Der Internist

, Volume 46, Issue 8, pp 847–860

Molekulare Zielstrukturen in der Onkologie

Schwerpunkt: Molekulare Ziele der Therapie

Zusammenfassung

Die Aufklärung der molekularen Pathogenese maligner Erkrankungen hat in den letzten Jahren deutliche Fortschritte erfahren. Insbesondere wurden molekulare und zelluläre Zielstrukturen identifiziert, die als Angriffspunkte für therapeutische Interventionen („targeted therapies“) dienen können.

Hierzu gehören Komponenten von zellulären Signalketten, wie z.B. Proteintyrosinkinasen (PTK), die durch Mutationen, Translokationen oder Überexpression aktiviert werden. Kleinmolekulare PTK-Inhibitoren, die als kompetitive ATP-Antagonisten fungieren, haben bei der CML, gastrointestinalen Stromatumoren sowie Bronchialkarzinomen bereits eine eindrückliche klinische Aktivität gezeigt. Eine weitere Gruppe von zellulären Zielstrukturen stellen tumorselektive Oberflächenproteine dar, die Angriffspunkte für monoklonale Antikörper darstellen. Dieses Therapiekonzept hat vor allem in der Lymphomtherapie breiten Einsatz gefunden.

Die Identifizierung von molekularen Zielstrukturen, die kritisch für den malignen Phänotyp sind, führt in eine neue Ära integrierter molekularer Diagnostik und Therapie in der Onkologie.

Schlüsselwörter

Onkologische Therapie Monoklonale Antikörper Proteintyrosinkinasen Molekulare Zielstrukturen Hämatologische Neoplasien 

Molecular target structures in oncology

Abstract

Substantial progress has been made in recent years in understanding the molecular pathogenesis of malignant disorders, especially in identification of molecular targets for therapeutic interventions (“targeted therapies”).

An important group of therapeutical targets are signaling cascades, e.g. protein tyrosine kinases (PTK) that are activated by mutations, translocations or overexpression. Small molecule inhibitors that compete with ATP and inhibit kinase activity have produced clinical impressive responses in chronic myeloid leukemia, gastrointestinal stroma tumors and non-small cell lung cancer. Another group of cellular targets is represented by tumor-selective cell surface proteins that can serve as target structures for antibodies. Therapeutical concepts using monoclonal antibodies have substantially improved response rates in patients with malignant lymphomas and are currently evaluated in other types of cancer.

The definition of molecular target structures critical for the malignant phenotype is driving a new era of integrated diagnostics and therapeutics in the field of oncology.

Keywords

Oncological therapy Monoclonal antibodies Protein tyrosine kinases Molecular target structures Hematological neoplasias 

Literatur

  1. 1.
    Bagrintseva K, Schwab R, Kohl TM et al. (2004) Mutations in the tyrosine kinase domain of FLT3 define a new molecular mechanism of acquired drug resistance to PTK inhibitors in FLT3-ITD-transformed hematopoietic cells. Blood 103: 2266–2275CrossRefPubMedGoogle Scholar
  2. 2.
    Baselga J, Albanell J (2002) Epithelial growth factor receptor interacting agents. Hematol Oncol Clin North Am 16: 1041–1063CrossRefPubMedGoogle Scholar
  3. 3.
    Berger U, Engelich G, Reiter A, Hochhaus A, Hehlmann R (2004) Imatinib and beyond — the new CML study IV. A randomized controlled comparison of imatinib vs imatinib/interferon-alpha vs imatinib/low-dose AraC vs imatinib after interferon-alpha failure in newly diagnosed chronic phase chronic myeloid leukemia. Ann Hematol 83: 258–264CrossRefPubMedGoogle Scholar
  4. 4.
    Bernstein ID (2002) CD33 as a target for selective ablation of acute myeloid leukemia. Clin Lymphoma 2: S9–11PubMedGoogle Scholar
  5. 5.
    Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411: 355–365CrossRefPubMedGoogle Scholar
  6. 6.
    Branford S, Rudzki Z, Parkinson I et al. (2004) Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations. Blood 104: 2926–2932CrossRefPubMedGoogle Scholar
  7. 7.
    Bross PF, Beitz J, Chen G et al. (2001) Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 7: 1490–1496PubMedGoogle Scholar
  8. 8.
    Buske C, Dreyling M, Unterhalt M, Hiddemann W (2004) [Monoclonal antibody treatment of malignant lymphoma]. Internist 45: 1370–1377CrossRefPubMedGoogle Scholar
  9. 9.
    Cobleigh MA, Vogel CL, Tripathy D et al. (1999) Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17: 2639–2648PubMedGoogle Scholar
  10. 10.
    Cools J, DeAngelo DJ, Gotlib J et al. (2003) A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 348: 1201–1214CrossRefPubMedGoogle Scholar
  11. 11.
    Corless CL, Fletcher JA, Heinrich MC (2004) Biology of gastrointestinal stromal tumors. J Clin Oncol 22: 3813–3825CrossRefPubMedGoogle Scholar
  12. 12.
    Cunningham D, Humblet Y, Siena S et al. (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351: 337–345PubMedGoogle Scholar
  13. 13.
    Demetri GD, von Mehren M, Blanke CD et al. (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347: 472–480CrossRefPubMedGoogle Scholar
  14. 14.
    Fenaux P, Chomienne C, Degos L (2001) All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia. Semin Hematol 38: 13–25CrossRefGoogle Scholar
  15. 15.
    Fukuoka M, Yano S, Giaccone G et al. (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial). J Clin Oncol 21: 2237–2246CrossRefPubMedGoogle Scholar
  16. 16.
    Glennie MJ, van de Winkel JG (2003) Renaissance of cancer therapeutic antibodies. Drug Discov Today 8: 503–510CrossRefPubMedGoogle Scholar
  17. 17.
    Hurwitz H, Fehrenbacher L, Novotny W et al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350: 2335–2342PubMedGoogle Scholar
  18. 18.
    Joensuu H, Fletcher C, Dimitrijevic S, Silberman S, Roberts P, Demetri G (2002) Management of malignant gastrointestinal stromal tumours. Lancet Oncol 3: 655–664CrossRefPubMedGoogle Scholar
  19. 19.
    Kobayashi S, Boggon TJ, Dayaram T et al. (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352: 786–792CrossRefPubMedGoogle Scholar
  20. 20.
    Kris MG, Natale RB, Herbst RS et al. (2003) Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290: 2149–2158CrossRefPubMedGoogle Scholar
  21. 21.
    Melnick A, Licht JD (1999) Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93: 3167–3215PubMedGoogle Scholar
  22. 22.
    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
  23. 23.
    Osborne CK, Zhao H, Fuqua SA (2000) Selective estrogen receptor modulators: structure, function, and clinical use. J Clin Oncol 18: 3172–3186PubMedGoogle Scholar
  24. 24.
    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
  25. 25.
    Pao W, Wang TY, Riely GJ et al. (2005) KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2: e17. Epub 2005 Jan 25CrossRefPubMedGoogle Scholar
  26. 26.
    Slamon DJ, Leyland-Jones B, Shak S et al. (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: 783–792CrossRefPubMedGoogle Scholar
  27. 27.
    Spiekermann K, Dirschinger RJ, Schwab R et al. (2003) The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth arrest and apoptosis in AML-derived cell lines expressing a constitutively activated FLT3. Blood 101: 1494–1504CrossRefPubMedGoogle Scholar
  28. 28.
    Stern M, Herrmann R (2005) Overview of monoclonal antibodies in cancer therapy: present and promise. Crit Rev Oncol Hematol 54: 11–29PubMedGoogle Scholar
  29. 29.
    Stirewalt DL, Radich JP (2003) The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer 3: 650–665CrossRefPubMedGoogle Scholar
  30. 30.
    Stone RM, DeAngelo DJ, Klimek V et al. (2005) Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 105: 54–60CrossRefPubMedGoogle Scholar

Copyright information

© Springer Medizin Verlag 2005

Authors and Affiliations

  1. 1.Klinische Kooperationsgruppe „Leukämie“, Medizinische Klinik III Klinikum Großhadern der Ludwig-Maximilians-Universität München und GSF-HämatologikumMünchen

Personalised recommendations