The impact of molecular targets in cancer drug development: Major hurdles and future strategies

Expert Review of Clinical Pharmacology

Volumn 6, Issue 1, 2013, Pages 23-34

  Hebar, Alexandra ^a   Valent, Peter ^a   Selzer, Edgar ^a  

^a MEDICAL UNIVERSITY OF VIENNA   (Austria)

Author keywords

cancer therapy; drug discovery and development; oncogene addiction; regulatory aspects; targeted drugs

Indexed keywords

ANTINEOPLASTIC AGENT; B RAF KINASE; CETUXIMAB; DASATINIB; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2; EXCISION REPAIR CROSS COMPLEMENTING PROTEIN 1; IMATINIB; K RAS PROTEIN; METHYLATED DNA PROTEIN CYSTEINE METHYLTRANSFERASE; NECITUMUMAB; PROTEIN P16; PROTEIN P53;

CANCER CHEMOTHERAPY; CANCER STEM CELL; COHORT ANALYSIS; DRUG COST; DRUG EFFICACY; DRUG SAFETY; DRUG SCREENING; GENE MUTATION; HUMAN; IN VITRO STUDY; LUNG NON SMALL CELL CANCER; MOLECULARLY TARGETED THERAPY; NONHUMAN; PATIENT SELECTION; PHENOTYPE; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; TUMOR MODEL; X RAY CRYSTALLOGRAPHY;

EID: 84871993429     PISSN: 17512433     EISSN: 17512441     Source Type: Journal    
DOI: 10.1586/ecp.12.71     Document Type: Review

References (80)

1. Schilsky RL. Personalized medicine in oncology: The future is now. Nat. Rev. Drug Discov. 9(5), 363-366 (2010
2. Heidelberger C. Cancer chemotherapy with purine and pyrimidine analogues. Annu. Rev. Pharmacol. 7, 101-124 (1967
3. Drews J. Drug discovery: A historical perspective. Science 287(5460), 1960-1964 (2000 (Pubitemid 30158662)
4. Strebhardt K, Ullrich A. Paul Ehrlich's magic bullet concept: 100 years of progress. Nat. Rev. Cancer 8(6), 473-480 (2008 (Pubitemid 351752547)
5. Rubin RP. A brief history of great discoveries in pharmacology: In celebration of the centennial anniversary of the founding of the American Society of Pharmacology and Experimental Therapeutics. Pharmacol. Rev. 59(4), 289-359 (2007
6. Jordan VC. The development of tamoxifen for breast cancer therapy: A tribute to the late Arthur L. Walpole. Breast Cancer Res. Treat. 11(3), 197-209 (1988
7. Aggarwal S. Targeted cancer therapies. Nat. Rev. Drug Discov. 9(6), 427-428 (2010
8. Hait WN. Anticancer drug development: The grand challenges. Nat. Rev. Drug Discov. 9(4), 253-254 (2010
9. Kamb A, Wee S, Lengauer C. Why is cancer drug discovery so difficulẗNat. Rev. Drug Discov. 6(2), 115-120 (2007 (Pubitemid 46745339)
10. Capdeville R, Buchdunger E, Zimmermann J, Matter A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat. Rev. Drug Discov. 1(7), 493-502 (2002
11. Collins I, Workman P. New approaches to molecular cancer therapeutics. Nat. Chem. Biol. 2(12), 689-700 (2006 (Pubitemid 44764211)
12. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289(5486), 1938-1942 (2000
13. Druker BJ, Sawyers CL, Kantarjian H et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N. Engl. J. Med. 344(14), 1038-1042 (2001 (Pubitemid 32267973)
14. Joensuu H, Roberts PJ, Sarlomo-Rikala M et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N. Engl. J. Med. 344(14), 1052-1056 (2001 (Pubitemid 32267975)
15. Caponigro G, Sellers WR. Advances in the preclinical testing of cancer therapeutic hypotheses. Nat. Rev. Drug Discov. 10(3), 179-187 (2011
16. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 100(1), 57-70 (2000 (Pubitemid 30046295)
17. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 144(5), 646-674 (2011
18. Roberts TG Jr, Lynch TJ Jr, Chabner BA. The Phase III trial in the era of targeted therapy: Unraveling the 'go or no go' decision. J. Clin. Oncol. 21(19), 3683-3695 (2003 (Pubitemid 46594063)
19. Selzer E. Impact of molecular targets in cancer drug development: Historical influence and future perspectives. Expert Rev. Clin. Pharmacol. 3(2), 161-163 (2010
20. Allegra CJ, Jessup JM, Somerfield MR et al. American Society of Clinical Oncology provisional clinical opinion: Testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J. Clin. Oncol. 27(12), 2091-2096 (2009
21. Peppercorn J, Perou CM, Carey LA. Molecular subtypes in breast cancer evaluation and management: Divide and conquer. Cancer Invest. 26(1), 1-10 (2008
22. Van De Vijver MJ, He YD, Van't Veer LJ et al. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 347(25), 1999-2009 (2002 (Pubitemid 35461656)
23. Rosenwald A, Wright G, Chan WC et al.; Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N. Engl. J. Med. 346(25), 1937-1947 (2002 (Pubitemid 34651353)
24. Greaves M, Maley CC. Clonal evolution in cancer. Nature 481(7381), 306-313 (2012
25. Gerlinger M, Rowan AJ, Horswell S et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366(10), 883-892 (2012
26. Valent P. Targeting of leukemia-Initiating cells to develop curative drug therapies: Straightforward but nontrivial concept. Curr. Cancer Drug Targets 11(1), 56-71 (2011
27. Yap TA, Sandhu SK, Workman P, de Bono JS. Envisioning the future of early anticancer drug development. Nat. Rev. Cancer 10(7), 514-523 (2010
28. US FDA. Guidance for Industry: Pharmacogenomic Data Submissions. US Department of Health and Human Services, DC, USA (2005
29. Ratner M. FDA Pharmacogenomics Guidance sends clear message to industry. Nat. Rev. Drug. Discov. 4(5), 359 (2005 (Pubitemid 40704100)
30. Simon R. Clinical trials for predictive medicine. Stat. Med. 31(25), 3031-3040 (2012
31. Simon R. Clinical trials for predictive medicine: New challenges and paradigms. Clin. Trials 7(5), 516-524 (2010
32. Verweij J, de Jonge M, Eskens F, Sleijfer S. Moving molecular targeted drug therapy towards personalized medicine: Issues related to clinical trial design. Mol. Oncol. 6(2), 196-203 (2012
33. Selzer E. Einsatz gezielter therapien in kombination mit radiotherapie. JATROS Hämatologie & Onkologie 1, 48-51 (2011
34. Bergethon K, Shaw AT, Ou SH et al. ROS1 rearrangements define a unique molecular class of lung cancers. J. Clin. Oncol. 30(8), 863-870 (2012
35. Shaw AT, Camidge DR, Engelman JA et al. Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. Presented at: 2012 ASCO Annual Meeting. Chicago, IL, USA, 1-5 June 2012 (Abstract 7508
36. Di Maio M. Is there still room for large registrative trials in unselected cancer patients̈The case of anti-epidermal growth factor receptor antibodies in advanced non-small-cell lung cancer. Expert Opin. Biol. Ther. 11(9), 1131-1133 (2011
37. Pirker R, Pereira JR, Szczesna A et al.; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): An open-label randomised Phase III trial. Lancet 373(9674), 1525-1531 (2009
38. Zuckerman R, Milne CP. Market watch: Industry perspectives on personalized medicine. Nat. Rev. Drug Discov. 11(3), 178 (2012
39. Fojo T, Grady C. How much is life worth: Cetuximab, non-small cell lung cancer, and the $440 billion question. J. Natl Cancer Inst. 101(15), 1044-1048 (2009
40. Kitano H. Cancer as a robust system: Implications for anticancer therapy. Nat. Rev. Cancer 4(3), 227-235 (2004 (Pubitemid 38337502)
41. Bakan A, Bahar I. The intrinsic dynamics of enzymes plays a dominant role in determining the structural changes induced upon inhibitor binding. Proc. Natl Acad. Sci. USA 106(34), 14349-14354 (2009
42. Hassell AM, An G, Bledsoe RK et al. Crystallization of protein-ligand complexes. Acta Crystallogr. D Biol. Crystallogr. 63(PT1), 72-79 (2007 (Pubitemid 46141482)
43. Chayen NE, Saridakis E. Protein crystallization: From purified protein to diffraction-quality crystal. Nat. Methods 5(2), 147-153 (2008 (Pubitemid 351181740)
44. Chua D, Fasching P, Ma B, Thongprasert S, Wirth L. Update on anti-EGFR therapy. J. Oncol. 2009, 157964 (2009
45. Yano S, Kondo K, Yamaguchi M et al. Distribution and function of EGFR in human tissue and the effect of EGFR tyrosine kinase inhibition. Anticancer Res. 23(5A), 3639-3650 (2003 (Pubitemid 37474306)
46. Yarden Y, Pines G. The ERBB network: At last, cancer therapy meets systems biology. Nat. Rev. Cancer 12(8), 553-563 (2012
47. Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a Phase 3 randomised trial, and relation between cetuximab-Induced rash and survival. Lancet Oncol. 11(1), 21-28 (2010
48. Weinstein IB, Joe A. Oncogene addiction. Cancer Res. 68(9), 3077-3080; discussion 3080 (2008
49. Weinstein IB. Cancer. Addiction to oncogenes - The Achilles heal of cancer. Science 297(5578), 63-64 (2002 (Pubitemid 34743088)
50. Lahaye T, Riehm B, Berger U et al. Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: A 4.5-year follow-up. Cancer 103(8), 1659-1669 (2005 (Pubitemid 40490027)
51. Nguyen LV, Vanner R, Dirks P, Eaves CJ. Cancer stem cells: An evolving concept. Nat. Rev. Cancer 12(2), 133-143 (2012
52. Bonnet D. Cancer stem cells: Lessons from leukaemia. Cell Prolif. 38(6), 357-361 (2005 (Pubitemid 41746368)
53. Dalerba P, Cho RW, Clarke MF. Cancer stem cells: Nodels and concepts. Annu. Rev. Med. 58, 267-284 (2007 (Pubitemid 46706514)
54. Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene 23(43), 7274-7282 (2004 (Pubitemid 39382161)
55. Singh SK, Clarke ID, Terasaki M et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63(18), 5821-5828 (2003 (Pubitemid 37187480)
56. Roeder I, Horn M, Glauche I, Hochhaus A, Mueller MC, Loeffler M. Dynamic modeling of imatinib-Treated chronic myeloid leukemia: Functional insights and clinical implications. Nat. Med. 12(10), 1181-1184 (2006 (Pubitemid 44527354)
57. Dingli D, Traulsen A, Pacheco JM. Stochastic dynamics of hematopoietic tumor stem cells. Cell Cycle 6(4), 461-466 (2007 (Pubitemid 46393451)
58. Komarova NL, Wodarz D. Effect of cellular quiescence on the success of targeted CML therapy. Plos One 2(10), e990 (2007
59. Karaman MW, Herrgard S, Treiber DK et al. A quantitative analysis of kinase inhibitor selectivity. Nat. Biotechnol. 26(1), 127-132 (2008
60. Bogoyevitch MA, Fairlie DP. A new paradigm for protein kinase inhibition: Blocking phosphorylation without directly targeting ATP binding. Drug Discov. Today 12(15-16), 622-633 (2007 (Pubitemid 47238645)
61. Vinkenborg JL, Karnowski N, Famulok M. Aptamers for allosteric regulation. Nat. Chem. Biol. 7(8), 519-527 (2011
62. O'Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat. Rev. Cancer 12(8), 513-526 (2012
63. Quintás-Cardama A, Kantarjian H, Cortes J. Imatinib and beyond-exploring the full potential of targeted therapy for CML. Nat. Rev. Clin. Oncol. 6(9), 535-543 (2009
64. Liebler DC, Guengerich FP. Elucidating mechanisms of drug-Induced toxicity. Nat. Rev. Drug Discov. 4(5), 410-420 (2005 (Pubitemid 40704124)
65. Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br. J. Cancer 96(12), 1788-1795 (2007 (Pubitemid 46912024)
66. Martel CL, Presant CA, Ebrahimi B et al. Bevacizumab-related toxicities: Association of hypertension and proteinuria. Comm. Oncol. 3, 90-93 (2006 (Pubitemid 43266945)
67. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 12(4), 237-251 (2012
68. Lindpaintner K. The impact of pharmacogenetics and pharmacogenomics on drug discovery. Nat. Rev. Drug Discov. 1(6), 463-469 (2002 (Pubitemid 37361489)
69. Shoemaker RH. The NCI60 human tumour cell line anticancer drug screen. Nat. Rev. Cancer 6(10), 813-823 (2006 (Pubitemid 44450469)
70. Karlsson EK, Lindblad-Toh K. Leader of the pack: Gene mapping in dogs and other model organisms. Nat. Rev. Genet. 9(9), 713-725 (2008
71. Paoloni M, Khanna C. Translation of new cancer treatments from pet dogs to humans. Nat. Rev. Cancer 8(2), 147-156 (2008 (Pubitemid 351161319)
72. Greaves P, Williams A, Eve M. First dose of potential new medicines to humans: How animals help. Nat. Rev. Drug Discov. 3(3), 226-236 (2004 (Pubitemid 38379989)
73. Mullard A. 2011 FDA drug approvals. Nat. Rev. Drug Discov. 11(2), 91-94 (2012
74. Knight ZA, Lin H, Shokat KM. Targeting the cancer kinome through polypharmacology. Nat. Rev. Cancer 10(2), 130-137 (2010
75. Pritchard JF, Jurima-Romet M, Reimer ML, Mortimer E, Rolfe B, Cayen MN. Making better drugs: Decision gates in non-clinical drug development. Nat. Rev. Drug Discov. 2(7), 542-553 (2003 (Pubitemid 37361746)
76. Kotz J. Phenotypic screening, take two. SciBX 5(15), doi:10.1038/scibx. 2012.380 (2012
77. Swinney DC, Anthony J. How were new medicines discovered̈Nat. Rev. Drug Discov. 10(7), 507-519 (2011
78. Maira SM, Stauffer F, Brueggen J et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol. Cancer Ther. 7(7), 1851-1863 (2008
79. Kaelin WG Jr. The concePTof synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 5(9), 689-698 (2005 (Pubitemid 41486362)
80. Chan DA, Giaccia AJ. Harnessing synthetic lethal interactions in anticancer drug discovery. Nat. Rev. Drug Discov. 10(5), 351-364 (2011