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Oncogenomics and the development of new cancer therapies

Nature volume 429, pages 469–474 (2004)Cite this article

Abstract

Scientists have sequenced the human genome and identified most of its genes. Now it is time to use these genomic data, and the high-throughput technology developed to generate them, to tackle major health problems such as cancer. To accelerate our understanding of this disease and to produce targeted therapies, further basic mutational and functional genomic information is required. A systematic and coordinated approach, with the results freely available, should speed up progress. This will best be accomplished through an international academic and pharmaceutical oncogenomics initiative.

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Figure 1: Figure 1 Types of target identified through comprehensive genome and transcriptome analysis of cancer cells.
Figure 2: Figure 2 Examples of general drug-screening approaches.
Figure 3

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References

  1. Vogelstein, B. & Kinzler, K. W. The Genetic Basis of Human Cancer (McGraw-Hill, New York, 2002).

    Google Scholar 

  2. Balmain, A., Gray, J. & Ponder, B. The genetics and genomics of cancer. Nature Genet. 33 (suppl.), 238–244 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Popescu, N. C. Comprehensive genetic analysis of cancer cells. J. Cell. Mol. Med. 4, 151–163 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. International Human Genome Sequencing Consotium. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

  5. Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Druker, B. J. STI571 (Gleevec) as a paradigm for cancer therapy. Trends Mol. Med. 8, S14S18 (2002).

  7. Kim, J. A. Targeted therapies for the treatment of cancer. Am. J. Surg. 186, 264–268 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Smith, I. E. Efficacy and safety of Herceptin in women with metastatic breast cancer: results from pivotal clinical studies. Anticancer Drugs (suppl. 4), S3–S10 (2001).

  9. Salgaller, M. Technology evaluation: bevacizumab, Genentech/Roche. Curr. Opin. Mol. Ther. 5, 657–667 (2003).

    CAS  PubMed  Google Scholar 

  10. Schadt, E. E., Monks, S. A. & Friend, S. H. A new paradigm for drug discovery: integrating clinical, genetic, genomic and molecular phenotype data to identify drug targets. Biochem. Soc. Trans. 31, 437–443 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Fischer, O. M., Streit, S., Hart, S. & Ullrich, A. Herceptin and Gleevec. Curr. Opin. Chem. Biol. 7, 490–495 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Bardelli, A. et al. Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300, 949 (2003).

  14. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).

  15. Hilgenfeld, E. et al. Spectral karyotyping in cancer cytogenetics. Methods Mol. Med. 68, 29–44 (2002).

    PubMed  Google Scholar 

  16. Lucito, R. et al. Representational oligonucleotide microarray analysis: a high-resolution method to detect genome copy number variation. Genome Res. 13, 2291–2305 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cowell, J. K. & Nowak, N. J. High-resolution analysis of genetic events in cancer cells using bacterial artificial chromosome arrays and comparative genome hybridization. Adv. Cancer Res. 90, 91–125 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Liang, G. et al. DNA methylation differences associated with tumor tissues identified by genome scanning analysis. Genomics 53, 260–268 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Cottrell, S. E. et al. A real-time PCR assay for DNA-methylation using methylation-specific blockers. Nucleic Acids Res. 32, e10 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Greshock, J. et al. 1-Mb resolution array-based comparative genomic hybridization using a BAC clone set optimized for cancer gene analysis. Genome Res. 14, 179–187 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang, T. L. et al. Digital karyotyping. Proc. Natl Acad. Sci. USA 99, 16156–16161 (2002).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang, T. L. et al. Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. Proc. Natl Acad. Sci. USA 101, 3089–3094 (2004).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  23. Volik, S. et al. End-sequence profiling: sequence-based analysis of aberrant genomes. Proc. Natl Acad. Sci. USA 100, 7696–7701 (2003).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  24. Beroud, C. & Soussi, T. UMD-p53 database: New mutations and analysis tools. Hum. Mutat. 21, 176–181 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Futreal, P. A. et al. A census of human cancer genes. Nature Rev. Cancer 4, 177–183 (2004).

    Article  CAS  Google Scholar 

  26. Ramaswamy, S., Ross, K. N., Lander, E. S. & Golub, T. R. A molecular signature of metastasis in primary solid tumors. Nature Genet. 33, 49–54 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Sorlie, T. et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc. Natl Acad. Sci. USA 100, 8418–8423 (2003).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rosenwald, A. et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J. Exp. Med. 198, 851–862 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. van 't Veer, L. J. et al. Expression profiling predicts outcome in breast cancer. Breast Cancer Res. 5, 57–58 (2003).

    Article  PubMed  Google Scholar 

  30. van de Vijver, M. J. et al. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 347, 1999–2009 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Nutt, C. L. Gene expression-based classification of malignant gliomas correlates better with survival than histological classification. Cancer Res. 63, 1602–1607 (2003).

    CAS  PubMed  Google Scholar 

  32. Dyrskjot, L. et al. Identifying distinct classes of bladder carcinoma using microarrays. Nature Genet. 33, 90–96 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Velculescu, V. E., Zhang, L., Vogelstein, B. & Kinzler, K. W. Serial analysis of gene-expression. Science 270, 484–487 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  34. Lal, A. et al. A public database for gene expression in human cancers. Cancer Res. 59, 5403–5407 (1999).

    CAS  PubMed  Google Scholar 

  35. Buckhaults, P. et al. Identifying tumor origin using a gene expression-based classification map. Cancer Res. 63, 4144–4149 (2003).

    CAS  PubMed  Google Scholar 

  36. Jongeneel, C. V. et al. Comprehensive sampling of gene expression in human cell lines with massively parallel signature sequencing. Proc. Natl Acad. Sci. USA 100, 4702–4705 (2003).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  37. Brentani, H. et al. The generation and utilization of a cancer-oriented representation of the human transcriptome by using expressed sequence tags Proc. Natl Acad. Sci. USA 100, 13418–13423 (2003).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  38. Strausberg, R. L. et al. An international database and integrated analysis tools for the study of cancer gene expression. Pharmacogenomics J. 2, 156–164 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Saha, S. et al. Using the transcriptome to annotate the genome. Nature Biotechnol. 20, 508–512 (2002).

    Article  CAS  Google Scholar 

  40. Ota, T. et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature Genet. 36, 40–45 (2004).

    Article  PubMed  Google Scholar 

  41. Strausberg, R. L. et al. Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc. Natl Acad. Sci. USA 99, 16899–16903 (2002).

    Article  ADS  PubMed  Google Scholar 

  42. Xu, Q. & Lee, C. Discovery of novel splice forms and functional analysis of cancer-specific alternative splicing in human expressed sequences. Nucleic Acids Res. 31, 5635–5643 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang, Z. et al. Computational analysis and experimental validation of tumor-associated alternative RNA splicing in human cancer. Cancer Res. 63, 655–657 (2003).

    CAS  PubMed  Google Scholar 

  44. Kriventseva, E. V. et al. Increase of functional diversity by alternative splicing. Trends Genet. 19, 124–128 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Strausberg, R. L., Simpson, A. J. & Wooster, R. Sequence-based cancer genomics: progress, lessons and opportunities. Nature Rev. Genet. 4, 409–418 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Drevs, J., Medinger, M., Schmidt-Gersbach, C., Weber, R. & Unger, C. Receptor tyrosine kinases: the main targets for new anticancer therapy. Curr. Drug Targets 4, 113–121 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Sausville, E. A., Elsayed, Y., Monga, M. & Kim, G. Signal transduction — directed cancer treatments. Annu. Rev. Pharmacol. Toxicol. 43, 199–231 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Cockerill, G. S. & Lackey, K. E. Small molecule inhibitors of the class 1 receptor tyrosine kinase family. Curr. Top. Med. Chem. 2, 1001–1010 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Wilhelm, S. & Chien, D. S. BAY 43-9006: preclinical data. Curr. Pharm. Des. 8, 2255–2257 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Joensuu, H. & Dimitrijevic, S. Tyrosine kinase inhibitor imatinib (STI571) as an anticancer agent for solid tumours. Ann. Med. 33, 451–455 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Demetri, G. D. Targeting the molecular pathophysiology of gastrointestinal stromal tumors with imatinib. Mechanisms, successes, and challenges to rational drug development. Hematol. Oncol. Clin. North Am. 16, 1115–1124 (2002).

    Article  PubMed  Google Scholar 

  52. Druker, B. Imatinib mesylate in the treatment of chronic myeloid leukaemia. Expert Opin. Pharmacother. 4, 963–971 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Tipping, A. J. & Melo, J. V. Imatinib mesylate in combination with other chemotherapeutic drugs: In vitro studies. Semin. Hematol. 40, 83–91 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Druker, B. Imatinib alone and in combination for chronic myeloid leukemia. Semin. Hematol. 40, 50–58 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Joensuu, H. et al. Management of malignant gastrointestinal stromal tumours. Lancet Oncol. 3, 655–664 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Joensuu, H. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N. Engl. J. Med. 344, 1052–1056 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. GIST SU11248 Study Group. Clinical activity and tolerability of the multi-targeted tyrosine kinase inhibitor SU11248 in patients (pts) with metastatic gastrointestinal stromal tumor (GIST) refractory to imatinib mesylate. Proc. Am. Soc. Clin. Oncol. 22, 814 (abstr. 3273) (2003).

  58. Egland, K. A., Vincent, J. J., Strausberg, R., Lee, B. & Pastan, I. Discovery of the breast cancer gene BASE using a molecular approach to enrich for genes encoding membrane and secreted proteins. Proc. Natl Acad. Sci. USA 100, 1099–1104 (2003).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  59. Olsson, P., Motegi, A., Bera, T. K., Lee, B. & Pastan, I. PRAC2: a new gene expressed in human prostate and prostate cancer. Prostate 56, 123–130 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Jager, D. Identification of a tissue-specific putative transcription factor in breast tissue by serological screening of a breast cancer library. Cancer Res. 61, 2055–2061 (2001).

    CAS  PubMed  Google Scholar 

  61. Bera, T. K. NGEP, a gene encoding a membrane protein detected only in prostate cancer and normal prostate. Proc. Natl Acad. Sci. USA 101, 3059–3064 (2004).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  62. Scanlan, M. J., Gure, A. O., Jungbluth, A. A., Old, L. J. & Chen, Y. T. Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol. Rev. 188, 22–32 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Scanlan, M. J., Simpson, A. J. & Old, L. J. The cancer/testis genes: review, standardization, and commentary. Cancer Immun. 4, 1 (2004).

    PubMed  Google Scholar 

  64. Scanlan, M. J. et al. Identification of cancer/testis genes by database mining and mRNA expression analysis. Int. J. Cancer 98, 485–492 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Old, L. J. Cancer/testis (CT) antigens - a new link between gametogenesis and cancer. Cancer Immun. 1, 1 (2001).

    CAS  PubMed  Google Scholar 

  66. Durrant, L. G. & Spendlove, I. Cancer vaccines entering Phase III clinical trials. Expert Opin. Emerg. Drugs 8, 489–500 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Jager, E., Jager, D. & Knuth, A. Antigen-specific immunotherapy and cancer vaccines. Int. J. Cancer 106, 817–820 (2003).

    Article  PubMed  CAS  Google Scholar 

  68. Albanell, J., Codony, J., Rovira, A., Mellado, B. & Gascon, P. Mechanism of action of anti-HER2 monoclonal antibodies: scientific update on trastuzumab and 2C4. Adv. Exp. Med. Biol. 532, 253–268 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Blackledge, G. & Averbusch, S. Gefitinib (‘Iressa’, ZD1839) and new epidermal growth factor receptor inhibitors. Br. J. Cancer 90, 566–572 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Coiffier, B. Immunochemotherapy: the new standard in aggressive non-Hodgkin's lymphoma in the elderly. Semin. Oncol. 30, 21–27 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Wannesson, L. & Ghielmini, M. Overview of antibody therapy in B-cell non-Hodgkin's lymphoma. Clin. Lymphoma 4 (suppl. 1), S5-S12 (2003).

    Article  PubMed  Google Scholar 

  72. Jain, R. K. Tumor angiogenesis and accessibility: role of vascular endothelial growth factor. Semin. Oncol. 29, 3–9 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Milenic, D. E. & Brechbiel, M. W. Targeting of radio-isotopes for cancer therapy. Cancer Biol. Ther. 3 (2004).

  74. Damle, N. K. & Frost, P. Antibody-targeted chemotherapy with immunoconjugates of calicheamicin. Curr. Opin. Pharmacol. 3, 386–390 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. McCormick, F. Cancer-specific viruses and the development of ONYX-015. Cancer Biol. Ther. 2 (suppl. 1), s157-s160 (2003).

    CAS  PubMed  Google Scholar 

  76. Tong, A. W., Zhang, Y. A., Cunningham, C., Maples, P. & Nemunaitis, J. Potential clinical application of antioncogene ribozymes for human lung cancer. Clin. Lung Cancer 2, 220–226 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Moon, C., Oh, Y. & Roth, J. A. Current status of gene therapy for lung cancer and head and neck cancer. Clin. Cancer Res. 9, 5055–5067 (2003).

    CAS  PubMed  Google Scholar 

  78. McNeish, I. A., Bell, S. J. & Lemoine, N. R. Gene therapy progress and prospects: cancer gene therapy using tumour suppressor genes. Gene Ther. 11, 497–503 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Torrance, C. J., Agrawal, V., Vogelstein, B. & Kinzler, K. W. Use of isogenic human cancer cells for high-throughput screening and drug discovery. Nature Biotechnol. 19, 940–945 (2001).

    Article  CAS  Google Scholar 

  80. Strausberg, R. L. & Schreiber, S. L. From knowing to controlling: a path from genomics to drugs using small molecule probes. Science 300, 294–295 (2003).

    Article  ADS  CAS  PubMed  Google Scholar 

  81. Koehler, A. N., Shamji, A. F. & Schreiber, S. L. Discovery of an inhibitor of a transcription factor using small molecule microarrays and diversity-oriented synthesis. J. Am. Chem. Soc. 125, 8420–8421 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Zerhouni, E. The NIH Roadmap. Science 302, 63–72 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Collins, F. S., Morgan, M. & Patrinos, A. The Human Genome Project: lessons from large-scale biology. Science 300, 286–290 (2003).

    Article  ADS  CAS  PubMed  Google Scholar 

  84. Newman, D. J., Cragg, G. M. & Snader, K. M. Natural products as sources of new drugs over the period 1981-2002. J. Nat. Prod. 66, 1022–1037 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Myers, N., Mittermeier, R. A., Mittermeier, C. G., da Fonseca, G. A. & Kent, J. Biodiversity hotspots for conservation priorities. Nature 403, 853–858 (2000).

    Article  ADS  CAS  PubMed  Google Scholar 

  86. Brizuela, L., Richardson, A., Marsischky, G. & Labaer, J. The FLEXGene repository: Exploiting the fruits of the genome projects by creating a needed resource to face the challenges of the post-genomic era. Arch. Med. Res. 33, 318–324 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Kretzschmar, T. & von Ruden, T. Antibody discovery: phage display. Curr. Opin. Biotechnol. 13, 598–602 (2002)

    Article  CAS  PubMed  Google Scholar 

  88. Brekke, O. H. & Loset, G. A. New technologies in therapeutic antibody development. Curr. Opin. Pharmacol. 3, 544–550 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Pasqualini, R. & Ruoslahti, E. Organ targeting in vivo using phage display peptide libraries. Nature 380, 364–366 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  90. Ellerby, H. M. et al. Anti-cancer activity of targeted pro-apoptotic peptides. Nature Med. 5, 1032–1038 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Scott, A. M. et al. A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin. Cancer Res. 9, 1639–1647 (2003).

    CAS  PubMed  Google Scholar 

  92. Welt, S. et al. Phase I study of anticolon cancer humanized antibody A33. Clin. Cancer Res. 9, 1338–1346 (2003).

    CAS  PubMed  Google Scholar 

  93. Scott, A. M. et al. Specific targeting, biodistribution, and lack of immunogenicity of chimeric anti-GD3 monoclonal antibody KM871 in patients with metastatic melanoma: results of a phase I trial. J. Clin. Oncol. 19, 3967–3987 (2001).

    Article  Google Scholar 

  94. Jager, E. et al. Induction of primary NY-ESO-1 immunity: CD8+ T lymphocyte and antibody responses in peptide-vaccinated patients with NY-ESO-1+ cancers. Proc. Natl Acad. Sci. USA 97, 12198–12203 (2000).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  95. Atanackovic, D. Vaccine-induced CD4+ T cell responses to MAGE-3 protein in lung cancer patients. J. Immunol. 172, 3289–3296 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Duyk, G. Attrition and translation. Science 302, 603–605 (2003).

    Article  ADS  CAS  PubMed  Google Scholar 

  97. Rapisarda, A. et al. Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. Cancer Res. 62, 4316–4324 (2002).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank G. Demetri for discussions and advice during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Mammalian Genomics, The Institute for Genomic Research, 9712 Medical Center Drive, Rockville, 2085, Maryland, USA

    Robert L. Strausberg

  2. Ludwig Institute for Cancer Research, 605 Third Avenue, New York, USA, 10158, New York

    Andrew J.G. Simpson & Lloyd J. Old

  3. Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, 21224, Maryland, USA

    Gregory J. Riggins

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Strausberg, R., Simpson, A., Old, L. et al. Oncogenomics and the development of new cancer therapies. Nature 429, 469–474 (2004). https://doi.org/10.1038/nature02627

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