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Text mining-based in silico drug discovery in oral mucositis caused by high-dose cancer therapy

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Abstract

Introduction

Oral mucositis (OM) is a major dose-limiting side effect of chemotherapy and radiation used in cancer treatment. Due to the complex nature of OM, currently available drug-based treatments are of limited efficacy.

Objectives

Our objectives were (i) to determine genes and molecular pathways associated with OM and wound healing using computational tools and publicly available data and (ii) to identify drugs formulated for topical use targeting the relevant OM molecular pathways.

Methods

OM and wound healing-associated genes were determined by text mining, and the intersection of the two gene sets was selected for gene ontology analysis using the GeneCodis program. Protein interaction network analysis was performed using STRING-db. Enriched gene sets belonging to the identified pathways were queried against the Drug-Gene Interaction database to find drug candidates for topical use in OM.

Results

Our analysis identified 447 genes common to both the “OM” and “wound healing” text mining concepts. Gene enrichment analysis yielded 20 genes representing six pathways and targetable by a total of 32 drugs which could possibly be formulated for topical application. A manual search on ClinicalTrials.gov confirmed no relevant pathway/drug candidate had been overlooked. Twenty-five of the 32 drugs can directly affect the PTGS2 (COX-2) pathway, the pathway that has been targeted in previous clinical trials with limited success.

Conclusions

Drug discovery using in silico text mining and pathway analysis tools can facilitate the identification of existing drugs that have the potential of topical administration to improve OM treatment.

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References

  1. Al-Dasooqi N, Sonis ST, Bowen JM, Bateman E, Blijlevens N, Gibson RJ, Logan RM, Nair RG, Stringer AM, Yazbeck R, Elad S, Lalla RV, Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral O (2013) Emerging evidence on the pathobiology of mucositis. Support Care Cancer 21:3233–3241

    Article  PubMed  Google Scholar 

  2. Andronis C, Sharma A, Virvilis V, Deftereos S, Persidis A (2011) Literature mining, ontologies and information visualization for drug repurposing. Brief Bioinform 12:357–368

    Article  PubMed  CAS  Google Scholar 

  3. Baran J, Gerner M, Haeussler M, Nenadic G, Bergman CM (2011) pubmed2ensembl: a resource for mining the biological literature on genes. PLoS One 6:e24716

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Barasch A, Epstein J, Tilashalski K (2009) Palifermin for management of treatment-induced oral mucositis in cancer patients. Biologics 3:111–116

    PubMed  PubMed Central  CAS  Google Scholar 

  5. Basso FG, Pansani TN, Soares DG, Scheffel DL, Bagnato VS, de Souza Costa CA, Hebling J (2015) Biomodulation of inflammatory cytokines related to oral mucositis by low-level laser therapy. Photochem Photobiol 91:952–956

    Article  PubMed  CAS  Google Scholar 

  6. Berg EL (2014) Systems biology in drug discovery and development. Drug Discov Today 19:113–125

    Article  PubMed  CAS  Google Scholar 

  7. Berker E, Kantarci A, Hasturk H, Van Dyke TE (2013) Blocking proinflammatory cytokine release modulates peripheral blood mononuclear cell response to Porphyromonas gingivalis. J Periodontol 84:1337–1345

    Article  PubMed  CAS  Google Scholar 

  8. Buache E, Etique N, Alpy F, Stoll I, Muckensturm M, Reina-San-Martin B, Chenard MP, Tomasetto C, Rio MC (2011) Deficiency in trefoil factor 1 (TFF1) increases tumorigenicity of human breast cancer cells and mammary tumor development in TFF1-knockout mice. Oncogene 30:3261–3273

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Caluwaerts S, Vandenbroucke K, Steidler L, Neirynck S, Vanhoenacker P, Corveleyn S, Watkins B, Sonis S, Coulie B, Rottiers P (2010) AG013, a mouth rinse formulation of Lactococcus lactis secreting human Trefoil Factor 1, provides a safe and efficacious therapeutic tool for treating oral mucositis. Oral Oncol 46:564–570

    Article  PubMed  CAS  Google Scholar 

  10. Carmona-Saez P, Chagoyen M, Tirado F, Carazo JM, Pascual-Montano A (2007) GENECODIS: a web-based tool for finding significant concurrent annotations in gene lists. Genome Biol 8:R3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Chaveli-Lopez B, Bagan-Sebastian JV (2016) Treatment of oral mucositis due to chemotherapy. J Clinical Exp Dent 8:e201–e209

    Google Scholar 

  12. Cheng KK, Chang AM (2003) Palliation of oral mucositis symptoms in pediatric patients treated with cancer chemotherapy. Cancer Nurs 26:476–484

    Article  PubMed  CAS  Google Scholar 

  13. Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE (2012) ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335:1503–1506

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Feng CJ, Guo JB, Jiang HW, Zhu SX, Li CY, Cheng B, Chen Y, Wang HY (2008) Spatio-temporal localization of HIF-1alpha and COX-2 during irradiation-induced oral mucositis in a rat model system. Int J Radiat Biol 84:35–45

    Article  PubMed  CAS  Google Scholar 

  15. Filicko J, Lazarus HM, Flomenberg N (2003) Mucosal injury in patients undergoing hematopoietic progenitor cell transplantation: new approaches to prophylaxis and treatment. Bone Marrow Transplant 31:1–10

    Article  PubMed  CAS  Google Scholar 

  16. Gruber S, Hamedinger D, Bozsaky E, Schmidt M, Wolfram K, Haagen J, Habelt B, Puttrich M, Dorr W (2015) Local hypoxia in oral mucosa (mouse) during daily fractionated irradiation—effect of pentoxifylline. Radiother Oncol 116:404–408

    Article  PubMed  CAS  Google Scholar 

  17. Han G, Bian L, Li F, Cotrim A, Wang D, Lu J, Deng Y, Bird G, Sowers A, Mitchell JB, Gutkind JS, Zhao R, Raben D, ten Dijke P, Refaeli Y, Zhang Q, Wang XJ (2013) Preventive and therapeutic effects of Smad7 on radiation-induced oral mucositis. Nat Med 19:421–428

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Hejna M, Kostler WJ, Raderer M, Steger GG, Brodowicz T, Scheithauer W, Wiltschke C, Zielinski CC (2001) Decrease of duration and symptoms in chemotherapy-induced oral mucositis by topical GM-CSF: results of a prospective randomised trial. Eur J Cancer 37:1994–2002

    Article  PubMed  CAS  Google Scholar 

  19. Kadekaro AL, Kavanagh R, Kanto H, Terzieva S, Hauser J, Kobayashi N, Schwemberger S, Cornelius J, Babcock G, Shertzer HG, Scott G, Abdel-Malek ZA (2005) alpha-Melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytes. Cancer Res 65:4292–4299

    Article  PubMed  CAS  Google Scholar 

  20. Khan ZE, Wang TC, Cui G, Chi AL, Dimaline R (2003) Transcriptional regulation of the human trefoil factor, TFF1, by gastrin 1. Gastroenterology 125:510–521

    Article  PubMed  CAS  Google Scholar 

  21. Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han L, He J, He S, Shoemaker BA, Wang J, Yu B, Zhang J, Bryant SH (2016) PubChem substance and compound databases. Nucleic Acids Res 44:D1202–D1213

    Article  PubMed  CAS  Google Scholar 

  22. Kostrica RR, Rottenberg J, Kvech J, Betka J, Jablonicky J (2002) Randomised double blind comparison of efficacy and tolerability of diclofenac mouthwash versus placebo in mucositis of oral cavity by radiotherapy. J Clin Res 5:1–15

    Google Scholar 

  23. Lalla RV, Choquette LE, Curley KF, Dowsett RJ, Feinn RS, Hegde UP, Pilbeam CC, Salner AL, Sonis ST, Peterson DE (2014) Randomized double-blind placebo-controlled trial of celecoxib for oral mucositis in patients receiving radiation therapy for head and neck cancer. Oral Oncol 50:1098–1103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Lalla RV, Pilbeam CC, Walsh SJ, Sonis ST, Keefe DM, Peterson DE (2010) Role of the cyclooxygenase pathway in chemotherapy-induced oral mucositis: a pilot study. Support Care Cancer 18:95–103

    Article  PubMed  Google Scholar 

  25. Liu H, Beck TN, Golemis EA, Serebriiskii IG (2014) Integrating in silico resources to map a signaling network. Methods Mol Biol 1101:197–245

    Article  PubMed  CAS  Google Scholar 

  26. Marsden VS, O'Connor L, O'Reilly LA, Silke J, Metcalf D, Ekert PG, Huang DC, Cecconi F, Kuida K, Tomaselli KJ, Roy S, Nicholson DW, Vaux DL, Bouillet P, Adams JM, Strasser A (2002) Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome. Nature 419:634–637

    Article  PubMed  CAS  Google Scholar 

  27. Moosavinasab S, Patterson J, Strouse R, Rastegar-Mojarad M, Regan K, Payne PR, Huang Y, Lin SM (2016) ‘RE:fine drugs’: an interactive dashboard to access drug repurposing opportunities Database (Oxford). https://doi.org/10.1093/database/baw083

  28. Mosca E, Bertoli G, Piscitelli E, Vilardo L, Reinbold RA, Zucchi I, Milanesi L (2009) Identification of functionally related genes using data mining and data integration: a breast cancer case study. BMC Bioinf 10(Suppl 12):S8

    Article  CAS  Google Scholar 

  29. Nicolatou-Galitis O, Sarri T, Bowen J, Di Palma M, Kouloulias VE, Niscola P, Riesenbeck D, Stokman M, Tissing W, Yeoh E, Elad S, Lalla RV, Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral O (2013) Systematic review of anti-inflammatory agents for the management of oral mucositis in cancer patients. Support Care Cancer 21:3179–3189

    Article  PubMed  Google Scholar 

  30. Nogales-Cadenas R, Carmona-Saez P, Vazquez M, Vicente C, Yang X, Tirado F, Carazo JM, Pascual-Montano A (2009) GeneCodis: interpreting gene lists through enrichment analysis and integration of diverse biological information. Nucleic Acids Res 37:W317–W322

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Pang L, Cai Y, Tang EH, Yan D, Kosuru R, Li H, Irwin MG, Ma H, Xia Z (2016) Cox-2 inhibition protects against hypoxia/reoxygenation-induced cardiomyocyte apoptosis via Akt-dependent enhancement of iNOS expression. Oxidative Med Cell Longev 2016:3453059

    Article  CAS  Google Scholar 

  32. Patte C, Laplanche A, Bertozzi AI, Baruchel A, Frappaz D, Schmitt C, Mechinaud F, Nelken B, Boutard P, Michon J (2002) Granulocyte colony-stimulating factor in induction treatment of children with non-Hodgkin’s lymphoma: a randomized study of the French Society of Pediatric Oncology. J Clin Oncol 20:441–448

    PubMed  CAS  Google Scholar 

  33. Shenep JL, Kalwinsky DK, Hutson PR, George SL, Dodge RK, Blankenship KR, Thornton D (1988) Efficacy of oral sucralfate suspension in prevention and treatment of chemotherapy-induced mucositis. J Pediatr 113:758–763

    Article  PubMed  CAS  Google Scholar 

  34. Shim JS, Liu JO (2014) Recent advances in drug repositioning for the discovery of new anticancer drugs. Int J Biol Sci 10:654–663

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Sonis ST (2007) Pathobiology of oral mucositis: novel insights and opportunities. J Support Oncol 5:3–11

    PubMed  CAS  Google Scholar 

  36. Sonis ST (2010) Efficacy of palifermin (keratinocyte growth factor-1) in the amelioration of oral mucositis. Core Evid 4:199–205

    PubMed  PubMed Central  Google Scholar 

  37. Sonis ST (2010) New thoughts on the initiation of mucositis. Oral Dis 16:597–600

    Article  PubMed  CAS  Google Scholar 

  38. Sonis ST, O'Donnell KE, Popat R, Bragdon C, Phelan S, Cocks D, Epstein JB (2004) The relationship between mucosal cyclooxygenase-2 (COX-2) expression and experimental radiation-induced mucositis. Oral Oncol 40:170–176

    Article  PubMed  CAS  Google Scholar 

  39. Stokman MA, Spijkervet FK, Burlage FR, Roodenburg JL (2005) Clinical effects of flurbiprofen tooth patch on radiation-induced oral mucositis. A pilot study. Support Care Cancer 13:42–48

    Article  PubMed  CAS  Google Scholar 

  40. Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43:D447–D452

    Article  PubMed  CAS  Google Scholar 

  41. Szklarczyk D, Santos A, von Mering C, Jensen LJ, Bork P, Kuhn M (2016) STITCH 5: augmenting protein-chemical interaction networks with tissue and affinity data. Nucleic Acids Res 44:D380–D384

    Article  PubMed  CAS  Google Scholar 

  42. Tabas-Madrid D, Nogales-Cadenas R, Pascual-Montano A (2012) GeneCodis3: a non-redundant and modular enrichment analysis tool for functional genomics. Nucleic Acids Res 40:W478–W483

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Tousi B (2015) The emerging role of bexarotene in the treatment of Alzheimer’s disease: current evidence. Neuropsychiatr Dis Treat 11:311–315

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Wagner AH, Coffman AC, Ainscough BJ, Spies NC, Skidmore ZL, Campbell KM, Krysiak K, Pan D, McMichael JF, Eldred JM, Walker JR, Wilson RK, Mardis ER, Griffith M, Griffith OL (2016) DGIdb 2.0: mining clinically relevant drug-gene interactions. Nucleic Acids Res 44:D1036–D1044

    Article  PubMed  CAS  Google Scholar 

  45. Yu S, Tranchevent LC, De Moor B, Moreau Y (2010) Gene prioritization and clustering by multi-view text mining. BMC Bioinf 11:28

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are thankful to the research team in the department of Oral Medicine and to Dr. Cory Brouwer for their helpful discussions at the beginning of this project.

Funding

This work was supported by Carolinas HealthCare System Research fund.

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Authors and Affiliations

  1. Department of Oral Medicine, Cannon Research Center, Carolinas HealthCare System, Charlotte, NC, USA

    Jon Kirk, Nirav Shah, Braxton Noll, Craig B. Stevens, Marshall Lawler, Farah B. Mougeot & Jean-Luc C. Mougeot

  2. Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, USA

    Jon Kirk & Jean-Luc C. Mougeot

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  1. Jon Kirk
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Electronic supplementary material

Supplementary Figure 1.

Targetable PTGS2/BCL2 subnetwork. Connecting line color indicates the type of information used to infer the association.Items were arranged manually for optimal viewing.(GIF 9kb)

High resolution image (TIFF 227kb)

Supplementary Figure 2.

KEGG diagram for the Nuclear Factor kappa-B signaling pathway, with relevant genes highlighted in red. The gene CFLAR is referred to here by its alias ‘c-FLIP.’ (GIF 166kb)

High resolution image (TIFF 1344kb)

Supplementary Figure 3.

KEGG diagram for the apoptosis pathway, with relevant genes highlighted in red. CFLAR is referred to here as ‘FLIP’; TP53 is referred to as ‘p53’; AKT1 is referred to as Akt/PKB. (GIF 166kb)

High resolution image (TIFF 1328kb)

Supplementary Table 1.

Total 48 genes identified by protein interaction analysis. KEGG enriched 89 significant genes yielded 48 genes with potential interactions using STRING.(DOCX 16kb)

Supplementary Table 2.

OM drug candidates targeting genes belonging to KEGG pathways associated with oral mucositis and cancer therapy. The table contains 50 most highly enriched KEGG pathways in the gene set intersecting the text mining search results for 'oral mucositis,' and the search results for genes affected by drugs that have been tested or are being tested in clinical trials for cancer therapy associated OM (ClinicalTrials.gov). The p-value is calculated using the hypergeometric distribution, which describes the probability of a number of a given type of genes appearing in the query set given the total number of those genes in the reference set (genome). (DOCX 26kb)

Supplementary Table 3.

OM drug candidates targeting genes belonging to KEGG pathways associated with wound healing and cancer therapy. The table contains the 52 most highly enriched KEGG pathways in the gene set intersecting the text mining search results for 'wound healing,' and the search results for genes affected by clinical trial drugs. The p-value is calculated using the hypergeometric distribution as described in the Supplementary Table 2 note above. (DOCX 27kb)

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Kirk, J., Shah, N., Noll, B. et al. Text mining-based in silico drug discovery in oral mucositis caused by high-dose cancer therapy. Support Care Cancer 26, 2695–2705 (2018). https://doi.org/10.1007/s00520-018-4096-2

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  • DOI: https://doi.org/10.1007/s00520-018-4096-2

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