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Signalübermittlungsinhibitoren

Identifikation und Entwicklung, Tyrosinkinaseinhibitoren, Antiangiogenesefaktoren und Thalidomidanaloga, Proteasomeninhibition

Signal transmission inhibitors

Identification and development, tyrosine kinase inhibitors, antiangiogenesis factors and thalidomide analogues, proteasome inhibitors

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Der Onkologe Aims and scope

Zusammenfassung

Die Hemmung der Tyrosinkinasen durch intrazellulär wirksame kleine Moleküle ist ein innovatives Therapieprinzip bei der Behandlung maligner Erkrankungen. Imatinib, ein Inhibitor der bcr-abl-Tyrosinkinase, ist Therapiestandard bei der CML und ebenso bei der Behandlung von Phi+-ALL, GIST und der Eosinophilen-Leukämie wirksam. Neue Tyrosinkinaseinhibitoren wie Dasatinib oder Nilotinib können durch andere Bindungseigenschaften bei imatinibresistenter CML Anwendung finden. Multityrosinkinaseinhibitoren wie z. B. Sunitinib und Sorafenib zeigen unter anderem Wirksamkeit beim Nierenzellkarzinom. Durch Erlotinib und Gefitinib ist beim nichtkleinzelligen Bronchialkarzinom eine signifikante Verlängerung des Überlebens möglich. Auch für das metastasierte Pankreaskarzinom zeigt Erlotinib in der Kombination mit Gemcitabin einen Überlebensvorteil. Lapatinib kann in Kombination mit Capecitabin eine Trastuzumab-Resistenz bei HER2-positivem Mammakarzinom überwinden.

Thalidomid und Lenalidomid entfalten ihre Wirkung als immunomodulatorische Medikamente (IMiDs) über verschiedene Mechanismen. Sowohl in der Mono- als auch in der Kombinationstherapie sind sehr gute Remissionsraten und ein verbessertes Gesamtüberleben beim multiplen Myelom erreichbar. Bei Patienten mit einem myelodysplastischen 5q-Syndrom konnte Lenalidomid langfristige Remissionen mit Erreichen einer Transfusionsunabhängigkeit induzieren. Ein komplett neues Therapieprinzip ist die Inhibition des Proteasoms. Die Induktion der Apoptose von Lymphom- und Myelomzelllinien ist auch auf die klinische Anwendung übertragbar und zeigt sehr gute Ansprechraten sowohl in der Mono- als auch in der Kombinationstherapie bei ansonsten refraktärem multiplem Myelom.

Für die beschriebenen neuen Therapieprinzipien, die sog. „targeted therapy“, zeigt sich in der klinischen Anwendung ein Nebenwirkungsspektrum, das sich von den herkömmlicher Zytostatika unterscheidet.

Abstract

Intracellular inhibition of tyrosine kinases with small molecules is an innovative therapeutic principal for malignant diseases. Inhibition of the bcr-abl tyrosine kinase with imatinib is the therapeutic standard for chronic myeloid leukaemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Phi+-ALL). Because imatinib inhibits c-kit and the platelet-derived growth factor (PDGF) receptor as well, it also has a therapeutic potential in gastrointestinal stromal tumors (GIST) or hypereosinophilic syndrome. Newer tyrosine kinases like dasatinib and nilotinib can overcome imatinib resistance in CML. The spectrum of diseases for multityrosine kinase inhibitors includes renal cell carcinoma, which is sensitive to sunitinib and sorafenib. Erlotinib and gefitinib prolong the survival for patients with non-small cell lung cancer in second and third line therapy. In combination with gemcitabine, erlotinib achieves a low survival benefit. Lapatinib is able to overcome trastuzumab resistant HER2 positive breast cancer in combination with capecitabine.

Thalidomide and the immunomodulatory drug lenalidomide show different mechanisms of action. For multiple myeloma, prolonged overall survival can be achieved with single agent or combination therapy. In patients with myelodysplastic 5q syndrome, lenalidomide induces long-term remission and independence with respect to transfusions. Inhibition of the proteasome with bortezomib is another novel therapeutic principal, to be used essentially in multiple myeloma with good remission rates in cases of refractory disease.

The new methods involving targeted therapies are accompanied by a different spectrum of adverse reactions than those found with conventional chemotherapy.

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Literatur

  1. Anderson KC (2005) Lenalidomide and thalidomide: mechanisms of action--similarities and differences. Semin Hematol 42: S3–8

    Article  Google Scholar 

  2. Atzpodien J, Kirchner H, Illiger HJ et al. (2001) IL-2 in combination with IFN- alpha and 5-FU versus tamoxifen in metastatic renal cell carcinoma: long-term results of a controlled randomized clinical trial. Br J Cancer 85: 1130–1136

    Article  PubMed  Google Scholar 

  3. Berenson JR, Jagannath S, Barlogie B et al. (2005) Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma. Cancer 104: 2141–2148

    Article  PubMed  Google Scholar 

  4. Cameron D et al. (2006) Lapatinib in combination with capecitabine demonstrates superior efficacy compared with capecitabine alone in ErbB2+ advanced or metastatic breast cancer (MBC) patients (pts) pretreated with chemotherapy and trastuzumab. Ann Oncol 17: 63, Abstract 41

    Google Scholar 

  5. 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: 1201–1214

    Article  PubMed  Google Scholar 

  6. Cusack JC Jr, Liu R, Houston M et al. (2001) Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res 61: 3535–3540

    PubMed  Google Scholar 

  7. Daley GQ, Van Etten RA, Baltimore D (1990) Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247: 824–830

    Article  PubMed  Google Scholar 

  8. Demetri GD, van Oosterom AT, Garrett CR et al. (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368: 1329–1338

    PubMed  Google Scholar 

  9. 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: 472–480

    Article  PubMed  Google Scholar 

  10. Dimopoulos MA, Spencer A, Attal M et al. (2005) Study of Lenalidomide Plus Dexamethasone Versus Dexamethasone Alone in Relapsed or Refractory Multiple Myeloma (MM): Results of a Phase 3 Study (MM-010). Blood 106: 6

    Article  Google Scholar 

  11. Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ et al. (2006) Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial. Cancer 107: 345–351

    Article  PubMed  Google Scholar 

  12. Druker B, Guilhot F, O’Brien S et al. (2006) Long-term benefits of imatinib (IM) for patients newly diagnosed with chronic myelogenous leukemia in chronic phase (CML-CP): The 5-year update from the IRIS study. J Clin Oncol 24: 6506, ASCO Annual Meeting

    Google Scholar 

  13. Druker BJ, Sawyers CL, Kantarjian H et al. (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344: 1038–1042

    Article  PubMed  Google Scholar 

  14. Druker BJ, Tamura S, Buchdunger E et al. (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2: 561–566

    Article  PubMed  Google Scholar 

  15. Escudier BC, Szczylik C, Eisen T et al. (2005) Randomized Phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43–9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol 23: LBA4510, ASCO Annual Meeting

    Google Scholar 

  16. Facon T, Mary J, Harousseau J et al. (2006) Superiority of melphalan-prednisone (MP) + thalidomide (THAL) over MP and autologous stem cell transplantation in the treatment of newly diagnosed elderly patients with multiple myeloma. J Clin Oncol 24: 1, ASCO Annual Meeting

    Article  PubMed  Google Scholar 

  17. 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) [corrected]. J Clin Oncol 21: 2237–2246

    Article  PubMed  Google Scholar 

  18. Fyfe GA, Fisher RI, Rosenberg SA et al. (1996) Long-term response data for 255 patients with metastatic renal cell carcinoma treated with high-dose recombinant interleukin-2 therapy. J Clin Oncol 14: 2410–2411

    PubMed  Google Scholar 

  19. Giaccone G, Herbst RS, Manegold C et al. (2004) Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial – INTACT 1. J Clin Oncol 22: 777–784

    Article  PubMed  Google Scholar 

  20. Harousseau JL, Attal M, Coiteux V et al. (2005) Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: Premilinary results of an IFM phase II study. Journal of Clinical Oncology 23: 598S–598S

    Google Scholar 

  21. Hideshima T, Mitsiades C, Akiyama M et al. (2003) Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 101: 1530–1534

    Article  PubMed  Google Scholar 

  22. Kantarjian H, Giles F, Wunderle L et al. (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354: 2542–2551

    Article  PubMed  Google Scholar 

  23. 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: 2149–2158

    Article  PubMed  Google Scholar 

  24. Kumar S, Gertz MA, Dispenzieri A et al. (2003) Response rate, durability of response, and survival after thalidomide therapy for relapsed multiple myeloma. Mayo Clin Proc 78: 34–39

    PubMed  Google Scholar 

  25. Lee KH, Lee JH, Choi SJ et al. (2005) Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia 19: 1509–1516

    Article  PubMed  Google Scholar 

  26. Lee S, Kim YJ, Min CK et al. (2005) The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 105: 3449–3457

    Article  PubMed  Google Scholar 

  27. List A, Kurtin S, Roe DJ et al. (2005) Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 352: 549–557

    Article  PubMed  Google Scholar 

  28. List AF, Dewald G, Bennett J et al. (2005) Hematologic and Cytogenetic (CTG) Response to Lenalidomide (CC-5013) in Patients with Transfusion-Dependent (TD) Myelodysplastic Syndrome (MDS) and Chromosome 5q31.1 Deletion: Results of the Multicenter MDS-003 Study. J Clin Oncol 23: 5, ASCO Annual Meeting

    PubMed  Google Scholar 

  29. Mateos MV, Hernandez JM, Hernandez MT et al. (2006) Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood 108: 2165–2172

    Article  PubMed  Google Scholar 

  30. Moore MJ, Goldstein D, Hamm J et al. (2005) Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG]. J Clin Oncol 23: 1

    PubMed  Google Scholar 

  31. Motzer RJ, Hutson TE, Tomczak P et al. (2006) Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alfa (IFN-α) as first-line systemic therapy for patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 24: LBA3, ASCO Annual Meeting

    Article  Google Scholar 

  32. Motzer RJ, Rini BI, Bukowski RM et al. (2006) Sunitinib in patients with metastatic renal cell carcinoma. Jama 295: 2516–2524

    Article  PubMed  Google Scholar 

  33. Naoe T and Kiyoi H (2004) Normal and oncogenic FLT3. Cell Mol Life Sci 61: 2932–2938

    Article  PubMed  Google Scholar 

  34. 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: 994–1004

    Article  PubMed  Google Scholar 

  35. O’Connor OA (2005) Marked clinical activity of the proteasome inhibitor bortezomib in patients with follicular and mantle-cell lymphoma. Clinical Lymphoma & Myeloma 6: 191–199

    Google Scholar 

  36. O’Hare T, Walters DK, Stoffregen EP et al. (2005) In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 65: 4500–4505

    Article  PubMed  Google Scholar 

  37. Oakervee HE, Popat R, Curry N et al. (2005) PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol 129: 755–762

    Article  PubMed  Google Scholar 

  38. Ottmann OG, Wassmann B (2005) Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Hematology (Am Soc Hematol Educ Program) 118–122

  39. Palumbo A, Bertola A, Falco P et al. (2004) Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma. Hematol J 5: 318–324

    Article  PubMed  Google Scholar 

  40. Rajkumar SV (2004) Thalidomide: tragic past and promising future. Mayo Clin Proc 79: 899–903

    PubMed  Google Scholar 

  41. Rajkumar SV, Hayman SR, Lacy MQ et al. (2005) Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 106: 4050–4053

    Article  PubMed  Google Scholar 

  42. Ravaud A, Gardner J, Hawkins R et al. (2006) Efficacy of lapatinib in patients with high tumor EGFR expression: Results of a phase III trial in advanced renal cell carcinoma (RCC). J Clin Oncol 24: 4502, ASCO Annual Meeting

    Google Scholar 

  43. Richardson P, Schlossman R, Jagannath S et al. (2004) Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity. Mayo Clin Proc 79: 875–882

    PubMed  Google Scholar 

  44. Richardson PG, Barlogie B, Berenson J et al. (2006) Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma: final time-to-event results from the SUMMIT trial. Cancer 106: 1316–1319

    Article  PubMed  Google Scholar 

  45. Richardson PG, Schlossman RL, Weller E et al. (2002) Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100: 3063–3067

    Article  PubMed  Google Scholar 

  46. Richardson PG, Sonneveld P, Schuster MW et al. (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352: 2487–2498

    Article  PubMed  Google Scholar 

  47. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353: 123–132

    Article  PubMed  Google Scholar 

  48. Spector NL, Blackwell K, Hurley J et al. (2006) EGF103009, a phase II trial of lapatinib monotherapy in patients with relapsed/refractory inflammatory breast cancer (IBC): Clinical activity and biologic predictors of response. J Clin Oncol 24, ASCO Annual Meeting

  49. Talpaz M, Shah NP, Kantarjian H et al. (2006) Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354: 2531–2541

    Article  PubMed  Google Scholar 

  50. Thatcher N, Chang A, Parikh P et al. (2005) Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366: 1527–1537

    Article  PubMed  Google Scholar 

  51. Ullrich A and Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61: 203–212

    Article  PubMed  Google Scholar 

  52. Weber DM, Chen C, Niesvizky R et al. (2006) Lenalidomide plus high-dose dexamethasone provides improved overall survival compared to high-dose dexamethasone alone for relapsed or refractory multiple myeloma (MM): Results of a North American phase III study (MM-009). J Clin Oncol 24: 7521, ASCO Annual Meeting

    Article  Google Scholar 

  53. Zalcberg JR, Verweij J, Casali PG et al. (2005) Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 41: 1751–1757

    Article  PubMed  Google Scholar 

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Interessenkonflikt

Es besteht kein Interessenkonflikt bei PD Dr. F. Weissinger. 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. Die Präsentation des Themas ist unabhängig und die Darstellung der Inhalte produktneutral.

Herr Dr. D. Fabbro ist Mitarbeiter von Novartis Pharma.

Herr Prof. H. Einsele gibt Vortragstätigkeiten für Ortho Biotec und Calgem an.

Trotz des möglichen Interessenkonflikts ist der Beitrag unabhängig und produktneutral.

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Authors and Affiliations

  1. Medizinische Klinik und Poliklinik II, Julius-Maximilians-Universität Würzburg, Klinikstraße 6–8, 97070, Würzburg, Deutschland

    F. Weissinger & H. Einsele

  2. Novartis Pharma, Basel, Deutschland

    D. Fabbro

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  1. F. Weissinger
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Die Autoren F. Weissinger und D. Fabbro sind gleichberechtigte Erstautoren.

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Weissinger, F., Fabbro, D. & Einsele, H. Signalübermittlungsinhibitoren. Onkologe 13, 213–226 (2007). https://doi.org/10.1007/s00761-006-1169-5

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