Drug Development in Cancer Medicine: Challenges for Targeted Approaches

  • Luis H. Camacho
Part of the Current Clinical Oncology™ book series (CCO)


Remarkable progress has been made in cancer medicine during the last two decades. The number of anticancer agents entering clinical trials has grown exponentially; and patients with diseases such as acute promyelocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, cutaneous T-cell lymphoma, colorectal cancer, breast cancer, GISTs, and renal cell carcinoma have already received some of the benefits from molecularly tailored strategies. Despite sustained progress, however, many patients have not yet benefited from this sophisticated approach, and cancer remains among the three most common causes of death worldwide. Carcinogenesis involves the accumulation of multiple molecular mutations responsible for deregulation of critical signaling pathways that control vital cellular functions. Targeting molecular structures on cancer cells is highly specific and can modulate vital functions such as cell growth, migration, differentiation, and survival. Targeted therapies are generally well tolerated, and the overall supportive treatments now available for cancer patients are better than in the past. Nonetheless, several challenges associated with anticancer agents, molecular targets, tumor assessment tools, clinical trial designs; and the drug development and approval process exist. Overcoming these challenges is critical to improve the early success achieved during the past two decades. It also is important to consider that the sophistication of this approach has extraordinarily increased the costs of drug development and patient care, making the application of these novel agents a privilege accorded to a small population of patients throughout the world. Some of these challenges and strategies for addressing them are summarized and discussed in this chapter.

Key Words

Targeted therapy Challenges Obstacles Drug development Clinical trials Phase I 


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  1. 1.
    Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996;2(5):561–6.PubMedGoogle Scholar
  2. 2.
    O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348(11):994–1004.PubMedGoogle Scholar
  3. 3.
    Van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001;358(9291):1421–3.PubMedGoogle Scholar
  4. 4.
    Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347(7):472–80.Google Scholar
  5. 5.
    Wyman K, Atkins MB, Prieto V, et al. Multicenter phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer 2006;106(9):2005–11.PubMedGoogle Scholar
  6. 6.
    Vuky J, Isacson C, Fotoohi M, et al. Phase II trial of imatinib (Gleevec) in patients with metastatic renal cell carcinoma. Invest New Drugs 2006;24(1):85–8.PubMedGoogle Scholar
  7. 7.
    Gross DJ, Munter G, Bitan M, et al. The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R. Endocr Relat Cancer 2006;13(2):535–40.PubMedGoogle Scholar
  8. 8.
    Bond M, Bernstein ML, Pappo A, et al. A phase II study of imatinib mesylate in children with refractory or relapsed solid tumors: a Children’s Oncology Group study. Pediatr Blood Cancer 2007 Jan 29; [Epub ahead of print].Google Scholar
  9. 9.
    Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279(5350):577–80.PubMedGoogle Scholar
  10. 10.
    Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21(23):4342–9.PubMedGoogle Scholar
  11. 11.
    Druker BJ. Imatinib: paradigm or anomaly? Cell Cycle 2004;3(7):833–5.PubMedGoogle Scholar
  12. 12.
    Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003;299(5607):708–10.PubMedGoogle Scholar
  13. 13.
    Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001;293(5531):876–80.PubMedGoogle Scholar
  14. 14.
    Sawyers CL. Research on resistance to cancer drug Gleevec. Science 2001;294(5548):1834.PubMedGoogle Scholar
  15. 15.
    Donato NJ, Wu JY, Stapley J, et al. Imatinib mesylate resistance through BCR-ABL independence in chronic myelogenous leukemia. Cancer Res 2004;64(2):672–7.PubMedGoogle Scholar
  16. 16.
    Shah NP, Nicoll JM, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002;2(2):117–25.PubMedGoogle Scholar
  17. 17.
    Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004;305(5682):399–401.PubMedGoogle Scholar
  18. 18.
    Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006;354(24):2531–41.PubMedGoogle Scholar
  19. 19.
    Kantarjian H, O’Brien S, Cortes J, et al. Survival advantage with imatinib mesylate therapy in chronic-phase chronic myelogenous leukemia (CML-CP) after IFN-alpha failure and in late CML-CP, comparison with historical controls. Clin Cancer Res 2004;10(1 Pt 1):68–75.PubMedGoogle Scholar
  20. 20.
    Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271(5256):1734–6.PubMedGoogle Scholar
  21. 21.
    De The H, Chomienne C, Lanotte M, et al. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 1990;347(6293):558–61.PubMedGoogle Scholar
  22. 22.
    Warrell RP Jr, de The H, Wang ZY, et al. Acute promyelocytic leukemia. N Engl J Med 1993;329(3):177–89.PubMedGoogle Scholar
  23. 23.
    Warrell RP Jr, Frankel SR, Miller WH Jr, et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med 1991;324(20):1385–93.PubMedGoogle Scholar
  24. 24.
    Soignet SL, Maslak P, Wang ZG, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 1998;339(19):1341–8.PubMedGoogle Scholar
  25. 25.
    Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001;19(18):3852–60.PubMedGoogle Scholar
  26. 26.
    He LZ, Tolentino T, Grayson P, et al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest 2001;108(9):1321–30.PubMedGoogle Scholar
  27. 27.
    Warrell RP Jr, He LZ, Richon V, et al. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst 1998;90(21):1621–5.Google Scholar
  28. 28.
    Nan X, Ng HH, Johnson CA, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 1998;393:386–9.PubMedGoogle Scholar
  29. 29.
    Maslak P, Chanel S, Camacho LH, et al. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia 2006;20(2):212–7.PubMedGoogle Scholar
  30. 30.
    Gilbert J, Gore SD, Herman JG, et al. The clinical application of targeting cancer through histone acetylation and hypomethylation. Clin Cancer Res 2004;10(14):4589–96.PubMedGoogle Scholar
  31. 31.
    Gore SD, Baylin S, Sugar E, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 2006;66(12):6361–9.PubMedGoogle Scholar
  32. 32.
    Lo Coco F, Zelent A, Kimchi A, et al. Progress in differentiation induction as a treatment for acute promyelocytic leukemia and beyond. Cancer Res 2002;62(19):5618–21.PubMedGoogle Scholar
  33. 33.
    Soriano AO, Yang H, Tong W, et al. Significant clinical activity of the combination of 5-azacytidine, valproic acid and all-trans retinoic (ATRA) acid in leukemia: results of a phase I/II study. Blood 2006;108(11).Google Scholar
  34. 34.
    Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood 2006;107(5):1761–7.PubMedGoogle Scholar
  35. 35.
    Giles R, Loberg RD. Can we target the chemokine network for cancer therapeutics? Curr Cancer Drug Targets 2006;6(8):659–70.PubMedGoogle Scholar
  36. 36.
    Barber MA, Welch HC. PI3K and RAC signalling in leukocyte and cancer cell migration. Bull Cancer 2006;93(5):E44–52.PubMedGoogle Scholar
  37. 37.
    Peruzzi B, Bottaro DP. Targeting the c-Met signaling pathway in cancer. Clin Cancer Res 2006;12:3657–60.PubMedGoogle Scholar
  38. 38.
    Devine SM, Flomenberg N, Vesole DH, et al. Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin’s lymphoma.J Clin Oncol 2004;22(6):1095–102.PubMedGoogle Scholar
  39. 39.
    Flomenberg N, Devine SM, Dipersio JF, et al. The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone. Blood 2005;106:1867–74.PubMedGoogle Scholar
  40. 40.
    Blank M, Shiloh Y. Programs for cell death: apoptosis is only one way to go. Cell Cycle 2007;6(6):686–95.PubMedGoogle Scholar
  41. 41.
    Danilov AV, Danilova OV, Klein AK, et al. Molecular pathogenesis of chronic lymphocytic leukemia. Curr Mol Med 2006;6(6):665–75.PubMedGoogle Scholar
  42. 42.
    Tsujimoto Y, Jaffe E, Cossman J, et al. Clustering of breakpoints on chromosome 11 in human B-cell neoplasms with the t(11;14) chromosome translocation. Nature 1985;315:340–3.PubMedGoogle Scholar
  43. 43.
    Adachi M, Tefferi A, Greipp PR, et al. Preferential linkage of bcl-2 to immunoglobulin light chain gene in chronic lymphocytic leukemia. J Exp Med 1990;171(2):559–64.PubMedGoogle Scholar
  44. 44.
    Schena M, Larsson LG, Gottardi D, et al. Growth- and differentiation-associated expression of bcl-2 in B-chronic lymphocytic leukemia cells. Blood 1992;79:2981–9.PubMedGoogle Scholar
  45. 45.
    Kitada S, Andersen J, Akar S, et al. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses. Blood 1998;91(9):3379–89.PubMedGoogle Scholar
  46. 46.
    Zapata JM, Krajewska M, Morse HC 3rd, et al. TNF receptor-associated factor (TRAF) domain and Bcl-2 cooperate to induce small B cell lymphoma/chronic lymphocytic leukemia in transgenic mice. Proc Natl Acad Sci U S A 2004;101(47):16600–5.PubMedGoogle Scholar
  47. 47.
    Lickliter JD, Cox J, McCarron J, et al. Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction. Br J Cancer 2007;96(4):600–8.PubMedGoogle Scholar
  48. 48.
    O’Brien S, Moore JO, Boyd TE, et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 2007;25(9):1114–20.PubMedGoogle Scholar
  49. 49.
    Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 2007;6(4):273–86.Google Scholar
  50. 50.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285(21):1182–6.PubMedGoogle Scholar
  51. 51.
    Folkman J, Kalluri R. Cancer without disease. Nature 2004;427:787.Google Scholar
  52. 52.
    Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004;10:909–15.PubMedGoogle Scholar
  53. 53.
    Rosenberg SA, Sherry RM, Morton KE, et al. Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma. J Immunol 2005;175(9):6169–76.PubMedGoogle Scholar
  54. 54.
    Ribas A, Butterfield LH, Glaspy JA, et al. Current developments in cancer vaccines and cellular immunotherapy. J Clin Oncol 2003;21:2415–32.PubMedGoogle Scholar
  55. 55.
    Chambers CA, Kuhns MS, Allison JP. Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses. Proc Natl Acad Sci U S A 1999;96(15):8603–8.PubMedGoogle Scholar
  56. 56.
    Chambers CA, Kuhns MS, Egen JG, et al. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 2001;19:565–94.PubMedGoogle Scholar
  57. 57.
    Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 2003;100(14):8372–7.PubMedGoogle Scholar
  58. 58.
    Ribas A, Camacho LH, Lopez-Berestein G, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 2005;23(35):8968–77.PubMedGoogle Scholar
  59. 59.
    Small EJ, Tchekmedyian NS, Rini BI, et al. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res 2007;13(6):1810–5.PubMedGoogle Scholar
  60. 60.
    Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A 2003;100(8):4712–7.PubMedGoogle Scholar
  61. 61.
    Peggs KS, Quezada SA, Korman AJ, et al. Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr Opin Immunol 2006;18(2):206–13.PubMedGoogle Scholar
  62. 62.
    Lankelma J. Tissue transport of anti-cancer drugs. Curr Pharm Des 2002;8(22):1987–93.PubMedGoogle Scholar
  63. 63.
    Dummer R, Garbe C, Thompson JA, et al. Randomized dose-escalation study evaluating peginterferon alfa-2a in patients with metastatic malignant melanoma. J Clin Oncol 2006;24(7):1188–94.PubMedGoogle Scholar
  64. 64.
    Green MD, Koelbl H, Baselga J, et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol 2003;14(1):29–35.PubMedGoogle Scholar
  65. 65.
    Li KC, Pandit SD, Guccione S, et al. Molecular imaging applications in nanomedicine. Biomed Microdevices 2004;6(2):113–6.PubMedGoogle Scholar
  66. 66.
    Miura D, Yoneyama D, Furuhata Y, et al. Paclitaxel enhances antibody-dependent cell-mediated cytotoxicity of trastuzumab by a rapid recruitment of natural killer cells in Her-2 overexpressing breast cancer. J Clin Oncol 2007;25(18S):3503.Google Scholar
  67. 67.
    Bild AH, Yao G, Chang JT, et al. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 2006;439(7074):353–7.PubMedGoogle Scholar
  68. 68.
    Peng B, Hayes M, Resta D, et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol 2004;22(5):935–42.PubMedGoogle Scholar
  69. 69.
    Arslan MA, Kutuk O, Basaga H. Protein kinases as drug targets in cancer. Curr Cancer Drug Targets 2006;6(7):623–34.PubMedGoogle Scholar
  70. 70.
    Soutschek J, Akinc A, Bramlage B, et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 2004;432(7014):173–8.PubMedGoogle Scholar
  71. 71.
    Dykxhoorn DM, Palliser D, Lieberman J. The silent treatment: siRNAs as small molecule drugs. Gene Ther 2006;13(6):541–52.PubMedGoogle Scholar
  72. 72.
    Ferrari M. Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer 2005;5(3):161–71.PubMedGoogle Scholar
  73. 73.
    Bashshur ZF, Bazarbachi A, Schakal A, et al. Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol 2006;142:1–9.PubMedGoogle Scholar
  74. 74.
    Lynch SS, Cheng CM. Bevacizumab for neovascular ocular diseases. Ann Pharmacother 2007;41:614–25.PubMedGoogle Scholar
  75. 75.
    Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350(21):2129–39.PubMedGoogle Scholar
  76. 76.
    Alsina M, Fonseca R, Wilson EF, et al. Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma. Blood 2004;103(9):3271–7.PubMedGoogle Scholar
  77. 77.
    Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol 2005;205(2):275–92.PubMedGoogle Scholar
  78. 78.
    Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 2003; 22(47):7265–79.PubMedGoogle Scholar
  79. 79.
    Efferth T, Volm M. Pharmacogenetics for individualized cancer chemotherapy. Pharmacol Ther 2005; 107(2):155–76.PubMedGoogle Scholar
  80. 80.
    Ferrando AA, Armstrong SA, Neuberg DS, et al. Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregulation. Blood 2003;102(1):262–8.PubMedGoogle Scholar
  81. 81.
    Cote JF, Kirzin S, Kramar A, et al. UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan. Clin Cancer Res 2007;13:3269–75.PubMedGoogle Scholar
  82. 82.
    DiMasi JA, Grabowski HG. Economics of new oncology drug development. J Clin Oncol 2007;25(2):209–16.PubMedGoogle Scholar
  83. 83.
    Schein PS, Scheffler B. Barriers to efficient development of cancer therapeutics. Clin Cancer Res 2006;12(11 Pt 1):3243–8.PubMedGoogle Scholar
  84. 84.
    Schrag D. The price tag on progress—chemotherapy for colorectal cancer. N Engl J Med 2004;351(4):317–9.PubMedGoogle Scholar
  85. 85.
    Milsted RA. Cancer drug approval in the United States, Europe, and Japan. Adv Cancer Res 2007;96:371–91.PubMedGoogle Scholar
  86. 86.
    Visscher MB. New drugs: the tortuous road to approval. Science 1967;156(773):313.Google Scholar
  87. 87.
    Johnson JR, Temple R. Food and Drug Administration requirements for approval of new anticancer drugs. Cancer Treat Rep 1985;69:1155–9.PubMedGoogle Scholar
  88. 88.
    Beitz J, Gnecco C, Justice R. Quality-of-life end points in cancer clinical trials: the U.S. Food and Drug Administration perspective. J Natl Cancer Inst Monogr 1996;(20):7–9.PubMedGoogle Scholar
  89. 89.
    Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. 2007. Accessed June 6, 2007, at Scholar
  90. 90.
    Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors; European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92(3):205–16.PubMedGoogle Scholar
  91. 91.
    King DM. The radiology of gastrointestinal stromal tumours (GIST). Cancer Imaging 2005;5:150–6.PubMedGoogle Scholar
  92. 92.
    Fidler IJ, Kim SJ, Langley RR. The role of the organ microenvironment in the biology and therapy of cancer metastasis. J Cell Biochem 2007;101:927–36.PubMedGoogle Scholar
  93. 93.
    Schmitt CA, Rosenthal CT, Lowe SW. Genetic analysis of chemoresistance in primary murine lymphomas. Nat Med 2000;6:1029–35.PubMedGoogle Scholar
  94. 94.
    Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization classification of neoplastic diseases of the haematopoietic and lymphoid tissues: report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Histopathology 2000;36(1):69–86.PubMedGoogle Scholar
  95. 95.
    Frei E 3rd, Karon M, Levin RH, et al. The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. Blood 1965;26(5):642–56.PubMedGoogle Scholar
  96. 96.
    Hainsworth JD, Sosman JA, Spigel DR, et al. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 2005;23:7889–96.PubMedGoogle Scholar
  97. 97.
    Dancey JE, Chen HX. Strategies for optimizing combinations of molecularly targeted anticancer agents. Nat Rev Drug Discov 2006;5(8):649–59.PubMedGoogle Scholar
  98. 98.
    De Vries EG, Gietema JA, de Jong S. Tumor necrosis factor-related apoptosis-inducing ligand pathway and its therapeutic implications. Clin Cancer Res 2006;12(8):2390–3.PubMedGoogle Scholar
  99. 99.
    Ahronheim JC, Bernholc AS, Clark WD. Age trends in autopsy rates: striking decline in late life. JAMA 1983;250:1182–6.PubMedGoogle Scholar
  100. 100.
    Groopman J. The right to a trial: should dying patients have access to experimental drugs? New Yorker 2006, pp 40–7.Google Scholar
  101. 101.
    Cortazar P, Johnson BE. Review of the efficacy of individualized chemotherapy selected by in vitro drug sensitivity testing for patients with cancer. J Clin Oncol 1999;17(5):1625–31.PubMedGoogle Scholar
  102. 102.
    Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 2006;24(29):4764–74.PubMedGoogle Scholar
  103. 103.
    Martin DS, Balis ME, Fisher B, et al. Role of murine tumor models in cancer treatment research. Cancer Res 1986;46(4 Pt 2):2189–92.PubMedGoogle Scholar
  104. 104.
    Nakayama T, Cho YC, Mine Y, et al. Expression of vascular endothelial growth factor and its receptors VEGFR-1 and 2 in gastrointestinal stromal tumors, leiomyomas and schwannomas. World J Gastroenterol 2006;12(38):6182–7.PubMedGoogle Scholar
  105. 105.
    Guidi AJ, Abu-Jawdeh G, Tognazzi K, et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in endometrial carcinoma. Cancer 1996;78:454–60.PubMedGoogle Scholar
  106. 106.
    Ozdemir F, Akdogan R, Aydin F, et al. The effects of VEGF and VEGFR-2 on survival in patients with gastric cancer. J Exp Clin Cancer Res 2006;25:83–8.PubMedGoogle Scholar
  107. 107.
    Pisacane AM, Risio M. VEGF and VEGFR-2 immunohistochemistry in human melanocytic naevi and cutaneous melanomas. Melanoma Res 2005;15(1):39–43.PubMedGoogle Scholar
  108. 108.
    Wu Y, Hooper AT, Zhong Z, et al. The vascular endothelial growth factor receptor (VEGFR-1) supports growth and survival of human breast carcinoma. Int J Cancer 2006;119:1519–29.PubMedGoogle Scholar
  109. 109.
    Chung GG, Yoon HH, Zerkowski MP, et al. Vascular endothelial growth factor, FLT-1, and FLK-1 analysis in a pancreatic cancer tissue microarray. Cancer 2006;106(8):1677–84.PubMedGoogle Scholar
  110. 110.
    Puputti M, Tynninen O, Sihto H, et al. Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas. Mol Cancer Res 2006;4(12):927–34.PubMedGoogle Scholar
  111. 111.
    Grau SJ, Trillsch F, Herms J, et al. Expression of VEGFR3 in glioma endothelium correlates with tumor grade. J Neurooncol 2007;82(2):141–50.PubMedGoogle Scholar
  112. 112.
    Marshall J. Clinical implications of the mechanism of epidermal growth factor receptor inhibitors. Cancer 2006;107(6):1207–18.PubMedGoogle Scholar
  113. 113.
    Smith JS, Lal A, Harmon-Smith M, et al. Association between absence of epidermal growth factor receptor immunoreactivity and poor prognosis in patients with atypical meningioma. J Neurosurg 2007;106:1034–40.Google Scholar
  114. 114.
    Johnston JB, Navaratnam S, Pitz MW, et al. Targeting the EGFR pathway for cancer therapy. Curr Med Chem 2006;13(29):3483–92.PubMedGoogle Scholar
  115. 115.
    Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003;3(1):11–22.PubMedGoogle Scholar
  116. 116.
    Dahlberg PS, Jacobson BA, Dahal G, et al. ERBB2 amplifications in esophageal adenocarcinoma. Ann Thorac Surg 2004;78:1790–800.PubMedGoogle Scholar
  117. 117.
    Ramachandran C, Rodriguez S, Ramachandran R, et al. Expression profiles of apoptotic genes induced by curcumin in human breast cancer and mammary epithelial cell lines. Anticancer Res 2005;25(5):3293–302.PubMedGoogle Scholar
  118. 118.
    Wooster R, Futreal AP, Stratton MR. Sequencing analysis of BRAF mutations in human cancers. Methods Enzymol 2005;407:218–24.PubMedGoogle Scholar
  119. 119.
    Salh B, Marotta A, Matthewson C, et al. Investigation of the Mek-MAP kinase-Rsk pathway in human breast cancer. Anticancer Res 1999;19:731–40.PubMedGoogle Scholar
  120. 120.
    Mishima K, Yamada E, Masui K, et al. Overexpression of the ERK/MAP kinases in oral squamous cell carcinoma. Mod Pathol 1998;11(9):886–91.PubMedGoogle Scholar
  121. 121.
    Garavello W, Nicolini G, Aguzzi A, et al. Selective reduction of extracellular signal-regulated protein kinase (ERK) phosphorylation in squamous cell carcinoma of the larynx. Oncol Rep 2006;16(3):479–84.PubMedGoogle Scholar
  122. 122.
    Jinawath A, Akiyama Y, Yuasa Y, et al. Expression of phosphorylated ERK1/2 and homeodomain protein CDX2 in cholangiocarcinoma. J Cancer Res Clin Oncol 2006;132:805–10.PubMedGoogle Scholar
  123. 123.
    Bergqvist J, Elmberger G, Ohd J, et al. Activated ERK1/2 and phosphorylated oestrogen receptor alpha are associated with improved breast cancer survival in women treated with tamoxifen. Eur J Cancer 2006;42(8):1104–12.PubMedGoogle Scholar
  124. 124.
    Milde-Langosch K, Bamberger AM, Rieck G, et al. Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer. Br J Cancer 2005;92(12):2206–15.PubMedGoogle Scholar
  125. 125.
    Liu SY, Yen CY, Yang SC, et al. Overexpression of Rac-1 small GTPase binding protein in oral squamous cell carcinoma. J Oral Maxillofac Surg 2004;62(6):702–7.PubMedGoogle Scholar
  126. 126.
    Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005 Jul 8;225(1):1–26. Epub 2004 Nov 11. Review.Google Scholar
  127. 127.
    Lee SH, Shin MS, Kim HS, et al. Somatic mutations of TRAIL-receptor 1 and TRAIL-receptor 2 genes in non-Hodgkin’s lymphoma. Oncogene 2001;20(3):399–403.PubMedGoogle Scholar
  128. 128.
    Arai T, Akiyama Y, Okabe S, et al. Genomic organization and mutation analyses of the DR5/TRAIL receptor 2 gene in colorectal carcinomas. Cancer Lett 1998;133:197–204.PubMedGoogle Scholar
  129. 129.
    Pai SI, Wu GS, Ozoren N, et al. Rare loss-of-function mutation of a death receptor gene in head and neck cancer. Cancer Res 1998;58(16):3513–8.PubMedGoogle Scholar
  130. 130.
    Planas-Silva MD, Bruggeman RD, Grenko RT, et al. Overexpression of c-Myc and Bcl-2 during progression and distant metastasis of hormone-treated breast cancer. Exp Mol Pathol 2007;82(1):85–90.PubMedGoogle Scholar
  131. 131.
    Hellemans P, van Dam PA, Weyler J, et al. Prognostic value of bcl-2 expression in invasive breast cancer. Br J Cancer 1995;72(2):354–60.PubMedGoogle Scholar
  132. 132.
    Popovic B, Jekic B, Novakovic I, et al. Bcl-2 expression in oral squamous cell carcinoma. Ann N Y Acad Sci 2007;1095:19–25.PubMedGoogle Scholar
  133. 133.
    Tas F, Duranyildiz D, Oguz H, et al. The value of serum Bcl-2 levels in advanced lung cancer patients. Med Oncol 2005;22:139–43.PubMedGoogle Scholar
  134. 134.
    Ganigi PM, Santosh V, Anandh B, et al. Expression of p53, EGFR, pRb and bcl-2 proteins in pediatric glioblastoma multiforme: a study of 54 patients. Pediatr Neurosurg 2005;41:292–9.PubMedGoogle Scholar
  135. 135.
    Yoshino T, Shiina H, Urakami S, et al. Bcl-2 expression as a predictive marker of hormone-refractory prostate cancer treated with taxane-based chemotherapy. Clin Cancer Res 2006;12(Pt 1):6116–24.PubMedGoogle Scholar
  136. 136.
    Yee D. Targeting insulin-like growth factor pathways. Br J Cancer 2006;94:465–8.PubMedGoogle Scholar
  137. 137.
    Happerfield LC, Miles DW, Barnes DM, et al. The localization of the insulin-like growth factor receptor 1 (IGFR-1) in benign and malignant breast tissue. J Pathol 1997;183:412–7.PubMedGoogle Scholar
  138. 138.
    Cardillo MR, Monti S, Di Silverio F, et al. Insulin-like growth factor (IGF)-I, IGF-II and IGF type I receptor (IGFR-I) expression in prostatic cancer. Anticancer Res 2003;23:3825–35.PubMedGoogle Scholar
  139. 139.
    Adams SF, Hickson JA, Hutto JY, et al. PDGFR-alpha as a potential therapeutic target in uterine sarcomas. Gynecol Oncol 2007;104:524–8.PubMedGoogle Scholar
  140. 140.
    Hofer MD, Fecko A, Shen R, et al. Expression of the platelet-derived growth factor receptor in prostate cancer and treatment implications with tyrosine kinase inhibitors. Neoplasia 2004;6:503–12.PubMedGoogle Scholar
  141. 141.
    Casali PG, Messina A, Stacchiotti S, et al. Imatinib mesylate in chordoma. Cancer 2004;101:2086–97.PubMedGoogle Scholar
  142. 142.
    MacDonald TJ, Brown KM, LaFleur B, et al. Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nat Genet 2001;29:143–52.PubMedGoogle Scholar
  143. 143.
    Lassus H, Sihto H, Leminen A, et al. Genetic alterations and protein expression of KIT and PDGFRA in serous ovarian carcinoma. Br J Cancer 2004;91:2048–55.PubMedGoogle Scholar
  144. 144.
    Burger H, den Bakker MA, Kros JM, et al. Activating mutations in c-KIT and PDGFRalpha are exclusively found in gastrointestinal stromal tumors and not in other tumors overexpressing these imatinib mesylate target genes. Cancer Biol Ther 2005;4:1270–4.PubMedGoogle Scholar
  145. 145.
    Carvalho I, Milanezi F, Martins A, et al. Overexpression of platelet-derived growth factor receptor alpha in breast cancer is associated with tumour progression. Breast Cancer Res 2005;7:R788–95.PubMedGoogle Scholar
  146. 146.
    Kitadai Y, Sasaki T, Kuwai T, et al. Expression of activated platelet-derived growth factor receptor in stromal cells of human colon carcinomas is associated with metastatic potential. Int J Cancer 2006;119:2567–74.PubMedGoogle Scholar
  147. 147.
    Golub TR, Barker GF, Lovett M, et al. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994;77:307–16.PubMedGoogle Scholar
  148. 148.
    Cools J, DeAngelo DJ, Gotlib J, et al. 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 2003;348:1201–14.PubMedGoogle Scholar
  149. 149.
    Singh A, Karnoub AE, Palmby TR, et al. Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation. Oncogene 2004;23:9369–80.PubMedGoogle Scholar
  150. 150.
    Tamborini E, Bonadiman L, Greco A, et al. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 2004;127:294–9.PubMedGoogle Scholar
  151. 151.
    Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786–92.PubMedGoogle Scholar
  152. 152.
    Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Genet 2006;7:21–33.PubMedGoogle Scholar

Copyright information

© Humana Press, Totowa, NJ 2008

Authors and Affiliations

  • Luis H. Camacho

There are no affiliations available

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