Drug Discovery in Oncology

  • Alex Matter
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Drug discovery in oncology has undergone profound changes over the past 20 yr; the rate of change has markedly accelerated over the last 5 yr, and it is therefore appropriate to take stock of these changes, and to ask what the next steps in this evolving landscape of concepts, skills, and technologies are likely to be. More than ever, drug discovery in oncology finds itself at the crossroads of academic research, industrial research and development (with a growing share by the biotech industry), clinical research, regulatory authorities, and public health, including major partners, such as the National Cancer Institute (NCI). All of these partners are driven, more than ever, by the forces related to productivity, i.e., a relentless drive for quality at manageable cost, within minimal time frames. These forces are behind the technological revolution that is still taking place, the drive to secure competitive patent positions, the drive to be faster on the market through streamlined R&D processes, the drive for a more efficient approval process and flexible handling of market access by health authorities, and the importance of pharmacoeconomic aspects for the payors at large, even in disease states, such as advanced cancer, in which the medical need is undisputed.


Drug Target Drug Discovery Combinatorial Chemistry Drug Screen Predictive Quality 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Connolly Martin Y, 3D QSAR. Current state, scope, and limitations, Perspect Drug Discovery Des 1998; 12/13/14:323.Google Scholar
  2. 2.
    Lam KS. Application of combinatorial library methods in cancer research and drug discovery. Anticancer Drug Des 1997; 12:145–167.PubMedGoogle Scholar
  3. 3.
    Van de Waterbeernd H, et al., Lundstedt T, et al. Intelligent combinatorial libraries. In: Computassisted Lead. Optim., [Eur. Symp. Quant. Struct.-Act. Relat.], 11th, Basel, Switzerland: Verlag Chimica Acta. 1997; 191–208.CrossRefGoogle Scholar
  4. 4.
    Tominaga Y. Novel 3D Descriptors using excluded volume 2: application to drug classification. J Chem Inf Comput Sci 1998; 38:1157–1160.CrossRefGoogle Scholar
  5. 5.
    Bernson MR, et al. Identification of multiple mRNA and DNA sequences from small tissue samples isolated by laser-assisted microdissection. Lab Invest 1998; 78:1267–1273Google Scholar
  6. 6.
    Carulli JP, et al. High throughput analysis of differential gene expressionk. J Cell Biochem 1998; Suppl. 30/31, 286–296CrossRefGoogle Scholar
  7. 7.
    Cook ND. Scintillation proximity assay: a versatile high-throughput screening technology. Drug Discovery Today 1996; 1:287–294CrossRefGoogle Scholar
  8. 8.
    Gosnell PA, et al. Compound library management in high throughput screening. J Biomol Screening 1997; 2:99–102CrossRefGoogle Scholar
  9. 9.
    Hartwell LH, et al. Integrating genetic approaches into the discovery of anticancer drugs. Science 1997; 278:1064–1068PubMedCrossRefGoogle Scholar
  10. 10.
    Hitoshi Y, et al. Toso, a cell surface, specific regulator of Fas-induced apoptosis in T cells. Immunity 1988; 8:461–471CrossRefGoogle Scholar
  11. 11.
    Hsieh F, et al. Automated high throughput multiple target screening of molecular libraries by microfluidic MALDI-TOF MS. J Biomol Screening 1998; 3:189–198CrossRefGoogle Scholar
  12. 12.
    Humphrey-Smith I, et al. Proteome research: complementarity and limitations with respect to the RNA and DNA worlds. Electrophoresis 1997; 18:1217–1242.CrossRefGoogle Scholar
  13. 13.
    Jayawickreme CK, et al. Gene expression systems in the development of high-throughput screens. Curr Opin Biotechnol 1997; 8:629–634PubMedCrossRefGoogle Scholar
  14. 14.
    Jensen ON, et al. Automation of matrix-assisted laser desorption/ionization mass spectrometry using fuzzy logic feedback control. Anal Chem 1997; 69:1706–1714PubMedCrossRefGoogle Scholar
  15. 15.
    Kolb AJ, et al. Homogeneous, time-resolved fluorescence method for drug discovery. High Throughput Screening 1997; 1:345–360Google Scholar
  16. 16.
    Lutz MW, et al. Experimental design for high-throughput screening. Drug Discovery Today 1996; 1:277–286CrossRefGoogle Scholar
  17. 17.
    Oldenburg KR. Development of an ultra-high throughput screening system: plate design, liquid handling, and image analysis. Proc SPIE-Int Soc Opt Eng 1988; 3259:197–208CrossRefGoogle Scholar
  18. 18.
    Oldenburg KR, et al. Assay miniaturization for ultra-high throughput screening of combinatorial and discrete compound libraries: a 9600-well (0.2 microliter) assay system. J Biomol Screening 1998; 3:55–62CrossRefGoogle Scholar
  19. 19.
    Picardo M, et al. Scintillation proximity assays. In: Devlin JP, ed. High Throughput Screening New York: Dekker. 1997; 307–316.Google Scholar
  20. 20.
    Shapiro MS, et al. NMR methods in combinatorial chemistry. Curr Opin Chem Biol 1998; 2:372–375PubMedCrossRefGoogle Scholar
  21. 21.
    Schena M, et al. Microarrays: biotechnology’s discovery platform for functional genomics. Trends Biotechnol 1998; 16:301–306PubMedCrossRefGoogle Scholar
  22. 22.
    Silverman L, et al. New assay technologies for high-throughput screening. Curr Opin Chem Biol 1998; 2:397–403PubMedCrossRefGoogle Scholar
  23. 23.
    Sittampalam GS, et al. High-throughput screening: advances in assay technologies. Curr Opin Chem Biol 1997; 1:384–391PubMedCrossRefGoogle Scholar
  24. 24.
    Sterrer S, et al. Fluorescence correlation spectroscopy (FCS) — a highly sensitive method to analyze drug/target interactions. J Recept Signal Transduction Res 1997; 17:511–520CrossRefGoogle Scholar
  25. 25.
    Van de Corput MPC, et al. Sensitive mRNA detection by fluorescence in situ hybridization using horseradish peroxidase-labeled oligodeoxynucleotides and tyramide signal amplification. J Histochem Cytochem 1998; 46:1249–1259PubMedCrossRefGoogle Scholar
  26. 26.
    Velculescu VE, et al. Serial analysis of gene expression. Science 1995; 270:484–487PubMedCrossRefGoogle Scholar
  27. 27.
    Welford SM, et al. Detection of differentially expressed genes in primary tumor tissues using representational differences analysis coupled to microarray hybridization. Nucleic Acids Res 1998; 26:3059–3065PubMedCrossRefGoogle Scholar
  28. 28.
    Wilkens L, et al. Analysis of hematologic diseases using conventional karyotyping, fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH). Hum Pathol 1998; 29:833–839PubMedCrossRefGoogle Scholar
  29. 29.
    Zlokarnik G, et al. Quantitation of transcription and clonal selection of single living cells with lactamase as reporter. Science 1988; 279:84–88CrossRefGoogle Scholar
  30. 30.
    Hof P. Crystal structure of the tyrosine phosphatase SHP-2. Cell (Cambridge, MA) 1998; 92:441–450.PubMedCrossRefGoogle Scholar
  31. 31.
    Kussie PH, et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science (Washington, DC) 1996; 274:948–953PubMedCrossRefGoogle Scholar
  32. 32.
    Russo AA, et al. Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumor suppressor p l 6INK4a. Nature (London) 1998; 395:237–243PubMedCrossRefGoogle Scholar
  33. 33.
    Xu W, et al. Three-dimensional structure of the tyrosine kinase c-Src. Nature (London) 1997; 385:595–602PubMedCrossRefGoogle Scholar
  34. 34.
    Blasco MA, et al. Mouse models for the study of telomerase. CIBA Found Symp 1997; 211(Telomeres and Telomerase), 160–176PubMedGoogle Scholar
  35. 35.
    Contag CH, et al. Visualizing gene expression in living mammals using a bioluminescent reporter. Photochem Photobiol 1997; 66:523–531PubMedCrossRefGoogle Scholar
  36. 36.
    Contag PR, et al. Bioluminescent indicators in living mammals. Nature Med 1998; 4:245–247PubMedCrossRefGoogle Scholar
  37. 37.
    Greenhalgh DA, et al. Multistage epidermal carcinogenesis in transgenic mice: cooperativity and paradox. J Invest Dermatol Symp Proc 1996; 1:162–176Google Scholar
  38. 38.
    Grim J, et al. erbB-2 knockout employing an intracellular single-chain antibody (sFv) accomplishes specific toxicity in erbB-2-expressing lung cancer cells. Am J Respir Cell Mol Biol 1996; 15:348–354PubMedGoogle Scholar
  39. 39.
    Hsu CX, et al. Longitudinal cohort analysis of lethal prostate cancer progression in transgenic mice. J Urol 1998; 160:1500–1505PubMedCrossRefGoogle Scholar
  40. 40.
    Jain RK, et al. Quantitative angiogenesis assays: progress and problems. Nature Med 1997; 3:1203–1208PubMedCrossRefGoogle Scholar
  41. 41.
    Kasper S, et al. Development, progression, and androgen-dependence of prostate tumors in probasinLarge T antigen transgenic mice: a model for prostate cancer. Lab Invest 1998; 78:319–333PubMedGoogle Scholar
  42. 42.
    McCormack SJ. Myc/p53 interactions in transgenic mouse mammary development, tumorigenesis and chromosomal instability. Oncogene 1998; 16:2755–2766PubMedCrossRefGoogle Scholar
  43. 43.
    Moreadith RW, et al. Gene targeting in embryonic stem cells. The new physiology and metabolism. J Mol Med (Berlin) 1997; 75:208–216PubMedCrossRefGoogle Scholar
  44. 44.
    Moore RC, et al. Gene targeting. In: Rosenberg RN, ed. The molecular and genetic basis of neurological disease. Mol Genet Basis Neurol Dis 2nd ed. Boston, MA: Butterworth-Heinemann. 1997; 33–48Google Scholar
  45. 45.
    Pierce AM, et al. Increased E2F1 activity induces skin tumors in mice heterozygous and nullizygous for p53. Proc Natl Acad Sci USA 1998; 95:8858–8863PubMedCrossRefGoogle Scholar
  46. 46.
    Polites HG. Transgenic modE1Applications to drug discovery. Int J Exp Path 1996; 77:257–262Google Scholar
  47. 47.
    Rowse GJ, et al. Genetic modulation of neu proto-oncogene-induced mammary tumorigenesis. Cancer Res 1998; 58:2675–2679PubMedGoogle Scholar
  48. 48.
    Van de Vrie W, et al. In vivo model systems in P-glycoprotein-mediated multidrug resistance. Crit Rev Clin Lab Sci 1998; 35:1–57PubMedCrossRefGoogle Scholar
  49. 49.
    Viney JL. Transgenic and gene knockout mice in cancer research. Cancer Metastasis Rev 1995; 14:77–90.PubMedCrossRefGoogle Scholar
  50. 50.
    Bardelli A, et al. Invasive-growth signaling by the Met/HGF receptor. The hereditary renal carcinoma connection. Biochim Biophys Acta 1997; 1333:M41-M51PubMedGoogle Scholar
  51. 51.
    Brandt-Rauf PW, et al. The c-erbB-2 protein in oncogenesis: molecular structure to molecular epi-demiology. Crit Rev Oncol 1994; 5:313–329Google Scholar
  52. 52.
    Bertelson AH, et al. High-throughput gene expression analysis using SAGE. Drug Discovery Today 1998; 3:152–159CrossRefGoogle Scholar
  53. 53.
    Goldman R, et al. Molecular epidemiology of breast cancer. In Vivo 1998; 12:43–48PubMedGoogle Scholar
  54. 54.
    Guha A, et al. Proliferation of human malignant astrocytomas is dependent on ras activation. Oncogene 1997; 15:2755–2765PubMedCrossRefGoogle Scholar
  55. 55.
    Harada N, et al. Molecular and epidemiological analyses of abnormal expression of aromatase in breast cancer. Pharmacogenetics 1995; 5:S59-S64PubMedCrossRefGoogle Scholar
  56. 56.
    Hussain SP, et al. Molecular epidemiology of human cancer. Recent Results Cancer Res 1998; 154:22–36PubMedCrossRefGoogle Scholar
  57. 57.
    Izzotti A, et al. Molecular epidemiology in cancer research. Int. J Oncol 1997; 11:1053–1069PubMedGoogle Scholar
  58. 58.
    Lalani E, et al. Molecular and cellular biology of prostate cancer. Cancer Metast Rev 1997; 16:29–66CrossRefGoogle Scholar
  59. 59.
    Latil A, et al. Genetic aspects of prostate cancer. Virchows Arch 1998; 432:389–406PubMedCrossRefGoogle Scholar
  60. 60.
    Lengauer C, et al. Genetic instabilities in human cancers. Nature (London) 1988; 396:643–649CrossRefGoogle Scholar
  61. 61.
    Lopez-Otin C, et al. Breast and prostate cancer: an analysis of common epidemiological, genetic, and biochemical features. Endocr Rev 1998; 19:365–396PubMedCrossRefGoogle Scholar
  62. 62.
    Madden SL, et al. SAGE transcript profiles for p53-dependent growth regulation. Oncogene 1997; 15:1079–1085PubMedCrossRefGoogle Scholar
  63. 63.
    Moskaluk CA, et al. Molecular genetics of pancreatic carcinoma. In: Reber HA ed., Pancreatic Cancer Totowa, NJ: Humana. 1998; 3–20CrossRefGoogle Scholar
  64. 64.
    Rao RN. Targets for cancer therapy in the cell cycle pathway. Curr Opin Oncol 1996; 8:516–524PubMedCrossRefGoogle Scholar
  65. 65.
    Sekido Y, et al. Progress in understanding the molecular pathogenesis of human lung cancer. Biochim Biophys Acta 1998; 1378:F21-F59PubMedGoogle Scholar
  66. 66.
    Spivack SD, et al. The molecular epidemiology of lung cancer. Crit Rev Toxicol 1997; 27:319–365PubMedCrossRefGoogle Scholar
  67. 67.
    Sweeney KJ, et al. Lack of relationship between CDK activity and G1 cyclin expression in breast cancer cells. Oncogene 1998; 16:2865–2878PubMedCrossRefGoogle Scholar
  68. 68.
    Takahashi C, et al. Detection of telomerase activity in prostate cancer by needle biopsy. Eur Urol 1997; 32:494–498.PubMedGoogle Scholar
  69. 69.
    Urquidi V, et al. Telomerase in cancer: clinical applications. Ann Med (Helsinki) 1998; 30:419–430PubMedCrossRefGoogle Scholar
  70. 70.
    Van de Woude GF, et al. Met-HGF/SF: tumorigenesis, invasion and metastasis. Ciba Found Symp (Plasminogen-Related Growth Factors) 1997; 212:119–132.Google Scholar
  71. 71.
    Weinstein IB. Contributions of molecular biology to cancer epidemiology. Ann NY Acad Sci 1995; 768:30–40PubMedCrossRefGoogle Scholar
  72. 72.
    Welch DR, et al. Genetic and epigenetic regulation of human breast cancer progression and metastasis. Endocr-Relat Cancer 1998; 5:155–197CrossRefGoogle Scholar
  73. 73.
    Qureshi KN, et al. Molecular biological changes in bladder cancer. Cancer Sury (Bladder Cancer) 1998; 31:77–97.Google Scholar
  74. 74.
    Zhang G, et al. Role of bc1–2 expression in breast carcinomas. Oncol Rep 1998; 5:1211–1216PubMedGoogle Scholar
  75. 75.
    Zhang L, et al. Gene expression profiles in normal and cancer cells. Science 1997; 276:1268–1272PubMedCrossRefGoogle Scholar
  76. 76.
    Bisoffi M, et al. Inhibition of human telomerase by a retrovirus expressing telomeric antisense RNA. Eur J Cancer 1998; 34:1242–1249PubMedCrossRefGoogle Scholar
  77. 77.
    Cragg GM, et al. Natural products in drug discovery and development. J Nat Prod 1997; 60:52–60PubMedCrossRefGoogle Scholar
  78. 78.
    Gibbs JB, et al. Farnesyltransferase inhibitors versus Ras inhibitors. Curr Opin Chem Biol 1997; 1:197–203PubMedCrossRefGoogle Scholar
  79. 79.
    Klohs WD, et al. Inhibitors of tyrosine kinase. Curr Opin Oncol 1997; 9:562–568PubMedCrossRefGoogle Scholar
  80. 80.
    Long BH, et al. Eleutherobin, a novel cytotoxic agent that induces tubulin polymerization is similar to paclitaxel (Taxol®). Cancer Res 1998; 58:1111–1115PubMedGoogle Scholar
  81. 81.
    Meijer L. Chemical inhibitors of cyclin-dependent kinases. Trends Cell Biol 1996; 6:393–397PubMedCrossRefGoogle Scholar
  82. 82.
    Moasser MM, et al. Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones. Proc Natl Acad Sci USA 1998; 95:1369–1374PubMedCrossRefGoogle Scholar
  83. 83.
    Moyer JD, et al. Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 1997; 57:4838–4848PubMedGoogle Scholar
  84. 84.
    Nicolaou KC, et al. Chemical biology of epothilones. Angew Chem Int Ed 1998; 37:2014–2045CrossRefGoogle Scholar
  85. 85.
    Njoroge FG, et al. Structure-activity relationship of 3-substituted N-(pyridinylacetyl)-4-(8-chloro-5,6dihydro-11 H-benzo[5,6]cycloheptal[1,2-b] pyridin-11-ylidene)-piperidine inhibitors of farnesyl-protein transferase: design and synthesis of in vivo active compounds. J Med Chem 1997; 40:4290–4301PubMedCrossRefGoogle Scholar
  86. 86.
    Parks ME, et al. Optimization of the hairpin polyamide design for recognition of the minor groove of DNA. JAm Chem Soc 1996; 118:6147–6152CrossRefGoogle Scholar
  87. 87.
    Perry PJ, et al. Telomeres and telomerase: targets for cancer chemotherapy? Expert Opin Ther Pat 1998; 8:1567–1586CrossRefGoogle Scholar
  88. 88.
    Rothenberg SM, et al. Intracellular combinatorial chemistry with peptides in selection of caspase-like inhibitors. NATO ASI Ser Ser. H (Gene therapy) 1998; 105:171–183.Google Scholar
  89. 89.
    Sugita K, et al. Inhibitors of Ras-transformation. Curr Pharm Des 1997; 3:323–334Google Scholar
  90. 90.
    Sun J, et al. Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts. Oncogene 1998; 16:1467–1473PubMedCrossRefGoogle Scholar
  91. 91.
    Traxler P. Tyrosine kinase inhibitors in cancer treatment (part II). Expert Opin Ther Pat 1998; 8:1599–1625CrossRefGoogle Scholar
  92. 92.
    Traxler P, et al. Design and synthesis of novel tyrosine kinase inhibitors using a pharmacophore model of the ATP-binding site of the EGF-R. J Pharm Belg 1997; 52:88–96PubMedGoogle Scholar
  93. 93.
    Yokoyama Y, et al. Attenuation of telomerase activity by a hammerhead ribozyme targeting the template region of telomerase RNA in endometrial carcinoma cells. Cancer Res 1998; 58:5406–5410PubMedGoogle Scholar
  94. 94.
    Yu AE, et al. Matrix metalloproteinases. Novel targets for directed cancer therapy. Drugs Aging 1997; 11:229–244PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Alex Matter

There are no affiliations available

Personalised recommendations