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Hedgehog pathway overexpression in pancreatic cancer is abrogated by new-generation taxoid SB-T-1216

The Pharmacogenomics Journal volume 17, pages 452–460 (2017)Cite this article

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Abstract

The Hedgehog pathway is one of the major driver pathways in pancreatic ductal adenocarcinoma. This study investigated prognostic importance of Hedgehog signaling pathway in pancreatic cancer patients who underwent a radical resection. Tumors and adjacent non-neoplastic pancreatic tissues were obtained from 45 patients with histologically verified pancreatic cancer. The effect of experimental taxane chemotherapy on the expression of Hedgehog pathway was evaluated in vivo using a mouse xenograft model prepared using pancreatic cancer cell line Paca-44. Mice were treated by experimental Stony Brook Taxane SB-T-1216. The transcript profile of 34 Hedgehog pathway genes in patients and xenografts was assessed using quantitative PCR. The Hedgehog pathway was strongly overexpressed in pancreatic tumors and upregulation of SHH, IHH, HHAT and PTCH1 was associated with a trend toward decreased patient survival. No association of Hedgehog pathway expression with KRAS mutation status was found in tumors. Sonic hedgehog ligand was overexpressed, but all other downstream genes were downregulated by SB-T-1216 treatment in vivo. Suppression of HH pathway expression in vivo by taxane-based chemotherapy suggests a new mechanism of action for treatment of this aggressive tumor.

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References

  1. Siegel R, Naishadham D, Jemal A . Cancer statistics, 2013. CA Cancer J Clin 2013; 63: 11–30.

    Article  Google Scholar 

  2. Ojima I, Chen J, Sun L, Borella CP, Wang T, Miller ML et al. Design, synthesis, and biological evaluation of new-generation taxoids. J Med Chem 2008; 51: 3203–3221.

    Article  CAS  Google Scholar 

  3. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321: 1801–1806.

    Article  CAS  Google Scholar 

  4. Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012; 491: 399–405.

    Article  CAS  Google Scholar 

  5. Witkiewicz AK, McMillan EA, Balaji U, Baek G, Lin WC, Mansour J et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun 2015; 6: 6744.

    Article  CAS  Google Scholar 

  6. Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003; 425: 851–856.

    Article  CAS  Google Scholar 

  7. Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP et al. A paracrine requirement for hedgehog signalling in cancer. Nature 2008; 455: 406–410.

    Article  CAS  Google Scholar 

  8. Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M et al. Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res 2004; 64: 6071–6074.

    Article  CAS  Google Scholar 

  9. Jimeno A, Feldmann G, Suarez-Gauthier A, Rasheed Z, Solomon A, Zou GM et al. A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development. Mol Cancer Ther 2009; 8: 310–314.

    Article  CAS  Google Scholar 

  10. Lin EH, Kao YR, Lin CA, Kuo TY, Yang SP, Hsu CF et al. Hedgehog pathway maintains cell survival under stress conditions, and drives drug resistance in lung adenocarcinoma. Oncotarget 2016; 7: 24179–24193.

    PubMed  PubMed Central  Google Scholar 

  11. Giroux Leprieur E, Vieira T, Antoine M, Rozensztajn N, Rabbe N, Ruppert AM et al. Sonic hedgehog pathway activation is associated with resistance to platinum-based chemotherapy in advanced non-small-cell lung carcinoma. Clin Lung Cancer 2015; 17: 301–308.

    Article  Google Scholar 

  12. Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 2011; 29: 4548–4554.

    Article  CAS  Google Scholar 

  13. Goldstein D, El-Maraghi RH, Hammel P, Heinemann V, Kunzmann V, Sastre J et al. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst 2015; 107: dju413.

    Article  Google Scholar 

  14. Awasthi N, Zhang C, Schwarz AM, Hinz S, Wang C, Williams NS et al. Comparative benefits of Nab-paclitaxel over gemcitabine or polysorbate-based docetaxel in experimental pancreatic cancer. Carcinogenesis 2013; 34: 2361–2369.

    Article  CAS  Google Scholar 

  15. Kovar J, Ehrlichova M, Smejkalova B, Zanardi I, Ojima I, Gut I . Comparison of cell death-inducing effect of novel taxane SB-T-1216 and paclitaxel in breast cancer cells. Anticancer Res 2009; 29: 2951–2960.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Moore PS, Sipos B, Orlandini S, Sorio C, Real FX, Lemoine NR et al. Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4/Smad4. Virchows Arch 2001; 439: 798–802.

    Article  CAS  Google Scholar 

  17. Hlavaty J, Petznek H, Holzmuller H, Url A, Jandl G, Berger A et al. Evaluation of a gene-directed enzyme-product therapy (GDEPT) in human pancreatic tumor cells and their use as in vivo models for pancreatic cancer. PLoS One 2012; 7: e40611.

    Article  CAS  Google Scholar 

  18. Mohelnikova-Duchonova B, Brynychova V, Hlavac V, Kocik M, Oliverius M, Hlavsa J et al. The association between the expression of solute carrier transporters and the prognosis of pancreatic cancer. Cancer Chemother Pharmacol 2013; 72: 669–682.

    Article  CAS  Google Scholar 

  19. Mohelnikova-Duchonova B, Brynychova V, Oliverius M, Honsova E, Kala Z, Muckova K et al. Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues. Pancreas 2013; 42: 707–716.

    Article  CAS  Google Scholar 

  20. Soucek P, Anzenbacher P, Skoumalova I, Dvorak M . Expression of cytochrome P450 genes in CD34+ hematopoietic stem and progenitor cells. Stem Cells 2005; 23: 1417–1422.

    Article  CAS  Google Scholar 

  21. Mohelnikova-Duchonova B, Oliverius M, Honsova E, Soucek P . Evaluation of reference genes and normalization strategy for quantitative real-time PCR in human pancreatic carcinoma. Dis Markers 2012; 32: 203–210.

    Article  CAS  Google Scholar 

  22. Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 2009; 55: 611–622.

    Article  CAS  Google Scholar 

  23. Livak KJ, Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402–408.

    Article  CAS  Google Scholar 

  24. Benjamini YHY . Controlling the False Discovery Rate: a practical and powerful approach to multiple testing. J Roy Statist Soc Ser B 1995; 57: 289–300.

    Google Scholar 

  25. Morton JP, Mongeau ME, Klimstra DS, Morris JP, Lee YC, Kawaguchi Y et al. Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci USA 2007; 104: 5103–5108.

    Article  CAS  Google Scholar 

  26. Marechal R, Bachet JB, Calomme A, Demetter P, Delpero JR, Svrcek M et al. Sonic hedgehog and Gli1 expression predict outcome in resected pancreatic adenocarcinoma. Clin Cancer Res 2015; 21: 1215–1224.

    Article  CAS  Google Scholar 

  27. Peddi PF, Cho M, Wang J, Gao F, Wang-Gillam A . Nab-paclitaxel monotherapy in refractory pancreatic adenocarcinoma. J Gastrointest Oncol 2013; 4: 370–373.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Pasca di Magliano M, Sekine S, Ermilov A, Ferris J, Dlugosz AA, Hebrok M . Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev 2006; 20: 3161–3173.

    Article  CAS  Google Scholar 

  29. Collins MA, Bednar F, Zhang Y, Brisset JC, Galban S, Galban CJ et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest 2012; 122: 639–653.

    Article  CAS  Google Scholar 

  30. Mills LD, Zhang Y, Marler RJ, Herreros-Villanueva M, Zhang L, Almada LL et al. Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation. J Biol Chem 2013; 288: 11786–11794.

    Article  CAS  Google Scholar 

  31. Sandhiya S, Melvin G, Kumar SS, Dkhar SA . The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother 2013; 4: 4–7.

    Article  CAS  Google Scholar 

  32. Kim EJ, Sahai V, Abel EV, Griffith KA, Greenson JK, Takebe N et al. Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma. Clin Cancer Res 2014; 20: 5937–5945.

    Article  CAS  Google Scholar 

  33. Lee JJ, Perera RM, Wang H, Wu DC, Liu XS, Han S et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc Natl Acad Sci USA 2014; 111: E3091–E3100.

    Article  CAS  Google Scholar 

  34. Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 2014; 25: 735–747.

    Article  CAS  Google Scholar 

  35. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369: 1691–1703.

    Article  CAS  Google Scholar 

  36. Otova B, Ojima I, Vaclavikova R, Hrdy J, Ehrlichova M, Soucek P et al. Second-generation taxanes effectively suppress subcutaneous rat lymphoma: role of disposition, transport, metabolism, in vitro potency and expression of angiogenesis genes. Invest New Drugs 2012; 30: 991–1002.

    Article  CAS  Google Scholar 

  37. Spencer CM, Faulds D . Paclitaxel. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of cancer. Drugs 1994; 48: 794–847.

    Article  CAS  Google Scholar 

  38. Botchkina GI, Zuniga ES, Rowehl RH, Park R, Bhalla R, Bialkowska AB et al. Prostate cancer stem cell-targeted efficacy of a new-generation taxoid, SBT-1214 and novel polyenolic zinc-binding curcuminoid, CMC2.24. PLoS One 2013; 8: e69884.

    Article  CAS  Google Scholar 

  39. Botchkina GI, Zuniga ES, Das M, Wang Y, Wang H, Zhu S et al. New-generation taxoid SB-T-1214 inhibits stem cell-related gene expression in 3D cancer spheroids induced by purified colon tumor-initiating cells. Mol Cancer 2010; 9: 192.

    Article  Google Scholar 

  40. Cochrane CR, Szczepny A, Watkins DN, Cain JE . Hedgehog signaling in the maintenance of cancer stem cells. Cancers (Basel) 2015; 7: 1554–1585.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Czech Science Foundation (grant no. P301/12/1734 to PS), and by Ministry of Health of the Czech Republic (grant no. 16-28375A to B M-D).

Author information

Authors and Affiliations

  1. Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic

    B Mohelnikova-Duchonova, V Brynychova & P Soucek

  2. Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic

    B Mohelnikova-Duchonova & R Lemstrova

  3. Department of Transplantation Surgery, Institute of Clinical and Experimental Medicine, Prague, Czech Republic

    M Kocik & M Oliverius

  4. Palacky University, Olomouc, Czech Republic

    B Duchonova

  5. Charles University in Prague, Prague, Czech Republic

    V Brynychova

  6. Department of Surgery, University Hospital and Medical Faculty, Masaryk University, Brno, Czech Republic

    J Hlavsa & Z Kala

  7. Department of Clinical and Transplantation Pathology, Institute of Clinical and Experimental Medicine, Prague, Czech Republic

    E Honsova

  8. Department of Pathology, University Hospital and Medical Faculty, Masaryk University, Brno, Czech Republic

    J Mazanec

  9. Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, NY, USA

    I Ojima

  10. Department of Physiology & Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland

    D J Hughes

  11. Randox Laboratories, Crumlin, UK

    J E Doherty, H A Murray & M A Crockard

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  1. B Mohelnikova-Duchonova
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Correspondence to B Mohelnikova-Duchonova.

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Mohelnikova-Duchonova, B., Kocik, M., Duchonova, B. et al. Hedgehog pathway overexpression in pancreatic cancer is abrogated by new-generation taxoid SB-T-1216. Pharmacogenomics J 17, 452–460 (2017). https://doi.org/10.1038/tpj.2016.55

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