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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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
Chan YC, Cheng SW, Irwin MG (2008) Perioperative use of statins in noncardiac surgery. Vasc Health Risk Manag 4:75–81
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Ager EI, Neo J, Christophi C (2008) The renin-angiotensin system and malignancy. Carcinogenesis 29:1675–1684. https://doi.org/10.1093/carcin/bgn171
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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)
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
The authors thank the EORTC Cancer Research Fund (ECRF) for providing the data of the CENTRIC study.
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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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)
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)
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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