Discovery and preclinical validation of drug indications using compendia of public gene expression data

Science Translational Medicine

Volumn 3, Issue 96, 2011, Pages

  Sirota, Marina ^a,b   Dudley, Joel T ^a,b   Kim, Jeewon ^c   Chiang, Annie P ^a,b   Morgan, Alex A ^a,b   Sweet Cordero, Alejandro ^a   Sage, Julien ^a,d   Butte, Atul J ^a,b  

^a STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b LUCILE PACKARD CHILDREN S HOSPITAL   (United States)

^c STANFORD CANCER INSTITUTE   (United States)

^d STANFORD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 MORPHOLINO 8 PHENYLCHROMONE; 3 HYDROXYKYNURENINE; 4 PHENYLBUTYRIC ACID; ACETYLSALICYLIC ACID; CIMETIDINE; DEXVERAPAMIL; FORSKOLIN; GEFITINIB; GELDANAMYCIN; MESALAZINE; PREDNISOLONE; RADICICOL; RALOXIFENE; SALAZOSULFAPYRIDINE; TOPIRAMATE; TRICHOSTATIN A; VORINOSTAT; WORTMANNIN;

ARTICLE; CARDIOMYOPATHY; COLITIS; CROHN DISEASE; DATA BASE; DERMATOMYOSITIS; DOWN REGULATION; DRUG EFFICACY; DRUG INDICATION; DRUG REPOSITIONING; DRUG RESEARCH; ENTERITIS; GENE EXPRESSION; GENE EXPRESSION PROFILING; GENETIC ANALYSIS; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; IN VITRO STUDY; IN VIVO STUDY; LUNG ADENOCARCINOMA; LUNG SQUAMOUS CELL CARCINOMA; MATHEMATICAL COMPUTING; MELANOMA; MICROARRAY ANALYSIS; NONHUMAN; PHENOTYPE; PLEURA MESOTHELIOMA; PRIORITY JOURNAL; STOMACH CANCER; TRANSITIONAL CELL CARCINOMA; ULCERATIVE COLITIS; UPREGULATION; ANIMAL; BIOLOGY; DRUG DESIGN; DRUG DEVELOPMENT; GENETICS; METHODOLOGY; PHYSIOLOGY;

ANIMALS; COMPUTATIONAL BIOLOGY; DRUG DESIGN; DRUG DISCOVERY; DRUG REPOSITIONING; GENE EXPRESSION; HUMANS;

EID: 84867338003     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.3001318     Document Type: Article

References (73)

1. T T Ashburn, K B Thor, Drug repositioning: Identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov. 3, 673-683 (2004).
2. J A DiMasi, R W Hansen, H G Grabowski, The price of innovation: New estimates of drug development costs. J. Health Econ. 22, 151-185 (2003).
3. C R Chong, D J Sullivan Jr., New uses for old drugs. Nature 448, 645-646 (2007).
4. J K Aronson, Old drugs - New uses. Br. J. Clin. Pharmacol. 64, 563-565 (2007).
5. P Y Lum, J M Derry, E E Schadt, Integrative genomics and drug development. Pharmacogenomics 10, 203-212 (2009).
6. E E Schadt, S H Friend, D A Shaywitz, A network view of disease and compound screening. Nat. Rev. Drug Discov. 8, 286-295 (2009).
7. X A Qu, R C Gudivada, A G Jegga, E K Neumann, B J Aronow, Inferring novel disease indications for known drugs by semantically linking drug action and disease mechanism relationships. BMC Bioinformatics 10 (Suppl. 5), S4 (2009).
8. M J Keiser, V. Setola, J J Irwin, C. Laggner, A I Abbas, S J Hufeisen, N H Jensen, M B Kuijer, R C Matos, T B Tran, R. Whaley, R A Glennon, J. Hert, K L Thomas, D D Edwards, B K Shoichet, B L Roth, Predicting new molecular targets for known drugs. Nature 462, 175-181 (2009).
9. L. Xie, J. Li, L. Xie, P E Bourne, Drug discovery using chemical systems biology: Identification of the protein-ligand binding network to explain the side effects of CETP inhibitors. PLoS Comput. Biol. 5, e1000387 (2009).
10. S L Kinnings, N. Liu, N. Buchmeier, P J Tonge, L. Xie, P E Bourne, Drug discovery using chemical systems biology: Repositioning the safe medicine Comtan to treat multi-drug and extensively drug resistant tuberculosis. PLoS Comput. Biol. 5, e1000423 (2009).
11. M. Schena, D. Shalon, R W Davis, P O Brown, Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270, 467-470 (1995).
12. R J Lipshutz, D. Morris, M. Chee, E. Hubbell, M J Kozal, N. Shah, N. Shen, R. Yang, S P Fodor, Using oligonucleotide probe arrays to access genetic diversity. Biotechniques 19, 442-447 (1995).
13. Y L Yap, X W Zhang, D. Smith, R. Soong, J. Hill, Molecular gene expression signature patterns for gastric cancer diagnosis. Comput. Biol. Chem. 31, 275-287 (2007).
14. A. Milano, S A Pendergrass, J L Sargent, L K George, T H McCalmont, M K Connolly, M L Whitfield, Molecular subsets in the gene expression signatures of scleroderma skin. PLoS One 3, e2696 (2008).
15. W ZWang, X. Guo, C. Duan, W J Ma, Y G Zhang, P. Xu, Z Q Gao, Z F Wang, H. Yan, Y F Zhang, Y X Yu, J C Chen, M J Lammi, Comparative analysis of gene expression profiles between the normal human cartilage and the one with endemic osteoarthritis. Osteoarthritis Cartilage 17, 83-90 (2009).
16. C S Walsh, S. Ogawa, H. Karahashi, D R Scoles, J C Pavelka, H. Tran, C W Miller, N. Kawamata, C. Ginther, J. Dering, M. Sanada, Y. Nannya, D J Slamon, H P Koeffler, B Y Karlan, ERCC5 is a novel biomarker of ovarian cancer prognosis. J. Clin. Oncol. 26, 2952-2958 (2008).
17. G. Hu, P. Agarwal, Human disease-drug network based on genomic expression profiles. PLoS One 4, e6536 (2009).
18. R. Dobrin, J. Zhu, C. Molony, C. Argman, M L Parrish, S. Carlson, M F Allan, D. Pomp, E E Schadt, Multi-tissue coexpression networks reveal unexpected subnetworks associated with disease. Genome Biol. 10, R55 (2009).
19. J T Dudley, R. Tibshirani, T. Deshpande, A J Butte, Disease signatures are robust across tissues and experiments. Mol. Syst. Biol. 5, 307 (2009).
20. M. Del Rio, F. Molina, C. Bascoul-Mollevi, V. Copois, F. Bibeau, P. Chalbos, C. Bareil, A. Kramar, N. Salvetat, C. Fraslon, E. Conseiller, V. Granci, B. Leblanc, B. Pau, P. Martineau, M. Ychou, Gene expression signature in advanced colorectal cancer patients select drugs and response for the use of leucovorin, fluorouracil, and irinotecan. J. Clin. Oncol. 25, 773-780 (2007).
21. J. Li, W H Wood III, K G Becker, A T Weeraratna, P J Morin, Gene expression response to cisplatin treatment in drug-sensitive and drug-resistant ovarian cancer cells. Oncogene 26, 2860-2872 (2007).
22. I. Fichtner, W. Slisow, J. Gill, M. Becker, B. Elbe, T. Hillebrand, M. Bibby, Anticancer drug response and expression of molecular markers in early-passage xenotransplanted colon carcinomas. Eur. J. Cancer 40, 298-307 (2004).
23. A. Holleman, M H Cheok, M L Den Boer, W. Yang, A J Veerman, K M Kazemier, D. Pei, C. Cheng, C H Pui, M V Relling, G E Janka-Schaub, R. Pieters, W E Evans, Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N. Engl. J. Med. 351, 533-542 (2004).
24. J. Robert, A. Vekris, P. Pourquier, J. Bonnet, Predicting drug response based on gene expression. Crit. Rev. Oncol. Hematol. 51, 205-227 (2004).
25. J. Lamb, E D Crawford, D. Peck, J W Modell, I C Blat, M J Wrobel, J. Lerner, J P Brunet, A. Subramanian, K N Ross, M. Reich, H. Hieronymus, G. Wei, S A Armstrong, S J Haggarty, P A Clemons, R. Wei, S A Carr, E S Lander, T R Golub, The Connectivity Map: Using gene-expression signatures to connect small molecules, genes, and disease. Science 313, 1929-1935 (2006).
26. K S Garman, C R Acharya, E. Edelman, M. Grade, J. Gaedcke, S. Sud, W. Barry, A M Diehl, D. Provenzale, G S Ginsburg, B M Ghadimi, T. Ried, J R Nevins, S. Mukherjee, D. Hsu, A. Potti, A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities. Proc. Natl. Acad. Sci. U.S.A. 105, 19432-19437 (2008).
27. S R Setlur, K D Mertz, Y. Hoshida, F. Demichelis, M. Lupien, S. Perner, A. Sboner, Y. Pawitan, O. Andrén, L A Johnson, J. Tang, H O Adami, S. Calza, A M Chinnaiyan, D. Rhodes, S. Tomlins, K. Fall, L A Mucci, P W Kantoff, M J Stampfer, S O Andersson, E. Varenhorst, J E Johansson, M. Brown, T R Golub, M A Rubin, Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. J. Natl. Cancer Inst. 100, 815-825 (2008).
28. V G Tusher, R. Tibshirani, G. Chu, Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl. Acad. Sci. U.S.A. 98, 5116-5121 (2001).
29. H. Okano, M. Jayachandran, A. Yoshikawa, V M Miller, Differential effects of chronic treatment with estrogen receptor ligands on regulation of nitric oxide synthase in porcine aortic endothelial cells. J. Cardiovasc. Pharmacol. 47, 621-628 (2006).
30. K J Ryan, C G Ray, Sherris Medical Microbiology (McGraw-Hill, New York, 2004).
31. R. Suzuki, H. Shimodaira, Pvclust: An R package for assessing the uncertainty in hierarchical clustering. Bioinformatics 22, 1540-1542 (2006).
32. P M Irving, R B Gearry, M P Sparrow, P R Gibson, Review article: Appropriate use of corticosteroids in Crohn's disease. Aliment. Pharmacol. Ther. 26, 313-329 (2007).
33. J T Dudley, M. Sirota, M. Shenoy, R. Pai, S. Roedder, A P Chiang, A A Morgan, M. Sarwal, P J Pasricha, A J Butte, Computational repositioning of the anticonvulsant topiramate for inflammatory bowel disease. Sci. Transl. Med. 3, 96ra76 (2011).
34. A. Jemal, F. Bray, M M Center, J. Ferlay, E. Ward, D. Forman, Global cancer statistics. CA Cancer J. Clin. 61, 69-90 (2011).
35. 2-receptor antagonists. Aliment. Pharmacol. Ther. 7 (Suppl. 2), 35-40 (1993).
36. D J Gertner, D S Rampton, T R Stevens, J E Lennard-Jones, Verapamil inhibits in-vitro leucotriene B4 release by rectal mucosa in active ulcerative colitis. Aliment. Pharmacol. Ther. 6, 163-168 (1992).
37. R N Fedorak, L R Empey, K. Walker, Verapamil alters eicosanoid synthesis and accelerates healing during experimental colitis in rats. Gastroenterology 102, 1229-1235 (1992).
38. H. Cheng, T. Force, Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics. Circ. Res. 106, 21-34 (2010).
39. D C Drummond, C O Noble, D B Kirpotin, Z. Guo, G K Scott, C C Benz, Clinical development of histone deacetylase inhibitors as anticancer agents. Annu. Rev. Pharmacol. Toxicol. 45, 495-528 (2005).
40. R. Schneider-Stock, M. Ocker, Epigenetic therapy in cancer: Molecular background and clinical development of histone deacetylase and DNA methyltransferase inhibitors. IDrugs 10, 557-561 (2007).
41. S. Shankar, R K Srivastava, Histone deacetylase inhibitors: Mechanisms and clinical significance in cancer: Mechanisms and clinical significance in cancerHDAC inhibitor-induced apoptosis. Adv. Exp. Med. Biol. 615, 261-298 (2008).
42. J. Gao, T. Chen, J. Liu, W. Liu, G. Hu, X. Guo, B. Yin, Y. Gong, J. Zhao, B. Qiang, J. Yuan, X. Peng, Loss of NECL1, a novel tumor suppressor, can be restored in glioma by HDAC inhibitor-trichostatin A through Sp1 binding site. Glia 57, 989-999 (2009).
43. K. Morita, T. Gotohda, H. Arimochi, M S Lee, S. Her, Histone deacetylase inhibitors promote neurosteroid-mediated cell differentiation and enhance serotonin-stimulated brain-derived neurotrophic factor gene expression in rat C6 glioma cells. J. Neurosci. Res. 87, 2608-2614 (2009).
44. C. Schwartz, V. Palissot, N. Aouali, S. Wack, N H Brons, B. Leners, M. Bosseler, G. Berchem, Valproic acid induces non-apoptotic cell death mechanisms in multiple myeloma cell lines. Int. J. Oncol. 30, 573-582 (2007).
45. 16INK4A upregulation and sensitization to chemotherapy in human melanoma cells. Cancer Biol. Ther. 6, 185-191 (2007).
46. E. Galanis, K A Jaeckle, M J Maurer, J M Reid, M M Ames, J S Hardwick, J F Reilly, A. Loboda, M. Nebozhyn, V R Fantin, V M Richon, B. Scheithauer, C. Giannini, P J Flynn, D F Moore Jr., J. Zwiebel, J C Buckner, Phase II trial of vorinostat in recurrent glioblastoma multiforme: A North Central Cancer Treatment Group study. J. Clin. Oncol. 27, 2052-2058 (2009).
47. H E Deubzer, V. Ehemann, A E Kulozik, F. Westermann, L. Savelyeva, A. Kopp-Schneider, D. Riester, M. Schwab, O. Witt, Anti-neuroblastoma activity of Helminthosporium carbonum (HC)-toxin is superior to that of other differentiating compounds in vitro. Cancer Lett. 264, 21-28 (2008).
48. H E Deubzer, V. Ehemann, F. Westermann, R. Heinrich, G. Mechtersheimer, A E Kulozik, M. Schwab, O. Witt, Histone deacetylase inhibitor Helminthosporium carbonum (HC)-toxin suppresses the malignant phenotype of neuroblastoma cells. Int. J. Cancer 122, 1891-1900 (2008).
49. S. Abbas, A. Bhoumik, R. Dahl, S. Vasile, S. Krajewski, N D Cosford, Z A Ronai, Preclinical studies of celastrol and acetyl isogambogic acid in melanoma. Clin. Cancer Res. 13, 6769-6778 (2007).
50. D. Eaton, R E Hawkins, Cimetidine in colorectal cancer - Are the effects immunological or adhesion-mediated? Br. J. Cancer 86, 159-160 (2002).
51. K. Furuta, S. Sato, T. Miyake, E. Okamoto, J. Ishine, S. Ishihara, Y. Amano, K. Adachi, Y. Kinoshita, Anti-tumor effects of cimetidine on hepatocellular carcinomas in diethylnitrosamine-treated rats. Oncol. Rep. 19, 361-368 (2008).
52. T. Natori, M. Sata, R. Nagai, M. Makuuchi, Cimetidine inhibits angiogenesis and suppresses tumor growth. Biomed. Pharmacother. 59, 56-60 (2005).
53. O. Sürücü, M. Middeke, I. Höschele, J. Kalder, S. Hennig, C. Dietz, I. Celik, Tumour growth inhibition of human pancreatic cancer xenografts in SCID mice by cimetidine. Inflamm. Res. 53 (Suppl. 1), S39-S40 (2004).
54. M E Osband, D. Hamilton, Y J Shen, E. Cohen, M. Shlesinger, P. Lavin, A. Brown, R. McCaffrey, Successful tumour immunotherapy with cimetidine in mice. Lancet 1, 636-638 (1981).
55. R R Gifford, R M Ferguson, B V Voss, Cimetidine reduction of tumour formation in mice. Lancet 1, 638-640 (1981).
56. R R Gifford, B V Voss, R M Ferguson, Cimetidine protection against lethal tumor challenge in mice. Surgery 90, 344-351 (1981).
57. A. Kumar, Cimetidine: An immunomodulator. DICP 24, 289-295 (1990).
58. C G Jiang, F R Liu, H M Xu, T. Wu, J. Gao, Effects of cimetidine on the biological behaviors of human gastric cancer cells. Zhonghua Yi Xue Za Zhi 86, 1813-1816 (2006).
59. K. Kobayashi, S. Matsumoto, T. Morishima, T. Kawabe, T. Okamoto, Cimetidine inhibits cancer cell adhesion to endothelial cells and prevents metastasis by blocking E-selectin expression. Cancer Res. 60, 3978-3984 (2000).
60. M. Fukuda, K. Kusama, H. Sakashita, Cimetidine inhibits salivary gland tumor cell adhesion to neural cells and induces apoptosis by blocking NCAM expression. BMC Cancer 8, 376 (2008).
61. Y A Lin, A P Chiang, R. Lin, P. Yao, R. Chen, A J Butte, Methodologies for extracting functional pharmacogenic experiments from international repository. AMIA Annu. Symp. Proc. 463-467 (2007).
62. A P Chiang, A J Butte, Data-driven methods to discover molecular determinants of serious adverse drug events. Clin. Pharmacol. Ther. 85, 259-268 (2009).
63. M. Campillos, M. Kuhn, A C Gavin, L J Jensen, P. Bork, Drug target identification using side-effect similarity. Science 321, 263-266 (2008).
64. T. Barrett, R. Edgar, Gene Expression Omnibus: Microarray data storage, submission, retrieval, and analysis. Methods Enzymol. 411, 352-369 (2006).
65. R. Edgar, M. Domrachev, A E Lash, Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30, 207-210 (2002).
66. A J Butte, R. Chen, Finding disease-related genomic experiments within an international repository: First steps in translational bioinformatics. AMIA Annu. Symp. Proc. 106-110 (2006).
67. A J Butte, I S Kohane, Creation and implications of a phenome-genome network. Nat. Biotechnol. 24, 55-62 (2006).
68. J. Dudley, A J Butte, Enabling integrative genomic analysis of high-impact human diseases through text mining. Pac. Symp. Biocomput. 580-591 (2008).
69. P. Warnat, R. Eils, B. Brors, Cross-platform analysis of cancer microarray data improves gene expression based classification of phenotypes. BMC Bioinformatics 6, 265 (2005).
70. M C Abba, Y. Hu, H. Sun, J A Drake, S. Gaddis, K. Baggerly, A. Sahin, C M Aldaz, Gene expression signature of estrogen receptor a status in breast cancer. BMC Genomics 6, 37 (2005).
71. R. Chen, L. Li, A J Butte, AILUN: Reannotating gene expression data automatically. Nat. Methods 4, 879 (2007).
72. J D Storey, A direct approach to false discovery rates. J. R. Stat. Soc. Ser. B 64, 479-498 (2002).
73. Acknowledgments: We thank A. Skrenchuk and B. Oskotsky (Stanford University) for computer support and E. Davydov, C. Do, S. Gross, and M. Schaub (Stanford University) for constructive discussion. We thank Q. Zheng of the Transgenic Mouse Research Center at the Stanford Comprehensive Cancer Center for help in conducting the mouse xenograft experiments. Funding: This work was supported by Lucile Packard Foundation for Children's Health, the Hewlett Packard Foundation, National Institute of General Medical Sciences (R01 GM079719), National Cancer Institute (R01 CA138256), National Library of Medicine (T15 LM007033), Howard Hughes Medical Institute, and Pharmaceutical Research and Manufacturers of America Foundation. Author contributions: M.S., J.T.D., A.P.C., and A.J.B. designed the study and carried out the analysis. J.K., A.S.-C., and J.S. carried out validation experiments. A.A.M. and A.P.C. assisted in the analysis. M.S., J.T.D., and A.J.B. wrote the paper. Competing interests: A.J.B. is on the scientific advisory board of NuMedii Inc. and Personalis and is a paid consultant for Lilly, Johnson and Johnson, Genstruct, Tercica, Ansh Labs, and Prevendia. J.T.D. is a consultant for NuMedii Inc. The other authors declare that they have no competing interests.