Gegenwart und Zukunft der molekularen Therapie – vom Genom zum Antigenom

Zusammenfassung

Genchips erlauben die Analyse des mehr oder weniger kompletten Genexpressionsprofils von Tumorzellen und normalen Geweben in einem einzigen Experiment. Drei Hauptmotive rufen unser Interesse an der Genchipanalyse wach: (i) Die Genchiptechnologie bietet eine neue diagnostische Zusatzuntersuchung. (ii) Wir erhoffen uns, mehr über die Biologie der Tumorzelle zu erfahren. (iii) Wir hoffen mit Hilfe dieser Technologie neue therapeutische Zielstrukturen zu finden. Ein Hauptziel dieser Studien ist die Identifikation geeigneter Antigene für immunologische Therapieansätze.

Summary

Genechips allow the analysis of the more or less complete gene expression profile of tumour cells and normal tissues in a single experiment. We are interested in genechip analysis for three reasons: (i) Genechips offer a new diagnostic tool. (ii) We hope that we learn more about the biology of tumour cells. (iii) We hope that we can identify new therapeutic targets. A major goal of these studies is the identification of suitable antigens for immunotherapeutical strategies.

Schlüsselwörter

Genchip - Tumorgenetik - Tumorimmunologie - Immuntherapie

Keywords

DNA-microarrays - tumour genetics - tumour immunology - immunotherapy

• Literatur

• 1 Armstrong SA, Staunton JE, Silverman LB, Pieters R, den Boer ML, Minden MD, Sallan SE, Lander ES, Golub TR, Korsmeyer SJ. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 2002; 30: 41-7.
• 2 Baltimore D. Our genome unveiled. Nature 2001; 409: 814-6.
• 3 Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18: 767-811.
• 4 Beer DG, Kardia SL, Huang CC, Giordano TJ, Levin AM, Misek DE, Lin L, Chen G, Gharib TG, Thomas DG, Lizyness ML, Kuick R, Hayasaka S, Taylor JM, Iannettoni MD, Orringer MB, Hanash S. Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med 2002; 8: 816-24.
• 5 Burdach S, Jürgens H. High-dose chemoradiotherapy (HDC) in the Ewing family of tumors (EFT). Crit Rev Oncol Hematol 2002; 41: 169-89.
• 6 Caballero OL, de Souza SJ, Brentani RR, Simpson AJ. Alternative spliced transcripts as cancer markers. Dis Markers 2001; 17: 67-75.
• 7 Capdeville R, Buchdunger E, Zimmermann J, Matter A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 2002; 1: 493-502.
• 8 Dagher R, Pham TA, Sorbara L, Kumar S, Long L, Bernstein D, Mackall C, Raffeld M, Tsokos M, Helman L. Molecular confirmation of Ewing sarcoma. J Pediatr Hematol Oncol 2001; 23: 221-4.
• 9 Döll C, Wulff B, Rössler J, Schaper J, Havers W. Primary B-cell lymphoma of bone in children. Eur J Pediatr 2001; 160: 239-42.
• 10 Gaugler B, Brouwenstijn N, Vantomme V, Szikora JP, Van der Spek CW, Patard JJ, Boon T, Schrier P, Van den Eynde BJ. A new gene coding for an antigen recognized by autologous cytolytic T lymphocytes on a human renal carcinoma. Immunogenetics 1996; 44: 323-30.
• 11 Gaugler B, Van den Eynde B, van der Bruggen P, Romero P, Gaforio JJ, De Plaen E, Lethe B, Brasseur F, Boon T. Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. J Exp Med 1994; 179: 921-30.
• 12 Hofmann WK, de Vos S, Tsukasaki K, Wachsman W, Pinkus GS, Said JW, Koeffler HP. Altered apoptosis pathways in mantle cell lymphoma detected by oligonucleotide microarray. Blood 2001; 98: 787-94.
• 13 Ikeda H, Lethe B, Lehmann F, van Baren N, Baurain JF, de Smet C, Chambost H, Vitale M, Moretta A, Boon T, Coulie PG. Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity 1997; 6: 199-208.
• 14 Jasny BR, Kennedy D. The human genome. Science 2001; 291: 1153.
• 15 Kang X, Kawakami Y, el-Gamil M, Wang R, Sakaguchi K, Yannelli JR, Appella E, Rosenberg SA, Robbins PF. Identification of a tyrosinase epitope recognized by HLA-A24-restricted, tumor-infiltrating lymphocytes. J Immunol 1995; 155: 1343-8.
• 16 Khan J, Wei JS, Ringner M, Saal LH, Ladanyi M, Westermann F, Berthold F, Schwab M, Antonescu CR, Peterson C, Meltzer PS. Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks. Nat Med 2001; 7: 673-9.
• 17 Kubuschok B, Schmits R, Hartmann F, Cochlovius C, Breit R, Konig J, Pistorius G, Schilling M, Renner C, Pfreundschuh M. Use of spontaneous Epstein-Barr virus-lymphoblastoid cell lines genetically modified to express tumor antigen as cancer vaccines: mutated p21 ras oncogene in pancreatic carcinoma as a model. Hum Gene Ther 2002; 13: 815-27.
• 18 Lafond RE. (ed) Cancer, the outlaw cell. 2nd ed.. New York: Oxford University Press; 1988
• 19 Ligibel JA, Winer EP. Trastuzumab/chemotherapy combinations in metastatic breast cancer. Semin Oncol 2002; 29 (Suppl. 11) 38-43.
• 20 Miura K, Bowman ED, Simon R, Peng AC, Robles AI, Jones RT, Katagiri T, He P, Mizukami H, Charboneau L, Kikuchi T, Liotta LA, Nakamura Y, Harris CC. Laser capture microdissection and microarray expression analysis of lung adenocarcinoma reveals tobacco smoking- and prognosis-related molecular profiles. Cancer Res 2002; 62: 3244-50.
• 21 Nussbaum AK, Kuttler C, Hadeler KP, Rammensee HG, Schild H. PAProC: a prediction algorithm for proteasomal cleavages available on the WWW. Immunogenetics 2001; 53: 87-94.
• 22 Ozdemirli M, Fanburg-Smith JC, Hartmann DP, Shad AT, Lage JM, Magrath IT, Azumi N, Harris NL, Cossman J, Jaffe ES. Precursor B-Lymphoblastic lymphoma presenting as a solitary bone tumor and mimicking Ewing’s sarcoma: a report of four cases and review of the literature. Am J Surg Pathol 1998; 22: 795-804.
• 23 Pajic A, Staege MS, Dudziak D, Schuhmacher M, Spitkovsky D, Eissner G, Brielmeier M, Polack A, Bornkamm GW. Antagonistic effects of c-myc and Epstein-Barr virus latent genes on the phenotype of human B cells. Int J Cancer 2001; 93: 810-6.
• 24 Parker KC, Bednarek MA, Coligan JE. Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol 1994; 152: 163-75.
• 25 Rammensee HG, Bevan MJ. Evidence from in vitro studies that tolerance to self antigens is MHC-restricted. Nature 1984; 308: 741-4.
• 26 Röpke M, Hald J, Guldberg P, Zeuthen J, Norgaard L, Fugger L, Svejgaard A, Van der Burg S, Nijman HW, Melief CJ, Claesson MH. Spontaneous human squamous cell carcinomas are killed by a human cytotoxic T lymphocyte clone recognizing a wild-type p53-derived peptide. Proc Natl Acad Sci U S A 1996; 93: 14704-7.
• 27 Scotlandi K, Chano T, Benini S, Serra M, Manara MC, Cerisano V, Picci P, Baldini N. Identification of EWS/FLI-1 transcripts in giant-cell tumor of bone. Int J Cancer 2000; 87: 328-35.
• 28 Shaughnessy Jr J, Gabrea A, Qi Y, Brents L, Zhan F, Tian E, Sawyer J, Barlogie B, Bergsagel PL, Kuehl M. Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. Blood 2001; 98: 217-23.
• 29 Shipp MA, Ross KN, Tamayo P, Weng AP, Kutok JL, Aguiar RC, Gaasenbeek M, Angelo M, Reich M, Pinkus GS, Ray TS, Koval MA, Last KW, Norton A, Lister TA, Mesirov J, Neuberg DS, Lander ES, Aster JC, Golub TR. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 2002; 8: 68-74.
• 30 Skipper JC, Kittlesen DJ, Hendrickson RC, Deacon DD, Harthun NL, Wagner SN, Hunt DF, Engelhard VH, Slingluff Jr CL. Shared epitopes for HLA-A3-restricted melanomareactive human CTL include a naturally processed epitope from Pmel-17/gp100. J Immunol 1996; 157: 5027-33.
• 31 Staege MS, Lee SP, Frisan T, Mautner J, Scholz S, Pajic A, Rickinson AB, Masucci MG, Polack A, Bornkamm GW. MYC overexpression imposes a nonimmunogenic phenotype on Epstein-Barr virus-infected B cells. Proc Natl Acad Sci U S A 2002; 99: 4550-5.
• 32 Stanislawski T, Voss RH, Lotz C, Sadovnikova E, Willemsen RA, Kuball J, Ruppert T, Bolhuis RL, Melief CJ, Huber C, Stauss HJ, Theobald M. Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. Nat Immunol 2001; 10: 962-70.
• 33 Stevanovic S. Structural basis of immunogenicity. Transpl Immunol 2002; 10: 133-6.
• 34 Traversari C, van der Bruggen P, Luescher IF, Lurquin C, Chomez P, Van Pel A, De Plaen E, Amar-Costesec A, Boon T. A nonapeptide encoded by human gene MAGE-1 is recognized on HLA-A1 by cytolytic T lymphocytes directed against tumor antigen MZ2-E. J Exp Med 1992; 176: 1453-7.
• 35 Tsang KY, Zaremba S, Nieroda CA, Zhu MZ, Hamilton JM, Schlom J. Generation of human cytotoxic T cells specific for human carcinoembryonic antigen epitopes from patients immunized with recombinant vaccinia-CEA vaccine. J Natl Cancer Inst 1995; 87: 982-90.
• 36 Van den Eynde B, Peeters O, De Backer O, Gaugler B, Lucas S, Boon T. A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. J Exp Med 1995; 182: 689-98.
• 37 Voehringer DW, Hirschberg DL, Xiao J, Lu Q, Roederer M, Lock CB, Herzenberg LA, Steinman L, Herzenberg LA. Gene microarray identification of redox and mitochondrial elements that control resistance or sensitivity to apoptosis. Proc Natl Acad Sci U S A 2000; 97: 2680-5.
• 38 Webb T. SNPs: can genetic variants control cancer susceptibility?. J Natl Cancer Inst 2002; 94: 476-8.
• 39 Willers J, Haffner A, Zepter K, Storz M, Urosevic M, Burg G, Dummer R. The interferon inhibiting cytokine IK is overexpressed in cutaneous T cell lymphoma derived tumor cells that fail to upregulate major histocompatibility complex class II upon interferon-gamma stimulation. J Invest Dermatol 2001; 116: 874-9.
• 40 Zhou H, Roy S, Schulman H, Natan MJ. Solution and chip arrays in protein profiling. Trends Biotechnol 2001; 19: S34-9.