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VeloceGenomics: An Accelerated in Vivo Drug Discovery Approach to Rapidly Predict the Biologic, Drug-Like Activity of Compounds, Proteins, or Genes

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Purpose

The aim of this study is to test the predictive power of in vivo multiorgan RNA expression profiling in identifying the biologic activity of molecules.

Methods

Animals were treated with compound A or B. At the end of the treatment period, in vivo multiorgan microarray-based gene expression data were collected. Investigators masked to the identity of the compounds analyzed the transcriptome signatures to define the molecular pathways affected by treatment and to hypothesize the biologic activity and potential therapeutic indications of the blinded compounds.

Results

For compound A, G-protein-coupled receptors and factors associated with cell growth were affected—growth hormone/insulin-like growth factor-1, glucagon/insulin axes, and general somatomedin-like activity. Deblinding showed the compound to be a somatostatin analog, SOM230, confirming the accuracy of the predicted biologic activity. For compound B, components of the inflammatory cascade potentially mediated by lipopolysaccharide, tumor necrosis factor, or proinflammatory cytokines were affected. The gene expression signatures were most consistent with an interleukin-6 family activity. Deblinding revealed that compound B was leukemia inhibitory factor.

Conclusions

VeloceGenomics is a strategy of coupling in vivo compound testing with genomic technologies. The process enables prediction of the mechanism of action and, coupled with other relevant data, prediction of the suitability of compounds for advancement in the drug development process.

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Abbreviations

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

ERK:

extracellular signal-related kinase

GH:

growth hormone

GPCR:

G-protein-coupled receptor

IGF:

insulin-like growth factor

IL:

interleukin

JAK:

Janus kinase

LIF:

leukemia inhibitory factor

LPS:

lipopolysaccharide

LRR:

leucine-rich repeats

MAPK:

mitogen-activated protein kinase

NF-κβ:

nuclear factor kappa beta

OSM:

oncostatin M

PI3K:

phosphatidylinositol 3 kinase

SOCS:

suppressor of cytokine signaling

SSTR:

somatostatin receptors

STAT:

signal transducer and activator of transcription

TIMP:

tissue inhibitor of metalloproteinase

TLR:

Toll-like receptor

TRAF:

tumor necrosis factor receptor-associated factor

References

  1. D. L. Gerhold R. V. Jensen S. R. Gullans (2002) ArticleTitleBetter therapeutics through microarrays Nat. Genet. 32 547–551 Occurrence Handle10.1038/ng1042 Occurrence Handle12454652

    Article  PubMed  Google Scholar 

  2. M. A. Lindsay (2003) ArticleTitleTarget discovery Nat. Rev., Drug Discov. 2 831–838

    Google Scholar 

  3. J. Drews (2000) ArticleTitleDrug discovery: a historical perspective Science 287 1960–1964

    Google Scholar 

  4. C. Debouck P. N. Goodfellow (1999) ArticleTitleDNA microarrays in drug discovery and development Nat. Genet. 21 48–50 Occurrence Handle10.1038/4475 Occurrence Handle9915501

    Article  PubMed  Google Scholar 

  5. H. Kubinyi (2003) ArticleTitleDrug research: myths, hype and reality Nat. Rev., Drug Discov. 2 665–668

    Google Scholar 

  6. D. F. Horrobin (2003) ArticleTitleModern biomedical research: an internally self-consistent universe with little contact with medical reality? Nat. Rev., Drug Discov. 2 151–154

    Google Scholar 

  7. E. Durr J. Yu K. M. Krasinska L. A. Carver J. R. Yates J. E. Testa P. Oh J. E. Schnitzer (2004) ArticleTitleDirect proteomic mapping of the lung microvascular endothelial cell surface in vivo and in cell culture Nat. Biotechnol. 22 985–992 Occurrence Handle10.1038/nbt993 Occurrence Handle15258593

    Article  PubMed  Google Scholar 

  8. I. Kola J. Landis (2004) ArticleTitleCan the pharmaceutical industry reduce attrition rates? Nat. Rev., Drug Discov. 3 711–715

    Google Scholar 

  9. H. Ellinger-Ziegelbauer B. Stuart B. Wahle W. Bomann H. J. Ahr (2004) ArticleTitleCharacteristic expression profiles induced by genotoxic carcinogens in rat liver Toxicol. Sci. 77 19–34 Occurrence Handle10.1093/toxsci/kfh016 Occurrence Handle14600272

    Article  PubMed  Google Scholar 

  10. Y. C. Patel (1999) ArticleTitleSomatostatin and its receptor family Front. Neuroendocrinol. 20 157–198 Occurrence Handle10.1006/frne.1999.0183 Occurrence Handle10433861

    Article  PubMed  Google Scholar 

  11. B. B. Fredholm W. W. Fleming P. M. Vanhoutte T. Godfraind (2002) ArticleTitleThe role of pharmacology in drug discovery Nat. Rev., Drug Discov. 1 237–238

    Google Scholar 

  12. P. Chomczynski N. Sacchi (1987) ArticleTitleSingle-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction Anal. Biochem. 162 156–159 Occurrence Handle2440339

    PubMed  Google Scholar 

  13. D. J. Lockhart H. Dong M. C. Byrne M. T. Follettie M. V. Gallo M. S. Chee M. Mittmann C. Wang M. Kobayashi H. Horton E. L. Brown (1996) ArticleTitleExpression monitoring by hybridization to high-density oligonucleotide arrays Nat. Biotechnol. 14 1675–1680 Occurrence Handle10.1038/nbt1296-1675 Occurrence Handle9634850

    Article  PubMed  Google Scholar 

  14. G. Liu A. E. Loraine R. Shigeta M. Cline J. Cheng V. Valmeekam S. Sun D. Kulp M. A. Siani-Rose (2003) ArticleTitleNetAffx: affymetrix probesets and annotations Nucleic Acids Res. 31 8–86 Occurrence Handle10.1093/nar/gng008

    Article  Google Scholar 

  15. K. C. Leung K. K. Ho (2001) ArticleTitleMeasurement of growth hormone, insulin-like growth factor I and their binding proteins: the clinical aspects Clin. Chim. Acta 313 119–123 Occurrence Handle10.1016/S0009-8981(01)00662-3 Occurrence Handle11694248

    Article  PubMed  Google Scholar 

  16. M. Giusti L. Bocca T. Florio A. Corsaro R. Spaziante G. Schettini F. Minuto (2002) ArticleTitleIn vitro effect of recombinant leptin and expression of leptin receptors on growth hormone-secreting human pituitary adenomas Clin. Endocrinol. 57 449–455 Occurrence Handle10.1046/j.1365-2265.2002.01612.x

    Article  Google Scholar 

  17. L. Cuttler P. A. Birkenbach M. Szabo (1989) ArticleTitleThe effect of age on prostaglandin E2 stimulation of growth hormone release from cultured rat pituitary cells Endocrinology 124 661–666 Occurrence Handle2912693

    PubMed  Google Scholar 

  18. S. Siehler D. Hoyer (1999) ArticleTitleCharacterisation of human recombinant somatostatin receptors. 3. Modulation of adenylate cyclase activity Naunyn-Schmiedeberg's Arch. Pharmacol. 360 510–521 Occurrence Handle10.1007/s002109900143

    Article  Google Scholar 

  19. M. Akbar F. Okajima H. Tomura M. A. Majid Y. Yamada S. Seino Y. Kondo (1994) ArticleTitlePhospholipase C activation and Ca2+ mobilization by cloned human somatotropin receptor subtypes 1–5, in transfected COS-7 cells FEBS Lett. 348 192–196 Occurrence Handle10.1016/0014-5793(94)00603-2 Occurrence Handle8034040

    Article  PubMed  Google Scholar 

  20. L. N. Møller C. E. Stidsen B. Hartmann J. J. Holst (2003) ArticleTitleSomatostatin receptors Biochim. Biophys. Acta 1616 1–84 Occurrence Handle14507421

    PubMed  Google Scholar 

  21. M. Tallent G. Liapakis A. M. O'Carroll S. J. Lolait M. Dichter T. Reisine (1996) ArticleTitleSomatostatin receptor subtypes sstr2 and sstr5 couple negatively to an L-type Ca2+ current in the pituitary cell line AtT-20 Neuroscience 71 1073–1081 Occurrence Handle10.1016/0306-4522(95)00510-2 Occurrence Handle8684611

    Article  PubMed  Google Scholar 

  22. H. J. Kreienkamp H. H. Honck D. Richter (1997) ArticleTitleCoupling of rat somatostatin receptor subtypes to a G-protein gated inwardly rectifying potassium channel (GIRK1) FEBS Lett. 419 92–94 Occurrence Handle10.1016/S0014-5793(97)01437-3 Occurrence Handle9426226

    Article  PubMed  Google Scholar 

  23. L. Buscail N. Delsque J. P. Esteve N. Saint-Laurent H. Prats P. Clerc P. Robberecht G. I. Bell C. Liebow A. V. Schally N. Vaysse C. Susini (1994) ArticleTitleStimulation of tyrosine phosphatase and inhibition of cell proliferation by somatostatin analogues: mediation by human somatostatin receptor subtypes SSTR1 and SSTR Proc. Natl. Acad. Sci. USA 91 2315–2319 Occurrence Handle7907795

    PubMed  Google Scholar 

  24. J. Held-Feindt F. Forstreuter T. Pufe R. Mentlein (2001) ArticleTitleInfluence of the somatostatin receptor sst2 on growth factor signal cascade in human glioma cells Mol. Brain Res. 87 12–21 Occurrence Handle10.1016/S0169-328X(00)00225-4 Occurrence Handle11223155

    Article  PubMed  Google Scholar 

  25. M. G. Cattaneo D. Amoroso G. Gussoni A. M. Sanguini L. M. Vicentini (1996) ArticleTitleA somatostatin analog inhibits MAP kinase activation and cell proliferation in human neuroblastoma and in human small cell lung carcinoma cell lines FEBS Lett. 397 164–168 Occurrence Handle10.1016/S0014-5793(96)01159-3 Occurrence Handle8955339

    Article  PubMed  Google Scholar 

  26. H. Lahlou J. Guillermet M. Hortala F. Vernejoul S. Pyronnet C. Bousquet C. Susini (2004) ArticleTitleMolecular signaling of somatostatin receptors Ann. N.Y. Acad. Sci. 1014 121–131 Occurrence Handle10.1196/annals.1294.012 Occurrence Handle15153426

    Article  PubMed  Google Scholar 

  27. G. I. Bell K. Yasuda H. Kong S. F. Law K. Raynor T. Reisine (1995) ArticleTitleMolecular biology of somatostatin receptors Ciba Found. Symp. 190 65–79 Occurrence Handle7587653

    PubMed  Google Scholar 

  28. M. H. RegenmortelVan (2000) ArticleTitleAre there two distinct research strategies for developing biologically active molecules: rational design and empirical selection? J. Mol. Recognit. 13 1–4 Occurrence Handle10.1002/(SICI)1099-1352(200001/02)13:1<1::AID-JMR490>3.0.CO;2-W Occurrence Handle10679890

    Article  PubMed  Google Scholar 

  29. J. E. Parrillo (1993) ArticleTitlePathogenetic mechanisms of septic shock N. Engl. J. Med. 328 1471–1477 Occurrence Handle10.1056/NEJM199305203282008 Occurrence Handle8479467

    Article  PubMed  Google Scholar 

  30. P. C. Heinrich I. Behrmann S. Haan H. M. Hermanns G. Muller-Newen F. Schaper (2003) ArticleTitlePrinciples of interleukin (IL)-6-type cytokine signaling and its regulation Biochem. J. 374 1–20 Occurrence Handle10.1042/BJ20030407 Occurrence Handle12773095

    Article  PubMed  Google Scholar 

  31. R. L. Modlin H. D. Brightbill P. J. Godowski (1999) ArticleTitleThe toll of innate immunity on microbial pathogens N. Engl. J. Med. 340 1834–1835 Occurrence Handle10.1056/NEJM199906103402312 Occurrence Handle10362831

    Article  PubMed  Google Scholar 

  32. K. Miyake (2003) ArticleTitleInnate recognition of lipopolysaccharide by CD14 and toll-like receptor 4-MD-2: unique roles for MD-2 Int. Immunopharmacol. 3 119–128 Occurrence Handle10.1016/S1567-5769(02)00258-8 Occurrence Handle12538042

    Article  PubMed  Google Scholar 

  33. E. M. Palsson-McDermott L. A. O'Neill (2004) ArticleTitleSignal transduction by the lipopolysaccharide receptor, toll-like receptor-4 Immunology 113 153–162 Occurrence Handle10.1111/j.1365-2567.2004.01976.x Occurrence Handle15379975

    Article  PubMed  Google Scholar 

  34. T. Ikezoe Y. Yang D. Heber H. Taguchi H. P. Koeffler (2003) ArticleTitlePC-SPES: a potent inhibitor of nuclear factor-kB rescues mice from lipopolysaccharide-induced septic shock Mol. Pharmacol. 64 1521–1529 Occurrence Handle10.1124/mol.64.6.1521 Occurrence Handle14645683

    Article  PubMed  Google Scholar 

  35. R. D. Fannin J. T. Auman M. E. Bruno S. O. Sieber S. M. Ward C. J. Tucker B. A. Merrick R. S. Paules (2005) ArticleTitleDifferential gene expression profiling in whole blood during acute systemic inflammation in lipopolysaccharide-treated rats Physiol. Genomics 21 92–104 Occurrence Handle10.1152/physiolgenomics.00190.2004 Occurrence Handle15781589

    Article  PubMed  Google Scholar 

  36. K. Jatta D. Wagsater L. Norgren B. Stenberg A. Sirsjo (2005) ArticleTitleLipopolysaccharide-induced cytokine and chemokine expression in human carotid lesions J. Vasc. Res. 42 266–271 Occurrence Handle10.1159/000085721 Occurrence Handle15886490

    Article  PubMed  Google Scholar 

  37. H. Bjorkbacka K. A. Fitzgerald F. Huet X. Li J. A. Gregory M. A. Lee C. M. Ordija N. E. Dowley D. T. Golenbock M. W. Freeman (2004) ArticleTitleThe induction of macrophage gene expression by LPS predominantly utilizes Myd88-independent signaling cascades Physiol. Genomics 19 319–330 Occurrence Handle10.1152/physiolgenomics.00128.2004 Occurrence Handle15367722

    Article  PubMed  Google Scholar 

  38. J. Inoue T. Ishida N. Tsukamoto N. Kobayashi A. Naito S. Azuma T. Yamamoto (2000) ArticleTitleTumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling Exp. Cell Res. 254 14–24 Occurrence Handle10.1006/excr.1999.4733 Occurrence Handle10623461

    Article  PubMed  Google Scholar 

  39. A. K. Garg B. B. Aggarwal (2002) ArticleTitleReactive oxygen intermediates in TNF signaling Mol. Immunol. 39 509–517 Occurrence Handle10.1016/S0161-5890(02)00207-9 Occurrence Handle12431383

    Article  PubMed  Google Scholar 

  40. H. Negoro E. Oh K. Tone Y. Kunisada K. Fujio T. Walsh Kishimoto K. Yamauchi-Takihara (2001) ArticleTitleGlycoprotein 130 regulates cardiac myocyte survival in doxorubicin-induced apoptosis through phosphatidylinositol 3-kinase/Akt phosphorylation and Bcl-xL/caspase-3 interaction Circulation 103 555–561 Occurrence Handle11157722

    PubMed  Google Scholar 

  41. M. Philip D. A. Rowley H. Schreiber (2004) ArticleTitleInflammation as a tumor promoter in cancer induction Semin. Cancer Biol. 14 433–439 Occurrence Handle10.1016/j.semcancer.2004.06.006 Occurrence Handle15489136

    Article  PubMed  Google Scholar 

  42. G. Florholmen K. B. Andersson A. Yndestad B. Austbo U. L. Henriksen G. Christensen (2004) ArticleTitleLeukaemia inhibitory factor alters expression of genes involved in rat cardiomyocyte energy metabolism Acta Physiol. Scand. 180 133–142

    Google Scholar 

  43. E. C. Gunther D. J. Stone R. W. Gerwien P. Bento M. P. Heyes (2003) ArticleTitlePrediction of clinical drug efficacy by classification of drug-induced genomic expression profiles in vitro Proc. Natl. Acad. Sci. USA 100 9608–9613 Occurrence Handle10.1073/pnas.1632587100 Occurrence Handle12869696

    Article  PubMed  Google Scholar 

  44. M. Williams (2004) ArticleTitleA return to the fundamentals of drug discovery? Curr. Opin. Investig. Drugs 5 29–33 Occurrence Handle14983970

    PubMed  Google Scholar 

  45. S. F. Alino A. Crespo F. Dasi (2003) ArticleTitleLong-term therapeutic levels of human alpha-1 antitrypsin in plasma after hydrodynamic injection of nonviral DNA Gene Ther. 10 1672–1679 Occurrence Handle10.1038/sj.gt.3302065 Occurrence Handle12923566

    Article  PubMed  Google Scholar 

  46. J. M. Kim S. H. Ho W. Hahn J. G. Jeong E. J. Park H. J. Lee S. S. Yu C. S. Lee Y. W. Lee S. Kim (2003) ArticleTitleElectro-gene therapy of collagen-induced arthritis by using an expression plasmid for the soluble p75 tumor necrosis factor receptor-Fc fusion protein Gene Ther. 10 1216–1224 Occurrence Handle10.1038/sj.gt.3301985 Occurrence Handle12858186

    Article  PubMed  Google Scholar 

  47. S. Lien H. B. Lowman (2003) ArticleTitleTherapeutic peptides Trends Biotechnol. 21 556–562 Occurrence Handle10.1016/j.tibtech.2003.10.005 Occurrence Handle14624865

    Article  PubMed  Google Scholar 

  48. G. Duyk (2003) ArticleTitleAttrition and translation Science 302 603–605

    Google Scholar 

  49. M. Kleinberg K. Wilkinson-Mosdell (2004) ArticleTitleCurrent and future considerations for the new classes of biologicals (Primer) Am. J. Health-Syst. Pharm. 61 695–708 Occurrence Handle15119576

    PubMed  Google Scholar 

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Acknowledgments

The authors thank Nicole Hartmann for expert technical assistance and Mark Bossie, PhD, and Maribeth Bogush, PhD, for assistance in preparation of the manuscript. This work was funded by Novartis Pharma AG.

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Authors and Affiliations

  1. Department of Exploratory Development, Biomarker Development, Novartis Pharma A.G., Postfach, 4002, Basel, Switzerland

    Ruben Papoian, Andreas Scherer, Muriel Saulnier, Frank Staedtler, André Cordier, Francois Legay, Gerard Maurer, Joerg Staeheli, Jacky Vonderscher & Salah-Dine Chibout

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  1. Ruben Papoian
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  2. Andreas Scherer
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  3. Muriel Saulnier
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  4. Frank Staedtler
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  5. André Cordier
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  10. Salah-Dine Chibout
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Correspondence to Salah-Dine Chibout.

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Papoian, R., Scherer, A., Saulnier, M. et al. VeloceGenomics: An Accelerated in Vivo Drug Discovery Approach to Rapidly Predict the Biologic, Drug-Like Activity of Compounds, Proteins, or Genes. Pharm Res 22, 1597–1613 (2005). https://doi.org/10.1007/s11095-005-6809-8

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