Rev Cancer 4: 956–965PubMedGoogle Scholar
  2. 2.
    Jonkers J, Berns A (2004) Oncogene addiction: sometimes a temporary slavery. Cancer Cell 6: 535–538PubMedGoogle Scholar
  3. 3.
    le Coutre P, Mologni L, Cleris L et al. (1999) In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. J Natl Cancer Inst 91: 163–168PubMedGoogle Scholar
  4. 4.
    Twombly R (2005) FDA Oncology Committee debates Iressa’s status following negative trial results. J Natl Cancer Inst 97: 473PubMedGoogle Scholar
  5. 5.
    Lynch TJ, Bell DW, Sordella R et al. (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350: 2129–2139CrossRefPubMedGoogle Scholar
  6. 6.
    Paez JG, Janne PA, Lee JC et al. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500CrossRefPubMedGoogle Scholar
  7. 7.
    Pao W, Miller VA (2005) Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 23: 2556–2568PubMedGoogle Scholar
  8. 8.
    Druker BJ (2004) Imatinib as a paradigm of targeted therapies. Adv Cancer Res 91: 1–30PubMedGoogle Scholar
  9. 9.
    Blay JY, Bonvalot S, Casali P et al. (2005) Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20–21 March 2004, under the auspices of ESMO. Ann Oncol 16: 566–578PubMedGoogle Scholar
  10. 10.
    Heinrich MC, Corless CL, Demetri GD et al. (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21: 4342–4349CrossRefPubMedGoogle Scholar
  11. 11.
    Mathas S, Rickers A, Bommert K et al. (2000) Anti-CD20- and B-cell receptor-mediated apoptosis: evidence for shared intracellular signaling pathways. Cancer Res 60: 7170–7176PubMedGoogle Scholar
  12. 12.
    Mounier N, Briere J, Gisselbrecht C et al. (2003) Rituximab plus CHOP (R-CHOP) overcomes bcl-2-associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood 101: 4279–4284PubMedGoogle Scholar
  13. 13.
    Jilani I, O’Brien S, Manshuri T et al. (2003) Transient down-modulation of CD20 by rituximab in patients with chronic lymphocytic leukemia. Blood 102: 3514–3520PubMedGoogle Scholar
  14. 14.
    Lin TS, Lucas MS, Byrd JC (2003) Rituximab in B-cell chronic lymphocytic leukemia. Semin Oncol 30: 483–492PubMedGoogle Scholar
  15. 15.
    Coiffier B, Lepage E, Briere J et al. (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346: 235–242PubMedGoogle Scholar
  16. 16.
    Lenz G, Dreyling M, Hoster E et al. (2005) Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 23: 1984–1992PubMedGoogle Scholar
  17. 17.
    Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23: 1011–1027PubMedGoogle Scholar
  18. 18.
    Belka C, Jendrossek V, Pruschy M et al. (2004) Apoptosis-modulating agents in combination with radiotherapy-current status and outlook. Int J Radiat Oncol Biol Phys 58: 542–554PubMedGoogle Scholar
  19. 19.
    Daniel PT, Wieder T, Sturm I, Schulze-Osthoff K (2001) The kiss of death: promises and failures of death receptors and ligands in cancer therapy. Leukemia 15: 1022–1032PubMedGoogle Scholar
  20. 20.
    von Haefen C, Gillissen B, Hemmati PG et al. (2004) Multidomain Bcl-2 homolog Bax but not Bak mediates synergistic induction of apoptosis by TRAIL and 5-FU through the mitochondrial apoptosis pathway. Oncogene 23: 8320–8332PubMedGoogle Scholar
  21. 21.
    Daniel PT, Schulze-Osthoff K, Belka C, Güner D (2003) Guardians of cell death: the Bcl-2 family proteins. Essays Biochem 39: 73–88PubMedGoogle Scholar
  22. 22.
    Baell JB, Huang DC (2002) Prospects for targeting the Bcl-2 family of proteins to develop novel cytotoxic drugs. Biochem Pharmacol 64: 851–863PubMedGoogle Scholar
  23. 23.
    Fulda S, Wick W, Weller M, Debatin KM (2002) Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 8: 808–815PubMedGoogle Scholar
  24. 24.
    Wang Z, Cuddy M, Samuel T et al. (2004) Cellular, biochemical, and genetic analysis of mechanism of small molecule IAP inhibitors. J Biol Chem 279: 48168–48176PubMedGoogle Scholar
  25. 25.
    Hasenjager A, Gillissen B, Muller A et al. (2004) Smac induces cytochrome c release and apoptosis independently from Bax/Bcl-x(L) in a strictly caspase-3-dependent manner in human carcinoma cells. Oncogene 23: 4523–4535PubMedGoogle Scholar
  26. 26.
    Sturm I, Bosanquet AG, Hermann S et al. (2003) Mutation of p53 and consecutive selective drug resistance in B-CLL occurs as a consequence of prior DNA-damaging chemotherapy. Cell Death Differ 10: 477–484PubMedGoogle Scholar
  27. 27.
    Bargou RC, Emmerich F, Krappmann D et al. (1997) Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin’s disease tumor cells. J Clin Invest 100: 2961–2969PubMedGoogle Scholar
  28. 28.
    O’Brien SG, Guilhot F, Larson RA et al. (2003) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348: 994–1004PubMedGoogle Scholar
  29. 29.
    Muller MC, Gattermann N, Lahaye T et al. (2003) Dynamics of BCR-ABL mRNA expression in first-line therapy of chronic myelogenous leukemia patients with imatinib or interferon alpha/ara-C. Leukemia 17: 2392–2400PubMedGoogle Scholar
  30. 30.
    Gambacorti-Passerini CB, Gunby RH et al. (2003) Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol 4: 75–85PubMedGoogle Scholar
  31. 31.
    Shah NP, Tran C, Lee FY et al. (2004) Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305: 399–401PubMedGoogle Scholar
  32. 32.
    O’Hare T, Walters DK, Deininger MW, Druker BJ (2005) AMN107: tightening the grip of imatinib. Cancer Cell 7: 117–119PubMedGoogle Scholar
  33. 33.
    Bruggemann M, Pott C, Ritgen M, Kneba M (2004) Significance of minimal residual disease in lymphoid malignancies. Acta Haematol 112: 111–119PubMedGoogle Scholar
  34. 34.
    Guener D, Sturm I, Hemmati P et al. (2003) Multigene analysis of Rb pathway and apoptosis control in esophageal squamous cell carcinoma identifies patients with good prognosis. Int J Cancer 103: 445–454PubMedGoogle Scholar
  35. 35.
    Güner D, Belka C, Daniel PT (2003) Disruption of cell death signaling in cancer: impact on disease prognosis and response to therapy. Curr Med Chem Anti-Canc Agents 3: 319–326Google Scholar
  36. 36.
    Hamblin TJ, Davis Z, Gardiner A et. al. (1999) Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94: 1848–1854PubMedGoogle Scholar
  37. 37.
    Klein U, Tu Y, Stolovitzky GA et al. (2001) Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 194: 1625–1638PubMedGoogle Scholar
  38. 38.
    Dave SS, Wright G, Tan B et al. (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351: 2159–2169CrossRefPubMedGoogle Scholar

Copyright information

© Springer Medizin Verlag 2005

Authors and Affiliations

  1. 1.Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie,Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Humboldt UniversitätBerlin
  2. 2.Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie Charité-Universitätsmedizin Berlin, Campus Buch, Humboldt UniversitätBerlin
  3. 3.Max Delbrück Centrum für Molukulare MedizinBerlin
  4. 4.Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie,Charité-Universitätsmedizin Berlin, Campus Virchow KlinikumBerlin

Personalised recommendations