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Do statins, ACE inhibitors or sartans improve outcome in primary glioblastoma?

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Abstract

Glioblastomas are malignant brain tumors with poor prognosis. Lately, data from clinical studies assessing the role of co-medications in different cancer types suggested reduced mortality and potential anti-tumor activity for statins, angiotensin-I converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (sartans). Here, we analysed the association of co-treatment with statins, ACEI or sartans with outcome in a cohort of 810 patients enrolled in the phase III CENTRIC and phase II CORE trials on the role of the integrin antagonist, cilengitide, in newly diagnosed glioblastoma with or without O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Progression-free survival (PFS) and overall survival (OS) were analysed for each medication in the pooled patient group. No association was found for co-medication with either drug for PFS or OS. Median OS was 22.1 (statins) versus 22.2 (control) months (HR 1.06, 95% CI 0.81–1.39, p = 0.69), 20.4 (ACEI) versus 22.6 (control) months (HR 1.25, 95% CI 0.96–1.62, p = 0.10), and 21.7 (sartans) versus 22.3 (control) months (HR 0.86, 95% CI 0.61–1.21, p = 0.38). None of the comparisons showed a signal for different PFS or OS when analyses were controlled for MGMT promoter methylation or treatment group (TMZ/RT → TMZ vs. RT + CIL + TMZ → TMZ + CIL). This secondary analysis of two large glioblastoma trials thus was unable to detect evidence for an association of the use of statins, ACEI or sartans with outcome in patients with newly diagnosed glioblastoma. These data challenge the rationale for prospective studies on the possible role of these non-tumor-specific drugs within the concept of drug repurposing.

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References

  1. Schmidt F, Groscurth P, Kermer M, Dichgans J, Weller M (2001) Lovastatin and phenylacetate induce apoptosis, but not differentiation, in human malignant glioma cells. Acta Neuropathol 101:217–224

    CAS  PubMed  Google Scholar 

  2. Chan YC, Cheng SW, Irwin MG (2008) Perioperative use of statins in noncardiac surgery. Vasc Health Risk Manag 4:75–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gauthaman K, Manasi N, Bongso A (2009) Statins inhibit the growth of variant human embryonic stem cells and cancer cells in vitro but not normal human embryonic stem cells. Br J Pharmacol 157:962–973. https://doi.org/10.1111/j.1476-5381.2009.00241.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wang IK, Lin-Shiau SY, Lin JK (2000) Induction of apoptosis by lovastatin through activation of caspase-3 and DNase II in leukaemia HL-60 cells. Pharmacol Toxicol 86:83–91

    Article  CAS  PubMed  Google Scholar 

  5. Shellman YG, Ribble D, Miller L, Gendall J, Vanbuskirk K, Kelly D, Norris DA, Dellavalle RP (2005) Lovastatin-induced apoptosis in human melanoma cell lines. Melanoma Res 15:83–89

    Article  CAS  PubMed  Google Scholar 

  6. Chapman-Shimshoni D, Yuklea M, Radnay J, Shapiro H, Lishner M (2003) Simvastatin induces apoptosis of B-CLL cells by activation of mitochondrial caspase 9. Exp Hematol 31:779–783

    Article  CAS  PubMed  Google Scholar 

  7. Jiang Z, Zheng X, Lytle RA, Higashikubo R, Rich KM (2004) Lovastatin-induced up-regulation of the BH3-only protein, Bim, and cell death in glioblastoma cells. J Neurochem 89:168–178. https://doi.org/10.1111/j.1471-4159.2004.02319.x

    Article  CAS  PubMed  Google Scholar 

  8. Yu X, Pan Y, Ma H, Li W (2013) Simvastatin inhibits proliferation and induces apoptosis in human lung cancer cells. Oncol Res 20:351–357. https://doi.org/10.3727/096504013X13657689382897

    Article  CAS  PubMed  Google Scholar 

  9. Denoyelle C, Vasse M, Korner M, Mishal Z, Ganne F, Vannier JP, Soria J, Soria C (2001) Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits the signaling pathways involved in the invasiveness and metastatic properties of highly invasive breast cancer cell lines: an in vitro study. Carcinogenesis 22:1139–1148

    Article  CAS  PubMed  Google Scholar 

  10. Maltese WA, Defendini R, Green RA, Sheridan KM, Donley DK (1985) Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Clin Investig 76:1748–1754. https://doi.org/10.1172/JCI112165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kubatka P, Kajo K, Zihlavnikova K, Adamicova K, Vybohova D, Pec M, Nosal V, Stollarova N, Bojkova B, Kassayova M, Orendas P (2012) Immunohistochemical and histomorphological analysis of rat mammary tumors after simvastatin treatment. Neoplasma 59:516–523. https://doi.org/10.4149/neo_2012_066

    Article  CAS  PubMed  Google Scholar 

  12. Yongjun Y, Shuyun H, Lei C, Xiangrong C, Zhilin Y, Yiquan K (2013) Atorvastatin suppresses glioma invasion and migration by reducing microglial MT1-MMP expression. J Neuroimmunol 260:1–8. https://doi.org/10.1016/j.jneuroim.2013.04.020

    Article  PubMed  Google Scholar 

  13. Chan DY, Chen GG, Poon WS, Liu PC (2008) Lovastatin sensitized human glioblastoma cells to TRAIL-induced apoptosis. J Neuro-oncol 86:273–283. https://doi.org/10.1007/s11060-007-9475-3

    Article  CAS  Google Scholar 

  14. Bababeygy SR, Polevaya NV, Youssef S, Sun A, Xiong A, Prugpichailers T, Veeravagu A, Hou LC, Steinman L, Tse V (2009) HMG-CoA reductase inhibition causes increased necrosis and apoptosis in an in vivo mouse glioblastoma multiforme model. Anticancer Res 29:4901–4908

    CAS  PubMed  Google Scholar 

  15. Murakami M, Goto T, Saito Y, Goto S, Kochi M, Ushio Y (2001) The inhibitory effect of simvastatin on growth in malignant gliomas—with special reference to its local application with fibrin glue spray in vivo. Int J Oncol 19:525–531

    CAS  PubMed  Google Scholar 

  16. Cardwell CR, Hicks BM, Hughes C, Murray LJ (2014) Statin use after colorectal cancer diagnosis and survival: a population-based cohort study. J Clin Oncol 32:3177–3183. https://doi.org/10.1200/JCO.2013.54.4569

    Article  PubMed  Google Scholar 

  17. Seckl MJ, Ottensmeier CH, Cullen M, Schmid P, Ngai Y, Muthukumar D, Thompson J, Harden S, Middleton G, Fife KM, Crosse B, Taylor P, Nash S, Hackshaw A (2017) Multicenter, phase III, randomized, double-blind, placebo-controlled trial of pravastatin added to first-line standard chemotherapy in small-cell lung cancer (LUNGSTAR). J Clin Oncol. https://doi.org/10.1200/JCO.2016.69.7391

    PubMed  PubMed Central  Google Scholar 

  18. Khakoo AY, Sidman RL, Pasqualini R, Arap W (2008) Does the renin-angiotensin system participate in regulation of human vasculogenesis and angiogenesis? Cancer Res 68:9112–9115. https://doi.org/10.1158/0008-5472.CAN-08-0851

    Article  CAS  PubMed  Google Scholar 

  19. Ager EI, Neo J, Christophi C (2008) The renin-angiotensin system and malignancy. Carcinogenesis 29:1675–1684. https://doi.org/10.1093/carcin/bgn171

    Article  CAS  PubMed  Google Scholar 

  20. Alhusban A, Al-Azayzih A, Goc A, Gao F, Fagan SC, Somanath PR (2014) Clinically relevant doses of candesartan inhibit growth of prostate tumor xenografts in vivo through modulation of tumor angiogenesis. J Pharmacol Exp Ther 350:635–645. https://doi.org/10.1124/jpet.114.216382

    Article  PubMed  PubMed Central  Google Scholar 

  21. Weigert C, Brodbeck K, Klopfer K, Haring HU, Schleicher ED (2002) Angiotensin II induces human TGF-beta 1 promoter activation: similarity to hyperglycaemia. Diabetologia 45:890–898. https://doi.org/10.1007/s00125-002-0843-4

    Article  CAS  PubMed  Google Scholar 

  22. Lanz TV, Ding Z, Ho PP, Luo J, Agrawal AN, Srinagesh H, Axtell R, Zhang H, Platten M, Wyss-Coray T, Steinman L (2010) Angiotensin II sustains brain inflammation in mice via TGF-beta. J Clin Investig 120:2782–2794. https://doi.org/10.1172/JCI41709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. George AJ, Thomas WG, Hannan RD (2010) The renin-angiotensin system and cancer: old dog, new tricks. Nat Rev Cancer 10:745–759. https://doi.org/10.1038/nrc2945

    Article  CAS  PubMed  Google Scholar 

  24. Fogarty DJ, Sanchez-Gomez MV, Matute C (2002) Multiple angiotensin receptor subtypes in normal and tumor astrocytes in vitro. Glia 39:304–313. https://doi.org/10.1002/glia.10117

    Article  PubMed  Google Scholar 

  25. Juillerat-Jeanneret L, Celerier J, Chapuis Bernasconi C, Nguyen G, Wostl W, Maerki HP, Janzer RC, Corvol P, Gasc JM (2004) Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma. Br J Cancer 90:1059–1068. https://doi.org/10.1038/sj.bjc.6601646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rooprai HK, Kandanearatchi A, Maidment SL, Christidou M, Trillo-Pazos G, Dexter DT, Rucklidge GJ, Widmer W, Pilkington GJ (2001) Evaluation of the effects of swainsonine, captopril, tangeretin and nobiletin on the biological behaviour of brain tumour cells in vitro. Neuropathol Appl Neurobiol 27:29–39

    Article  CAS  PubMed  Google Scholar 

  27. Nakagawa T, Kubota T, Kabuto M, Kodera T (1995) Captopril inhibits glioma cell invasion in vitro: involvement of matrix metalloproteinases. Anticancer Res 15:1985–1989

    CAS  PubMed  Google Scholar 

  28. Arrieta O, Guevara P, Escobar E, Garcia-Navarrete R, Pineda B, Sotelo J (2005) Blockage of angiotensin II type I receptor decreases the synthesis of growth factors and induces apoptosis in C6 cultured cells and C6 rat glioma. Br J Cancer 92:1247–1252. https://doi.org/10.1038/sj.bjc.6602483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, Aldape KD, Lhermitte B, Pietsch T, Grujicic D, Steinbach JP, Wick W, Tarnawski R, Nam DH, Hau P, Weyerbrock A, Taphoorn MJ, Shen CC, Rao N, Thurzo L, Herrlinger U, Gupta T, Kortmann RD, Adamska K, McBain C, Brandes AA, Tonn JC, Schnell O, Wiegel T, Kim CY, Nabors LB, Reardon DA, van den Bent MJ, Hicking C, Markivskyy A, Picard M, Weller M, European Organisation for R, Treatment of C, Canadian Brain Tumor C, team Cs (2014) Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071–22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 15: 1100–1108 https://doi.org/10.1016/S1470-2045(14)70379-1

    Article  CAS  PubMed  Google Scholar 

  30. Nabors LB, Fink KL, Mikkelsen T, Grujicic D, Tarnawski R, Nam do H, Mazurkiewicz M, Salacz M, Ashby L, Zagonel V, Depenni R, Perry JR, Hicking C, Picard M, Hegi ME, Lhermitte B, Reardon DA (2015) Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study. Neuro Oncol 17:708–717. https://doi.org/10.1093/neuonc/nou356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Afshordel S, Kern B, Clasohm J, Konig H, Priester M, Weissenberger J, Kogel D, Eckert GP (2015) Lovastatin and perillyl alcohol inhibit glioma cell invasion, migration, and proliferation–impact of Ras-/Rho-prenylation. Pharmacol Res 91:69–77. https://doi.org/10.1016/j.phrs.2014.11.006

    Article  CAS  PubMed  Google Scholar 

  32. Yu O, Eberg M, Benayoun S, Aprikian A, Batist G, Suissa S, Azoulay L (2014) Use of statins and the risk of death in patients with prostate cancer. J Clin Oncol 32:5–11. https://doi.org/10.1200/JCO.2013.49.4757

    Article  PubMed  Google Scholar 

  33. Makar GA, Holmes JH, Yang YX (2014) Angiotensin-converting enzyme inhibitor therapy and colorectal cancer risk. J Natl Cancer Inst 106:djt374. https://doi.org/10.1093/jnci/djt374

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kedika R, Patel M, Pena Sahdala HN, Mahgoub A, Cipher D, Siddiqui AA (2011) Long-term use of angiotensin converting enzyme inhibitors is associated with decreased incidence of advanced adenomatous colon polyps. J Clin Gastroenterol 45:e12–e16. https://doi.org/10.1097/MCG.0b013e3181ea1044

    Article  CAS  PubMed  Google Scholar 

  35. Ferris JS, McCoy L, Neugut AI, Wrensch M, Lai R (2012) HMG CoA reductase inhibitors, NSAIDs and risk of glioma. Int J Cancer 131:E1031–E1037. https://doi.org/10.1002/ijc.27536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gaist D, Andersen L, Hallas J, Sorensen HT, Schroder HD, Friis S (2013) Use of statins and risk of glioma: a nationwide case-control study in Denmark. Br J Cancer 108:715–720. https://doi.org/10.1038/bjc.2012.536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gaist D, Hallas J, Friis S, Hansen S, Sorensen HT (2014) Statin use and survival following glioblastoma multiforme. Cancer Epidemiol 38:722–727. https://doi.org/10.1016/j.canep.2014.09.010

    Article  PubMed  Google Scholar 

  38. Wu H, Jiang H, Lu D, Xiong Y, Qu C, Zhou D, Mahmood A, Chopp M (2009) Effect of simvastatin on glioma cell proliferation, migration, and apoptosis. Neurosurgery 65:1087–1096. https://doi.org/10.1227/01.NEU.0000360130.52812.1D (discussion 1096–1087)

    Article  PubMed  PubMed Central  Google Scholar 

  39. Januel E, Ursu R, Alkhafaji A, Marantidou A, Doridam J, Belin C, Levy-Piedbois C, Carpentier AF (2015) Impact of renin-angiotensin system blockade on clinical outcome in glioblastoma. Eur J Neurol 22:1304–1309. https://doi.org/10.1111/ene.12746

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank the EORTC Cancer Research Fund (ECRF) for providing the data of the CENTRIC study.

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Authors and Affiliations

  1. Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland

    Caroline Happold & Michael Weller

  2. European Organisation for Research and Treatment of Cancer, Brussels, Belgium

    Thierry Gorlia

  3. Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA

    L. Burt Nabors

  4. Edinburgh Cancer Centre, University of Edinburgh, Edinburgh, UK

    Sara C. Erridge

  5. Dana-Farber Cancer Institute, Boston, MA, USA

    David A. Reardon

  6. Merck KGaA, Darmstadt, Germany

    Christine Hicking & Martin Picard

  7. Department of Oncology, University Hospital Zurich, 8091, Zurich, Switzerland

    Roger Stupp

  8. Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland

    Caroline Happold

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  1. Caroline Happold
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For the EORTC Brain Tumor Group and on behalf of the CENTRIC and CORE Clinical Trial Groups

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Correspondence to Caroline Happold.

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Conflict of interest

CHa has received honoraria for advisory board participation from MSD. CHi is employee of Merck KGaA. DAR has received lab support from Acerta, Agenus, Celldex, EMD Serono, Acerta, Inovio, Midatech and Tragara, and honoraria for lectures or advisory board from Abbvie, Agenus, Amgen, Bristol Myers Squibb, Cavion, Celldex, EMD Serono, Genentech/Roche, Juno Pharmaceuticals, Merck, Midatech, Inovio, Momenta Pharmaceuticals, Novartis, Novocure, Oxigene, Regeneron, Stemline Therapeutics. RS has received honoraria for advisory board participation and consulting from Roche, Merck KGaA, MSD, Merck, Pfizer, Ipsen, Novartis and AbbVie. MW has received research grants from Acceleron, Actelion, Bayer, Isarna, Merck, Sharp & Dohme, Merck (EMD, Darmstadt), Novocure, OGD2, Piqur and Roche and honoraria for lectures or advisory board participation or consulting from Abbvie, BMS, Celldex, Immunocellular Therapeutics, Magforce, Merck, Sharp & Dohme, Merck (EMD, Darmstadt), Novocure, Pfizer, Roche, Teva and Tocagen.​ TG, LBN, SCE, and MP declare no conflict of interest.

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11060_2018_2786_MOESM1_ESM.pdf

Supplementary Figure 1 Prognostic significance of continued use (defined as captured medication intake at study baseline and at first visit after completion of radiochemotherapy) of statins (A,B), ACEI (C,D) or sartans (E,F) for PFS (A,C,E) and OS (B,D,F) (PDF 55 KB)

11060_2018_2786_MOESM2_ESM.pdf

Supplementary Figure 2 Prognostic significance of baseline use of statins vs. no statins in the patient cohort with documented hyperlipidemia only (A), or of ACEI and sartans vs. none of these drugs in the patient cohort with documented hypertension only (B) (PDF 44 KB)

Supplementary Table 1 (DOCX 11 KB)

Supplementary Table 2 (DOCX 14 KB)

Supplementary Table 3 (DOCX 13 KB)

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Happold, C., Gorlia, T., Nabors, L.B. et al. Do statins, ACE inhibitors or sartans improve outcome in primary glioblastoma?. J Neurooncol 138, 163–171 (2018). https://doi.org/10.1007/s11060-018-2786-8

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  • DOI: https://doi.org/10.1007/s11060-018-2786-8

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