Top

Published in:

Open Access 01-12-2018 | Research

Akt and mTORC1 signaling as predictive biomarkers for the EGFR antibody nimotuzumab in glioblastoma

Authors: Michael W. Ronellenfitsch, Pia S. Zeiner, Michel Mittelbronn, Hans Urban, Torsten Pietsch, Dirk Reuter, Christian Senft, Joachim P. Steinbach, Manfred Westphal, Patrick N. Harter

Published in: Acta Neuropathologica Communications | Issue 1/2018

Abstract

Glioblastoma (GB) is the most frequent primary brain tumor in adults with a dismal prognosis despite aggressive treatment including surgical resection, radiotherapy and chemotherapy with the alkylating agent temozolomide. Thus far, the successful implementation of the concept of targeted therapy where a drug targets a selective alteration in cancer cells was mainly limited to model diseases with identified genetic drivers. One of the most commonly altered oncogenic drivers of GB and therefore plausible therapeutic target is the epidermal growth factor receptor (EGFR). Trials targeting this signaling cascade, however, have been negative, including the phase III OSAG 101-BSA-05 trial. This highlights the need for further patient selection to identify subgroups of GB with true EGFR-dependency. In this retrospective analysis of treatment-naïve samples of the OSAG 101-BSA-05 trial cohort, we identify the EGFR signaling activity markers phosphorylated PRAS40 and phosphorylated ribosomal protein S6 as predictive markers for treatment efficacy of the EGFR-blocking antibody nimotuzumab in MGMT promoter unmethylated GBs. Considering the total trial population irrespective of MGMT status, a clear trend towards a survival benefit from nimotuzumab was already detectable when tumors had above median levels of phosphorylated ribosomal protein S6. These results could constitute a basis for further investigations of nimotuzumab or other EGFR- and downstream signaling inhibitors in selected patient cohorts using the reported criteria as candidate predictive biomarkers.

Available only for authorised users

Babak S, Mason WP (2018) mTOR inhibition in glioblastoma: requiem for a dream? Neuro-oncology: noy034-noy034. https://doi.org/10.1093/neuonc/noy034

Bar-Peled L, Sabatini DM (2014) Regulation of mTORC1 by amino acids. Trends Cell Biol 24:400–406. https://doi.org/10.1016/j.tcb.2014.03.003 CrossRefPubMedPubMedCentral

Bode U, Massimino M, Bach F, Zimmermann M, Khuhlaeva E, Westphal M, Fleischhack G (2012) Nimotuzumab treatment of malignant gliomas. Expert Opin Biol Ther 12:1649–1659. https://doi.org/10.1517/14712598.2012.733367 CrossRefPubMed

Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG Jr (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18:2893–2904CrossRefPubMedPubMedCentral

Chiang GG, Abraham RT (2005) Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. J Biol Chem 280:25485–25490. https://doi.org/10.1074/jbc.%20M501707200 CrossRefPubMed

Chinnaiyan P, Won M, Wen PY, Rojiani AM, Werner-Wasik M, Shih HA, Ashby LS, Michael Yu H-H, Stieber VW, Malone SC et al (2017) A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: results of NRG oncology RTOG 0913. Neuro-oncology: nox209-nox209. https://doi.org/10.1093/neuonc/nox209

Chong DQ, Toh XY, Ho IA, Sia KC, Newman JP, Yulyana Y, Ng WH, Lai SH, Ho MM, Dinesh N et al (2015) Combined treatment of Nimotuzumab and rapamycin is effective against temozolomide-resistant human gliomas regardless of the EGFR mutation status. BMC Cancer 15:255. https://doi.org/10.1186/s12885-015-1191-3 CrossRefPubMedPubMedCentral

Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D et al (2008) Antitumor activity of rapamycin in a phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 5:e8CrossRefPubMedPubMedCentral

Combs SE, Rieken S, Wick W, Abdollahi A, von Deimling A, Debus J, Hartmann C (2011) Prognostic significance of IDH-1 and MGMT in patients with glioblastoma: one step forward, and one step back? Radiat Oncol 6:115. https://doi.org/10.1186/1748-717X-6-115 CrossRefPubMedPubMedCentral

10.

Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, Finan PM, Kwiatkowski DJ, Murphy LO, Manning BD (2012) TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell 47:535–546. https://doi.org/10.1016/j.molcel.2012.06.009 CrossRefPubMedPubMedCentral

11.

Fry DW, Kraker AJ, McMichael A, Ambroso LA, Nelson JM, Leopold WR, Connors RW, Bridges AJ (1994) A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science 265:1093–1095CrossRefPubMed

12.

Gieryng A, Pszczolkowska D, Walentynowicz KA, Rajan WD, Kaminska B (2017) Immune microenvironment of gliomas. Lab Investig 97:498–518. https://doi.org/10.1038/labinvest.2017.19 CrossRefPubMed

13.

Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013 CrossRefPubMed

14.

Harter PN, Jennewein L, Baumgarten P, Ilina E, Burger MC, Thiepold AL, Tichy J, Zornig M, Senft C, Steinbach JP et al (2015) Immunohistochemical assessment of phosphorylated mTORC1-pathway proteins in human brain tumors. PLoS One 10:e0127123. https://doi.org/10.1371/journal.pone.0127123 CrossRefPubMedPubMedCentral

15.

Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003CrossRefPubMed

16.

Hegi ME, Liu L, Herman JG, Stupp R, Wick W, Weller M, Mehta MP, Gilbert MR (2008) Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol Off J Am Soc Clin Oncol 26:4189–4199. https://doi.org/10.1200/JCO.2007.11.5964 CrossRef

17.

Hockel M, Knoop C, Schlenger K, Vorndran B, Baussmann E, Mitze M, Knapstein PG, Vaupel P (1993) Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol 26:45–50CrossRefPubMed

18.

Huang J, Yuan X, Pang Q, Zhang H, Yu J, Yang B, Zhou L, Zhang F, Liu F (2018) Radiosensitivity enhancement by combined treatment of nimotuzumab and celecoxib on nasopharyngeal carcinoma cells. Drug Des Devel Ther 12:2223–2231. https://doi.org/10.2147/DDDT.S163595 CrossRefPubMedPubMedCentral

19.

Inoki K, Li Y, Zhu T, Wu J, Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4:648–657CrossRefPubMed

20.

Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590CrossRefPubMed

21.

Kennedy BC, Showers CR, Anderson DE, Anderson L, Canoll P, Bruce JN, Anderson RC (2013) Tumor-associated macrophages in glioma: friend or foe? J Oncol 2013:486912. https://doi.org/10.1155/2013/486912 CrossRefPubMedPubMedCentral

22.

Kessler T, Sahm F, Sadik A, Stichel D, Hertenstein A, Reifenberger G, Zacher A, Sabel M, Tabatabai G, Steinbach J et al (2018) Molecular differences in IDH wildtype glioblastoma according to MGMT promoter methylation. Neuro-Oncology 20:367–379. https://doi.org/10.1093/neuonc/nox160 CrossRefPubMed

23.

Kovacina KS, Park GY, Bae SS, Guzzetta AW, Schaefer E, Birnbaum MJ, Roth RA (2003) Identification of a proline-rich Akt substrate as a 14-3-3 binding partner. J Biol Chem 278:10189–10194. https://doi.org/10.1074/jbc.%20M210837200 CrossRefPubMed

24.

Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820. https://doi.org/10.1007/s00401-016-1545-1 CrossRefPubMed

25.

Louis DNC, Webster K, Ohgaki H (2007) WHO classification of Tumours of the central nervous system. In: IARC WHO classification of Tumours, 4th edn. World health organization, City

26.

Luo W, Liu W, Hu X, Hanna M, Caravaca A, Paul SM (2015) Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody. Sci Rep 5:11161. https://doi.org/10.1038/srep11161 CrossRefPubMedPubMedCentral

27.

Mandel JJ, Yust-Katz S, Patel AJ, Cachia D, Liu D, Park M, Yuan Y, Kent TA, de Groot JF (2018) Inability of positive phase II clinical trials of investigational treatments to subsequently predict positive phase III clinical trials in glioblastoma. Neuro-Oncology 20:113–122. https://doi.org/10.1093/neuonc/nox144 CrossRefPubMed

28.

Massimino M, Bode U, Biassoni V, Fleischhack G (2011) Nimotuzumab for pediatric diffuse intrinsic pontine gliomas. Expert Opin Biol Ther 11:247–256. https://doi.org/10.1517/14712598.2011.546341 CrossRefPubMed

29.

McBride SM, Perez DA, Polley MY, Vandenberg SR, Smith JS, Zheng S, Lamborn KR, Wiencke JK, Chang SM, Prados MD et al (2010) Activation of PI3K/mTOR pathway occurs in most adult low-grade gliomas and predicts patient survival. J Neuro-Oncol 97:33–40. https://doi.org/10.1007/s11060-009-0004-4 CrossRef

30.

Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ et al (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024CrossRefPubMed

31.

Meyuhas O (2015) Ribosomal protein S6 phosphorylation: four decades of research. Int Rev Cell Mol Biol 320:41–73. https://doi.org/10.1016/bs.ircmb.2015.07.006 CrossRefPubMed

32.

Network TCGAR (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068CrossRef

33.

Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, Wolinsky Y, Kruchko C, Barnholtz-Sloan J (2014) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro-oncology 16(Suppl 4):iv1–i63. https://doi.org/10.1093/neuonc/nou223 CrossRefPubMedPubMedCentral

34.

Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J, Mueller M, Fumagalli S, Kozma SC, Thomas G (2004) S6K1(−/−)/S6K2(−/−) mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 24:3112–3124CrossRefPubMedPubMedCentral

35.

Phillips AC, Boghaert ER, Vaidya KS, Mitten MJ, Norvell S, Falls HD, DeVries PJ, Cheng D, Meulbroek JA, Buchanan FG et al (2016) ABT-414, an antibody-drug conjugate targeting a tumor-selective EGFR epitope. Mol Cancer Ther 15:661–669. https://doi.org/10.1158/1535-7163.MCT-15-0901 CrossRefPubMed

36.

Poon CC, Sarkar S, Yong VW, Kelly JJP (2017) Glioblastoma-associated microglia and macrophages: targets for therapies to improve prognosis. Brain J Neurol 140:1548–1560. https://doi.org/10.1093/brain/aww355 CrossRef

37.

Qu YY, Hu SL, Xu XY, Wang RZ, Yu HY, Xu JY, Chen L, Dong GL (2013) Nimotuzumab enhances the radiosensitivity of cancer cells in vitro by inhibiting radiation-induced DNA damage repair. PLoS One 8:e70727. https://doi.org/10.1371/journal.pone.0070727 CrossRefPubMedPubMedCentral

38.

Ronellenfitsch MW, Brucker DP, Burger MC, Wolking S, Tritschler F, Rieger J, Wick W, Weller M, Steinbach JP (2009) Antagonism of the mammalian target of rapamycin selectively mediates metabolic effects of epidermal growth factor receptor inhibition and protects human malignant glioma cells from hypoxia-induced cell death. Brain 132:1509–1522CrossRefPubMed

39.

Ronellenfitsch MW, Steinbach JP, Wick W (2010) Epidermal growth factor receptor and mammalian target of rapamycin as therapeutic targets in malignant glioma: current clinical status and perspectives. Target Oncol 5:183–191CrossRefPubMed

40.

Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM (2010) Ragulator-rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141:290–303. https://doi.org/10.1016/j.cell.2010.02.024 CrossRefPubMedPubMedCentral

41.

Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25:903–915. https://doi.org/10.1016/j.molcel.2007.03.003 CrossRefPubMed

42.

Semenza GL (2013) HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest 123:3664–3671. https://doi.org/10.1172/JCI67230 CrossRefPubMedPubMedCentral

43.

Shinojima N, Tada K, Shiraishi S, Kamiryo T, Kochi M, Nakamura H, Makino K, Saya H, Hirano H, Kuratsu J et al (2003) Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res 63:6962–6970PubMed

44.

Sorensen MD, Dahlrot RH, Boldt HB, Hansen S, Kristensen BW (2018) Tumour-associated microglia/macrophages predict poor prognosis in high-grade gliomas and correlate with an aggressive tumour subtype. Neuropathol Appl Neurobiol 44:185–206. https://doi.org/10.1111/nan.12428 CrossRefPubMed

45.

Steinbach JP, Klumpp A, Wolburg H, Weller M (2004) Inhibition of epidermal growth factor receptor signaling protects human malignant glioma cells from hypoxia-induced cell death. Cancer Res 64:1575–1578CrossRefPubMed

46.

Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466. https://doi.org/10.1016/S1470-2045(09)70025-7 CrossRefPubMed

47.

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMed

48.

Talavera A, Friemann R, Gomez-Puerta S, Martinez-Fleites C, Garrido G, Rabasa A, Lopez-Requena A, Pupo A, Johansen RF, Sanchez O et al (2009) Nimotuzumab, an antitumor antibody that targets the epidermal growth factor receptor, blocks ligand binding while permitting the active receptor conformation. Cancer Res 69:5851–5859. https://doi.org/10.1158/0008-5472.CAN-08-4518 CrossRefPubMed

49.

Testa JR, Tsichlis PN (2005) AKT signaling in normal and malignant cells. Oncogene 24:7391–7393. https://doi.org/10.1038/sj.onc.1209100 CrossRefPubMed

50.

Thiepold AL, Lorenz NI, Foltyn M, Engel AL, Dive I, Urban H, Heller S, Bruns I, Hofmann U, Drose S et al (2017) Mammalian target of rapamycin complex 1 activation sensitizes human glioma cells to hypoxia-induced cell death. Brain J Neurol 140:2623–2638. https://doi.org/10.1093/brain/awx196 CrossRef

51.

van den Bent M, Gan HK, Lassman AB, Kumthekar P, Merrell R, Butowski N, Lwin Z, Mikkelsen T, Nabors LB, Papadopoulos KP et al (2017) Efficacy of depatuxizumab mafodotin (ABT-414) monotherapy in patients with EGFR-amplified, recurrent glioblastoma: results from a multi-center, international study. Cancer Chemother Pharmacol 80:1209–1217. https://doi.org/10.1007/s00280-017-3451-1 CrossRefPubMedPubMedCentral

52.

van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF, Clement PM, Frenay M, Campone M, Baurain JF et al (2009) Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol 27:1268–1274CrossRefPubMedPubMedCentral

53.

Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, Ashby L, Mechtler L, Goldlust SA, Iwamoto F et al (2017) Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol 18:1373–1385. https://doi.org/10.1016/S1470-2045(17)30517-X CrossRefPubMed

54.

Weller M, Kaulich K, Hentschel B, Felsberg J, Gramatzki D, Pietsch T, Simon M, Westphal M, Schackert G, Tonn JC et al (2014) Assessment and prognostic significance of the epidermal growth factor receptor vIII mutation in glioblastoma patients treated with concurrent and adjuvant temozolomide radiochemotherapy. Int J Cancer 134:2437–2447. https://doi.org/10.1002/ijc.28576 CrossRefPubMed

55.

Westphal M, Heese O, Steinbach JP, Schnell O, Schackert G, Mehdorn M, Schulz D, Simon M, Schlegel U, Senft C et al (2015) A randomised, open label phase III trial with nimotuzumab, an anti-epidermal growth factor receptor monoclonal antibody in the treatment of newly diagnosed adult glioblastoma. Eur J Cancer. https://doi.org/10.1016/j.ejca.2014.12.019

56.

Wick W, Gorlia T, Bady P, Platten M, van den Bent MJ, Taphoorn MJ, Steuve J, Brandes AA, Hamou MF, Wick A et al (2016) Phase II study of radiotherapy and Temsirolimus versus Radiochemotherapy with Temozolomide in patients with newly diagnosed glioblastoma without MGMT promoter Hypermethylation (EORTC 26082). Clin Cancer Res 22:4797–4806. https://doi.org/10.1158/1078-0432.CCR-15-3153 CrossRefPubMed

57.

Wolff JE, Rytting ME, Vats TS, Zage PE, Ater JL, Woo S, Kuttesch J, Ketonen L, Mahajan A (2012) Treatment of recurrent diffuse intrinsic pontine glioma: the MD Anderson Cancer Center experience. J Neuro-Oncol 106:391–397. https://doi.org/10.1007/s11060-011-0677-3 CrossRef

58.

Zeiner PS, Preusse C, Blank AE, Zachskorn C, Baumgarten P, Caspary L, Braczynski AK, Weissenberger J, Bratzke H, Reiss S et al (2015) MIF receptor CD74 is restricted to microglia/macrophages, associated with a M1-polarized immune milieu and prolonged patient survival in gliomas. Brain Pathol 25:491–504. https://doi.org/10.1111/bpa.12194 CrossRefPubMed

Title: Akt and mTORC1 signaling as predictive biomarkers for the EGFR antibody nimotuzumab in glioblastoma
Authors: Michael W. Ronellenfitsch
Pia S. Zeiner
Michel Mittelbronn
Hans Urban
Torsten Pietsch
Dirk Reuter
Christian Senft
Joachim P. Steinbach
Manfred Westphal
Patrick N. Harter
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2018
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-018-0583-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Akt and mTORC1 signaling as predictive biomarkers for the EGFR antibody nimotuzumab in glioblastoma

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2018

Loss of Tmem106b is unable to ameliorate frontotemporal dementia-like phenotypes in an AAV mouse model of C9ORF72-repeat induced toxicity

Clinical significance of polyglutamylation in primary central nervous system lymphoma

Preserving prion strain identity upon replication of prions in vitro using recombinant prion protein

Integrated proteomics and network analysis identifies protein hubs and network alterations in Alzheimer’s disease

Diffuse microvascular C5b-9 deposition is a common feature in muscle and nerve biopsies from diabetic patients

CD74 regulates complexity of tumor cell HLA class II peptidome in brain metastasis and is a positive prognostic marker for patient survival