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01.01.2007 | Leitthema

Molekulare Grundlagen der zielgerichteten Tumortherapie

verfasst von: Prof. Dr. P. Daniel

Erschienen in: Die Onkologie | Ausgabe 1/2007

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Zusammenfassung

Wesentliche neue Erkenntnisse zur Pathogenese maligner Tumoren ermöglichen eine rationale Basis für die Entwicklung neuer Therapieansätze, die gezielt und effizient genetische Defekte in malignen Tumoren nutzen. Im Gegensatz zu konventionellen, zumeist DNA schädigenden Therapien ermöglichen diese niedermolekularen Inhibitoren oder monoklonalen Antikörper hierdurch eine wesentlich selektivere, „zielgerichtete“ Therapie solcher Tumoren, die als Zielstruktur einen entsprechenden Gendefekt tragen oder ein entsprechendes Genexpressionsprofil zeigen. Wichtige Zielstrukturen sind Rezeptortyrosinkinasen, in Karzinomen insbesondere Komponenten des EGF-Rezeptor-Signalwegs. Neue Zielstrukturen sind Komponenten des PI3-/Akt-Kinase/mTOR-Signalwegs und Regulatoren von Zellüberleben und Zelltod. Da diese Therapien nur dann wirken können, wenn der Tumor den entsprechenden Gendefekt trägt, müssen zielgerichtete Tumortherapien durch eine adäquate molekulare Diagnostik ergänzt werden. Nur dadurch können die Patienten identifiziert werden, die von den neuen, gezielten Therapeutika profitieren werden.
Literatur
1.
Zurück zum Zitat Herbst RS, Fukuoka M, Baselga, J (2004) Gefitinib-a novel targeted approach to treating cancer. Nat Rev Cancer 4: 956–965CrossRefPubMed Herbst RS, Fukuoka M, Baselga, J (2004) Gefitinib-a novel targeted approach to treating cancer. Nat Rev Cancer 4: 956–965CrossRefPubMed
2.
Zurück zum Zitat Ren R (2005) Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 5: 172–183CrossRefPubMed Ren R (2005) Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 5: 172–183CrossRefPubMed
3.
Zurück zum Zitat Jonkers J, Berns A (2004) Oncogene addiction: sometimes a temporary slavery. Cancer Cell 6: 535–538PubMed Jonkers J, Berns A (2004) Oncogene addiction: sometimes a temporary slavery. Cancer Cell 6: 535–538PubMed
4.
Zurück zum Zitat 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: 163–168CrossRefPubMed 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: 163–168CrossRefPubMed
5.
Zurück zum Zitat Gill GN, Kawamoto T, Coche C et al. (1984) Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem 259: 7755–7760PubMed Gill GN, Kawamoto T, Coche C et al. (1984) Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem 259: 7755–7760PubMed
6.
Zurück zum Zitat Hubbard SR (2005) EGF receptor inhibition: Attacks on multiple fronts. Cancer Cell 7: 287–288CrossRefPubMed Hubbard SR (2005) EGF receptor inhibition: Attacks on multiple fronts. Cancer Cell 7: 287–288CrossRefPubMed
7.
Zurück zum Zitat Meyerhardt JA, Mayer, RJ (2005) Systemic therapy for colorectal cancer. N Engl J Med 352: 476–487CrossRefPubMed Meyerhardt JA, Mayer, RJ (2005) Systemic therapy for colorectal cancer. N Engl J Med 352: 476–487CrossRefPubMed
8.
Zurück zum Zitat Twombly R (2005) FDA Oncology Committee debates Iressa’s status following negative trial results. J Natl Cancer Inst 97: 473PubMed Twombly R (2005) FDA Oncology Committee debates Iressa’s status following negative trial results. J Natl Cancer Inst 97: 473PubMed
9.
Zurück zum Zitat 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: 2129–2139PubMed 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: 2129–2139PubMed
10.
Zurück zum Zitat Paez JG, Janne PA, Lee JC et al. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500CrossRefPubMed Paez JG, Janne PA, Lee JC et al. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500CrossRefPubMed
11.
Zurück zum Zitat 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: 2556–2568CrossRefPubMed 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: 2556–2568CrossRefPubMed
12.
Zurück zum Zitat Smith J (2005) Erlotinib: small-molecule targeted therapy in the treatment of non-small-cell lung cancer. Clin Ther 27: 1513–1534CrossRefPubMed Smith J (2005) Erlotinib: small-molecule targeted therapy in the treatment of non-small-cell lung cancer. Clin Ther 27: 1513–1534CrossRefPubMed
13.
Zurück zum Zitat Eberhard DA, Johnson BE, Amler LC et al. (2005) Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 23: 5900–5909CrossRefPubMed Eberhard DA, Johnson BE, Amler LC et al. (2005) Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 23: 5900–5909CrossRefPubMed
14.
Zurück zum Zitat Giaccone G, Gallegos Ruiz M, Le Chevalier et al. (2006) Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study. Clin Cancer Res 12: 6049–6055CrossRefPubMed Giaccone G, Gallegos Ruiz M, Le Chevalier et al. (2006) Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study. Clin Cancer Res 12: 6049–6055CrossRefPubMed
15.
Zurück zum Zitat Herbst RS, Prager D, Hermann R et al. (2005) TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23: 5892–5899CrossRefPubMed Herbst RS, Prager D, Hermann R et al. (2005) TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23: 5892–5899CrossRefPubMed
16.
Zurück zum Zitat Druker BJ (2004) Imatinib as a paradigm of targeted therapies. Adv Cancer Res 91: 1-30PubMed Druker BJ (2004) Imatinib as a paradigm of targeted therapies. Adv Cancer Res 91: 1-30PubMed
17.
Zurück zum Zitat 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: 4342–4349 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: 4342–4349
18.
Zurück zum Zitat 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: 566–578CrossRefPubMed 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: 566–578CrossRefPubMed
19.
Zurück zum Zitat 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: 7170–7176PubMed 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: 7170–7176PubMed
20.
Zurück zum Zitat 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: 4279–4284CrossRefPubMed 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: 4279–4284CrossRefPubMed
21.
Zurück zum Zitat 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: 3514–3520CrossRefPubMed 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: 3514–3520CrossRefPubMed
22.
Zurück zum Zitat 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: 235–242CrossRefPubMed 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: 235–242CrossRefPubMed
23.
Zurück zum Zitat 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: 1984–1992 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: 1984–1992
24.
Zurück zum Zitat Hurwitz H, Fehrenbacher L, Novotny W et al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350: 2335–2342CrossRefPubMed Hurwitz H, Fehrenbacher L, Novotny W et al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350: 2335–2342CrossRefPubMed
25.
Zurück zum Zitat Kabbinavar FF, Schulz J, McCleod M et al. (2005) Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 23: 3697–3705 Kabbinavar FF, Schulz J, McCleod M et al. (2005) Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 23: 3697–3705
26.
Zurück zum Zitat Baka S, Clamp AR, Jayson GC (2006) A review of the latest clinical compounds to inhibit VEGF in pathological angiogenesis. Expert Opin Ther Targets 10: 867–876CrossRefPubMed Baka S, Clamp AR, Jayson GC (2006) A review of the latest clinical compounds to inhibit VEGF in pathological angiogenesis. Expert Opin Ther Targets 10: 867–876CrossRefPubMed
27.
Zurück zum Zitat Potapova O, Laird AD, Nannini MA et al. (2006) Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248. Mol Cancer Ther 5: 1280–1289CrossRefPubMed Potapova O, Laird AD, Nannini MA et al. (2006) Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248. Mol Cancer Ther 5: 1280–1289CrossRefPubMed
28.
Zurück zum Zitat Motzer RJ, Michaelson MD, Redman BG et al. (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24: 16–24 Motzer RJ, Michaelson MD, Redman BG et al. (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24: 16–24
29.
Zurück zum Zitat Sansal I, Sellers WR (2004) The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 22: 2954–2963CrossRefPubMed Sansal I, Sellers WR (2004) The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 22: 2954–2963CrossRefPubMed
30.
Zurück zum Zitat Sarbassov DD, Ali SM, Sengupta S et al. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22: 159–168CrossRefPubMed Sarbassov DD, Ali SM, Sengupta S et al. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22: 159–168CrossRefPubMed
32.
Zurück zum Zitat Belka C, Jendrossek V, Pruschy M, Vink S et al. (2004) Apoptosis-modulating agents in combination with radiotherapy-current status and outlook. Int J Radiat Oncol Biol Phys 58: 542–554CrossRefPubMed Belka C, Jendrossek V, Pruschy M, Vink S et al. (2004) Apoptosis-modulating agents in combination with radiotherapy-current status and outlook. Int J Radiat Oncol Biol Phys 58: 542–554CrossRefPubMed
33.
Zurück zum Zitat Daniel PT, Wieder T, Sturm I et al. (2001) The kiss of death: promises and failures of death receptors and ligands in cancer therapy. Leukemia 15: 1022–1032CrossRefPubMed Daniel PT, Wieder T, Sturm I et al. (2001) The kiss of death: promises and failures of death receptors and ligands in cancer therapy. Leukemia 15: 1022–1032CrossRefPubMed
34.
Zurück zum Zitat 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: 8320–8332CrossRefPubMed 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: 8320–8332CrossRefPubMed
35.
Zurück zum Zitat Trauzold A, Siegmund D, Schniewind B et al. (2006) TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma. Oncogene e-pub ahead of print, Doi: 10.1038/sj.onc.1209719 Trauzold A, Siegmund D, Schniewind B et al. (2006) TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma. Oncogene e-pub ahead of print, Doi: 10.1038/sj.onc.1209719
36.
Zurück zum Zitat Barnhart BC, Legembre P, Pietras E et al. (2004) CD95 ligand induces motility and invasiveness of apoptosis-resistant tumor cells. Embo J 23: 3175–3185CrossRefPubMed Barnhart BC, Legembre P, Pietras E et al. (2004) CD95 ligand induces motility and invasiveness of apoptosis-resistant tumor cells. Embo J 23: 3175–3185CrossRefPubMed
37.
Zurück zum Zitat Stuhmer T, Chatterjee M, Hildebrandt M et al. (2005) Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma. Blood 106: 3609–3617CrossRefPubMed Stuhmer T, Chatterjee M, Hildebrandt M et al. (2005) Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma. Blood 106: 3609–3617CrossRefPubMed
38.
Zurück zum Zitat Daniel PT, Schulze-Osthoff K, Belka C et al. (2003) Guardians of cell death: the Bcl-2 family proteins. Essays Biochem 39: 73–88PubMed Daniel PT, Schulze-Osthoff K, Belka C et al. (2003) Guardians of cell death: the Bcl-2 family proteins. Essays Biochem 39: 73–88PubMed
39.
Zurück zum Zitat Baell JB, Huang,, DC (2002) Prospects for targeting the Bcl-2 family of proteins to develop novel cytotoxic drugs. Biochem Pharmacol 64: 851–863CrossRefPubMed Baell JB, Huang,, DC (2002) Prospects for targeting the Bcl-2 family of proteins to develop novel cytotoxic drugs. Biochem Pharmacol 64: 851–863CrossRefPubMed
40.
Zurück zum Zitat Oltersdorf T, Elmore SW, Shoemaker AR et al. (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435: 677–681CrossRefPubMed Oltersdorf T, Elmore SW, Shoemaker AR et al. (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435: 677–681CrossRefPubMed
41.
Zurück zum Zitat van Delft MF, Wei AH, Mason KD et al. (2006) The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell10: 389–399 van Delft MF, Wei AH, Mason KD et al. (2006) The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell10: 389–399
42.
Zurück zum Zitat Juin P, Geneste O, Raimbaud E et al. (2004) Shooting at survivors: Bcl-2 family members as drug targets for cancer. Biochim Biophys Acta 1644: 251–260CrossRefPubMed Juin P, Geneste O, Raimbaud E et al. (2004) Shooting at survivors: Bcl-2 family members as drug targets for cancer. Biochim Biophys Acta 1644: 251–260CrossRefPubMed
43.
Zurück zum Zitat Fulda S, Wick W, Weller M et al. (2002) Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 8: 808–815PubMed Fulda S, Wick W, Weller M et al. (2002) Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 8: 808–815PubMed
44.
Zurück zum Zitat 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: 48168–48176CrossRefPubMed 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: 48168–48176CrossRefPubMed
45.
Zurück zum Zitat 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: 4523–4535CrossRefPubMed 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: 4523–4535CrossRefPubMed
Metadaten
Titel
Molekulare Grundlagen der zielgerichteten Tumortherapie
verfasst von
Prof. Dr. P. Daniel
Publikationsdatum
01.01.2007
Verlag
Springer-Verlag
Erschienen in
Die Onkologie / Ausgabe 1/2007
Print ISSN: 2731-7226
Elektronische ISSN: 2731-7234
DOI
https://doi.org/10.1007/s00761-006-1166-8

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