Skip to main content

Advertisement

SpringerLink
Log in

When the Ends Are Really the Beginnings: Targeting Telomerase for Treatment of GBM

  • Neuro-Oncology (LE Abrey, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

High-throughput genomic sequencing has identified alterations in the gene encoding human telomerase reverse transcriptase (TERT) as points of interest for elucidating the oncogenic mechanism of multiple different cancer types, including gliomas. In gliomas, the TERT promoter mutation (TPM) and resultant overexpression of TERT are observed mainly in the most aggressive (primary glioblastoma/grade IV astrocytoma) and the least aggressive (grade II oligodendroglioma) cases. This article reviews recent research on (1) the mechanism of TERT activation in glioma, (2) downstream consequences of TERT overexpression on glioma pathogenesis, and (3) targeting TPMs as a therapeutic strategy.

Recent Findings

New molecular classifications for gliomas include using TPMs, where the mutant group demonstrates the worst prognosis. Though a canonical function of TERT is established in regard to telomere maintenance, recent studies on non-canonical functions of TERT explore varied roles of telomerase in tumor progression and maintenance.

Summary

Somatic alterations of the TERT promoter present a promising target for novel therapeutics development in primary glioma treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Ostrom Q, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro-Oncology. 2013;15(Suppl 2):56–ii56. https://doi.org/10.1093/neuonc/not151.

    Article  Google Scholar 

  2. Norden AD, Drappatz J, Wen PY. Antiangiogenic therapies for high-grade glioma. Nat Rev Neurol. 2009;5(11):610–20. https://doi.org/10.1038/nrneurol.2009.159.

    Article  CAS  PubMed  Google Scholar 

  3. Claes A, Idema A, Wesseling P. Diffuse glioma growth: a guerilla war. Acta Neuropathol. 2007;114(5):443–58. https://doi.org/10.1007/s00401-007-0293-7.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462–77. https://doi.org/10.1016/j.cell.2013.09.034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A. 2013;110:6021–6. https://doi.org/10.1073/pnas.1303607110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Vinagre J, Almeida A, Populo H, Batista R, Lyra J, Pinto V, et al. Frequency of TERT promoter mutations in human cancers. Nat Commun. 2013;4:2185. https://doi.org/10.1038/ncomms3185.

    Article  PubMed  Google Scholar 

  7. Barthel FP, Wei W, Tang M, Martinez-Ledesma E, Hu X, Amin SB, et al. Systematic analysis of telomere length and somatic alterations in 31 cancer types. Nat Genet. 2017;49:349–57. https://doi.org/10.1038/ng.3781.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lee J, Solomon DA, Tihan T. The role of histone modifications and telomere alterations in the pathogenesis of diffuse gliomas in adults and children. J Neuro-Oncol. 2017;132(1):1–11. https://doi.org/10.1007/s11060-016-2349-9.

    Article  Google Scholar 

  9. Blackburn EH. Telomerase and cancer: Kirk A. Landon—AACR prize for basic cancer research lecture. Mol Cancer Res: MCR. 2005;3(9):477–82. https://doi.org/10.1158/1541-7786.MCR-05-0147.

    Article  CAS  PubMed  Google Scholar 

  10. • Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell. 2016;164(3):550–63. https://doi.org/10.1016/j.cell.2015.12.028. The authors molecularly profiled 1122 gliomas to provide a comprehensive report on improved disease classification and molecular correlations. They also reported telomere lengths and TERT expression between TERT promoter mutant and ATRX mutant cases.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. •• Bell RJ, Rube HT, Kreig A, Mancini A, Fouse SD, Nagarajan RP, et al. Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science. 2015;348(6238):1036–9. https://doi.org/10.1126/science.aab0015. The two most common TERT promoter mutations result in a sequence recognized by the transcription factor, GABP. This study provided the first evidence towards a mechanism for TERT reactivation, dependent on promoter mutations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Balasubramanian S, Hurley LH, Neidle S. Targeting G-quadruplexes in gene promoters: a novel anticancer strategy? Nat Rev Drug Discov. 2011;10(4):261–75. https://doi.org/10.1038/nrd3428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Akincilar SC, Khattar E, Boon PL, Unal B, Fullwood MJ, Tergaonkar V. Long-range chromatin interactions drive mutant TERT promoter activation. Cancer Discov. 2016;6(11):1276–91. https://doi.org/10.1158/2159-8290.CD-16-0177.

    Article  PubMed  Google Scholar 

  14. • Stern JL, Theodorescu D, Vogelstein B, Papadopoulos N, Cech TR. Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers. Genes Dev. 2015;29:2219–24. https://doi.org/10.1101/gad.269498.115. The authors describe chromatin state changes and recruitment of GABP to the TERT promoter mutation across multiple cancer cell lines.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Li Y, Zhou QL, Sun W, Chandrasekharan P, Cheng HS, Ying Z, et al. Non-canonical NF-kappaB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation. Nat Cell Biol. 2015;17(10):1327–38. https://doi.org/10.1038/ncb3240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 1985;43(2 Pt 1):405–13.

    Article  CAS  PubMed  Google Scholar 

  17. Campisi J, Kim SH, Lim CS, Rubio M. Cellular senescence, cancer and aging: the telomere connection. Exp Gerontol. 2001;36(10):1619–37.

    Article  CAS  PubMed  Google Scholar 

  18. •• Chiba K, Lorbeer FK, Shain AH, McSwiggen DT, Schruf E, Oh A, et al. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science. 2017;357:1416–20. https://doi.org/10.1126/science.aao0535. The authors report a mechanism by which cells with TERT promoter mutations can, paradoxically, have short telomeres.

    Article  CAS  PubMed  Google Scholar 

  19. Fallet E, Jolivet P, Soudet J, Lisby M, Gilson E, Teixeira MT. Length-dependent processing of telomeres in the absence of telomerase. Nucleic Acids Res. 2014;42(6):3648–65. https://doi.org/10.1093/nar/gkt1328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li JS, Miralles Fuste J, Simavorian T, Bartocci C, Tsai J, Karlseder J et al. TZAP: a telomere-associated protein involved in telomere length control. Science 2017;355(6325):638-41. https://doi.org/10.1126/science.aah6752.

  21. Ahmad F, Patrick S, Sheikh T, Sharma V, Pathak P, Malgulwar PB, et al. TERT-EZH2 network regulates lipid metabolism and DNA damage responses in glioblastoma. J Neurochem. 2017;143:671–83. https://doi.org/10.1111/jnc.14152.

    Article  CAS  PubMed  Google Scholar 

  22. Strickland M, Stoll EA. Metabolic reprogramming in glioma. Front. Cell Dev. Biol. 2017;5:43. https://doi.org/10.3389/fcell.2017.00043.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Barthel F, Wesseling P, Verhaak R. Reconstructing the molecular life history of gliomas. bioRxiv. 2017. https://doi.org/10.1101/192369.

  24. Cong Y, Shay JW. Actions of human telomerase beyond telomeres. Cell Res. 2008;18:725–32. https://doi.org/10.1038/cr.2008.74.

    Article  CAS  PubMed  Google Scholar 

  25. Jakob S, Schroeder P, Lukosz M, Buchner N, Spyridopoulos I, Altschmied J, et al. Nuclear protein tyrosine phosphatase Shp-2 is one important negative regulator of nuclear export of telomerase reverse transcriptase. J Biol Chem. 2008;283(48):33155–61. https://doi.org/10.1074/jbc.M805138200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. •• Maida Y, Yasukawa M, Furuuchi M, Lassmann T, Possemato R, Okamoto N, et al. An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA. Nature. 2009;461(7261):230–5. https://doi.org/10.1038/nature08283. This study describes a non-canonical function of TERT in mitochondria, where it acts as an RNA-dependent RNA polymerase (RdRP) (see reference citation [63] for clinical trial study design of targeting RdRP function in glioblastoma).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sulkowski PL, Corso CD, Robinson ND, Scanlon SE, Purshouse KR, Bai H, et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med. 2017;9(375):eaal2463. https://doi.org/10.1126/scitranslmed.aal2463.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Low KC, Tergaonkar V. Telomerase: central regulator of all of the hallmarks of cancer. Trends Biochem Sci. 2013;38:426–34. https://doi.org/10.1016/j.tibs.2013.07.001.

    Article  CAS  PubMed  Google Scholar 

  29. Herms JW, von Loewenich FD, Behnke J, Markakis E, Kretzschmar HA. c-myc oncogene family expression in glioblastoma and survival. Surg Neurol. 1999;51(5):536–42.

    Article  CAS  PubMed  Google Scholar 

  30. Koh CM, Khattar E, Leow SC, Liu CY, Muller J, Ang WX, et al. Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity. J Clin Invest. 2015;125(5):2109–22. https://doi.org/10.1172/JCI79134.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, et al. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature. 2009;460(7251):66–72. https://doi.org/10.1038/nature08137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Listerman I, Gazzaniga FS, Blackburn EH. An investigation of the effects of the core protein telomerase reverse transcriptase on Wnt signaling in breast cancer cells. Mol Cell Biol. 2014;34(2):280–9. https://doi.org/10.1128/MCB.00844-13.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hu B, Wang Q, Wang YA, Hua S, Sauv CEG, Ong D, et al. Epigenetic activation of WNT5A drives glioblastoma stem cell differentiation and invasive growth. Cell. 2016;167:1281–1295.e18. https://doi.org/10.1016/j.cell.2016.10.039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lee Y, Lee JK, Ahn SH, Lee J, Nam DH. WNT signaling in glioblastoma and therapeutic opportunities. Lab Invest. 2016;96(2):137–50. https://doi.org/10.1038/labinvest.2015.140.

    Article  CAS  PubMed  Google Scholar 

  35. Martinez P, Blasco MA. Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nat Rev Cancer. 2011;11(3):161–76. https://doi.org/10.1038/nrc3025.

    Article  CAS  PubMed  Google Scholar 

  36. Haendeler J, Drose S, Buchner N, Jakob S, Altschmied J, Goy C, et al. Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler Thromb Vasc Biol. 2009;29(6):929–35. https://doi.org/10.1161/ATVBAHA.109.185546.

    Article  CAS  PubMed  Google Scholar 

  37. Khattar E, Kumar P, Liu CY, Akincilar SC, Raju A, Lakshmanan M, et al. Telomerase reverse transcriptase promotes cancer cell proliferation by augmenting tRNA expression. J Clin Invest. 2016;126(10):4045–60. https://doi.org/10.1172/JCI86042.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Li Y, Cheng HS, Chng WJ, Tergaonkar V. Activation of mutant TERT promoter by RAS-ERK signaling is a key step in malignant progression of BRAF-mutant human melanomas. Proc Natl Acad Sci U S A. 2016;113(50):14402–7. https://doi.org/10.1073/pnas.1611106113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vallarelli AF, Rachakonda PS, Andre J, Heidenreich B, Riffaud L, Bensussan A, et al. TERT promoter mutations in melanoma render TERT expression dependent on MAPK pathway activation. Oncotarget. 2016;7(33):53127–36. https://doi.org/10.18632/oncotarget.10634.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Matsumura N, Nakajima N, Yamazaki T, Nagano T, Kagoshima K, Nobusawa S, et al. Concurrent TERT promoter and BRAF V600E mutation in epithelioid glioblastoma and concomitant low-grade astrocytoma. Neuropathology. 2017;37(1):58–63. https://doi.org/10.1111/neup.12318.

    Article  CAS  PubMed  Google Scholar 

  41. Batista R, Cruvinel-Carloni A, Vinagre J, Peixoto J, Catarino TA, Campanella NC, et al. The prognostic impact of TERT promoter mutations in glioblastomas is modified by the rs2853669 single nucleotide polymorphism. Int J Cancer. 2016;139(2):414–23. https://doi.org/10.1002/ijc.30057.

    Article  CAS  PubMed  Google Scholar 

  42. Beck S, Jin X, Sohn YW, Kim JK, Kim SH, Yin J, et al. Telomerase activity-independent function of TERT allows glioma cells to attain cancer stem cell characteristics by inducing EGFR expression. Molecules Cells. 2011;31(1):9–15. https://doi.org/10.1007/s10059-011-0008-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Spiegl-Kreinecker S, Lotsch D, Ghanim B, Pirker C, Mohr T, Laaber M, et al. Prognostic quality of activating TERT promoter mutations in glioblastoma: interaction with the rs2853669 polymorphism and patient age at diagnosis. Neuro-Oncology. 2015;17(9):1231–40. https://doi.org/10.1093/neuonc/nov010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Simon M, Hosen I, Gousias K, Rachakonda S, Heidenreich B, Gessi M, et al. TERT promoter mutations: a novel independent prognostic factor in primary glioblastomas. Neuro-Oncology. 2015;17(1):45–52. https://doi.org/10.1093/neuonc/nou158.

    Article  CAS  PubMed  Google Scholar 

  45. Mosrati MA, Malmstrom A, Lysiak M, Krysztofiak A, Hallbeck M, Milos P, et al. TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma. Oncotarget. 2015;6(18):16663–73. https://doi.org/10.18632/oncotarget.4389.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Gao K, Li G, Qu Y, Wang M, Cui B, Ji M, et al. TERT promoter mutations and long telomere length predict poor survival and radiotherapy resistance in gliomas. Oncotarget. 2016;7:8712–25. https://doi.org/10.18632/oncotarget.6007.

    PubMed  Google Scholar 

  47. Fan X, Wang Y, Liu Y, Liu X, Zhang C, Wang L, et al. Brain regions associated with telomerase reverse transcriptase promoter mutations in primary glioblastomas. J Neuro-Oncol. 2016;128:455–62. https://doi.org/10.1007/s11060-016-2132-y.

    Article  CAS  Google Scholar 

  48. Ersoy TF, Keil VC, Hadizadeh DR, Gielen GH, Fimmers R, Waha A, et al. New prognostic factor telomerase reverse transcriptase promotor mutation presents without MR imaging biomarkers in primary glioblastoma. Neuroradiology. 2017;59(12):1223–31. https://doi.org/10.1007/s00234-017-1920-1.

    Article  PubMed  Google Scholar 

  49. Arita H, Yamasaki K, Matsushita Y, Nakamura T, Shimokawa A, Takami H, et al. A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas. Acta Neuropathol Commun. 2016;4(1):79. https://doi.org/10.1186/s40478-016-0351-2.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Nguyen HN, Lie A, Li T, Chowdhury R, Liu F, Ozer B, et al. Human TERT promoter mutation enables survival advantage from MGMT promoter methylation in IDH1 wild-type primary glioblastoma treated by standard chemoradiotherapy. Neuro-Oncology. 2017;19(3):394–404. https://doi.org/10.1093/neuonc/now189.

    PubMed  Google Scholar 

  51. Labussiere M, Boisselier B, Mokhtari K, Di Stefano AL, Rahimian A, Rossetto M, et al. Combined analysis of TERT, EGFR, and IDH status defines distinct prognostic glioblastoma classes. Neurology. 2014;83(13):1200–6. https://doi.org/10.1212/WNL.0000000000000814.

    Article  CAS  PubMed  Google Scholar 

  52. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110. https://doi.org/10.1016/j.ccr.2009.12.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Baerlocher G, Vulto I, de Jong G, Lansdorp P. Flow cytometry and FISH to measure the average length of telomeres (flow FISH). Nat Protoc. 2006;1:2365–76. https://doi.org/10.1038/nprot.2006.263.

    Article  CAS  PubMed  Google Scholar 

  54. Gunkel M, Chung I, Worz S, Deeg KI, Simon R, Sauter G, et al. Quantification of telomere features in tumor tissue sections by an automated 3D imaging-based workflow. Methods. 2017;114:60–73. https://doi.org/10.1016/j.ymeth.2016.09.014.

    Article  CAS  PubMed  Google Scholar 

  55. O'callaghan NJ, Fenech M. A quantitative PCR method for measuring absolute telomere length. Biological procedures Online. 2011;13:3. https://doi.org/10.1186/1480-9222-13-3.

  56. Feuerbach L, Sieverling L, Deeg K, Ginsbach P, Hutter B, Buchhalter I et al. TelomereHunter: telomere content estimation and characterization from whole genome sequencing data 2016. bioRxiv. https://doi.org/10.1101/065532.

  57. Ding Z, Mangino M, Aviv A, Spector T, Durbin R. Estimating telomere length from whole genome sequence data. Nucleic Acids Res. 2014;42:e75. https://doi.org/10.1093/nar/gku181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chen Y, Wu Y, Huang X, Qu P, Li G, Jin T, et al. Leukocyte telomere length: a novel biomarker to predict the prognosis of glioma patients. J Cancer Res Clin Oncol. 2015;141(10):1739–47. https://doi.org/10.1007/s00432-015-1938-x.

    Article  CAS  PubMed  Google Scholar 

  59. • Goldvaser H, Gutkin A, Beery E, Edel Y, Nordenberg J, Wolach O, et al. Characterisation of blood-derived exosomal hTERT mRNA secretion in cancer patients: a potential pan-cancer marker. Br J Cancer. 2017;117:353–7. https://doi.org/10.1038/bjc.2017.166. This study presents the measurement and use of exosomal mRNA to detect TERT transcripts across multiple cancers.

    Article  CAS  PubMed  Google Scholar 

  60. Miyazaki T, Pan Y, Joshi K, Purohit D, Hu B, Demir H, et al. Telomestatin impairs glioma stem cell survival and growth through the disruption of telomeric G-quadruplex and inhibition of the proto-oncogene, c-Myb. Clin Cancer Res. 2012;18(5):1268–80. https://doi.org/10.1158/1078-0432.CCR-11-1795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Shin-ya K, Wierzba K, Matsuo K, Ohtani T, Yamada Y, Furihata K, et al. Telomestatin, a novel telomerase inhibitor from Streptomyces anulatus. J Am Chem Soc. 2001;123(6):1262–3.

    Article  CAS  PubMed  Google Scholar 

  62. Nakamura T, Okabe S, Yoshida H, Iida K, Ma Y, Sasaki S, et al. Targeting glioma stem cells in vivo by a G-quadruplex-stabilizing synthetic macrocyclic hexaoxazole. Sci Rep. 2017;7(1):3605. https://doi.org/10.1038/s41598-017-03785-8.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Marian CO, Cho SK, McEllin BM, Maher EA, Hatanpaa KJ, Madden CJ, et al. The telomerase antagonist, imetelstat, efficiently targets glioblastoma tumor-initiating cells leading to decreased proliferation and tumor growth. Clin Cancer Res. 2010;16(1):154–63. https://doi.org/10.1158/1078-0432.CCR-09-2850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Takahashi M, Miki S, Fukuoka K, Maida Y, Hayashi M, Hamada A, et al. EXTH-50. Development of investigator initiated clinical trial of TERT-targeting therapy using eribulin mesylate in patients with recurrent glioblastoma. Neuro-oncology. 2017;19(suppl_6):vi83–vi. https://doi.org/10.1093/neuonc/nox168.342.

    Article  Google Scholar 

  65. Hasegawa D, Okabe S, Okamoto K, Nakano I, Shin-ya K, Seimiya H. G-quadruplex ligand-induced DNA damage response coupled with telomere dysfunction and replication stress in glioma stem cells. Biochem Biophys Res Commun. 2016;471(1):75–81. https://doi.org/10.1016/j.bbrc.2016.01.176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhou G, Liu X, Li Y, Xu S, Ma C, Wu X, et al. Telomere targeting with a novel G-quadruplex-interactive ligand BRACO-19 induces T-loop disassembly and telomerase displacement in human glioblastoma cells. Oncotarget. 2016;7(12):14925–39. https://doi.org/10.18632/oncotarget.7483.

    PubMed  PubMed Central  Google Scholar 

  67. • Kang HJ, Cui Y, Yin H, Scheid A, Hendricks WP, Schmidt J, et al. A pharmacological chaperone molecule induces cancer cell death by restoring tertiary DNA structures in mutant hTERT promoters. J Am Chem Soc. 2016;138:13673–92. https://doi.org/10.1021/jacs.6b07598. This study reports the efficacy of a novel small molecule designed to correct the tertiary structure of the TERT promoter region which is lost as a result of TERT promoter mutations.

    Article  CAS  Google Scholar 

  68. Bollam SR, Dhruv HD, Kang H-J, Peng S, Gokhale V, Hurley L, et al. Abstract 1169: mtTERT promoter as a target for treatment of glioblastoma. Cancer Res. 2017;77:1169.

    Article  Google Scholar 

  69. Berardinelli F, Siteni S, Tanzarella C, Stevens MF, Sgura A, Antoccia A. The G-quadruplex-stabilising agent RHPS4 induces telomeric dysfunction and enhances radiosensitivity in glioblastoma cells. DNA Repair. 2015;25:104–15. https://doi.org/10.1016/j.dnarep.2014.10.009.

    Article  CAS  PubMed  Google Scholar 

  70. Nemunaitis J, Tong AW, Nemunaitis M, Senzer N, Phadke AP, Bedell C, et al. A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors. Mol Ther. 2010;18(2):429–34. https://doi.org/10.1038/mt.2009.262.

    Article  CAS  PubMed  Google Scholar 

  71. Martinez P, Blasco MA. Telomere-driven diseases and telomere-targeting therapies. J Cell Biol. 2017;216(4):875–87. https://doi.org/10.1083/jcb.201610111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. •• Salloum R, Hummel TR, Kumar SS, Dorris K, Li S, Lin T, et al. A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study. J Neuro-Oncol. 2016;129:443–51. https://doi.org/10.1007/s11060-016-2189-7. The authors summarize findings from an investigator-sponsored study to determine efficacy of imetelstat (inhibition of telomerase RNA) in pediatric CNS malignancies and show intratumoral reduction of telomerase activity.

    Article  CAS  Google Scholar 

  73. Hu Y, Shi G, Zhang L, Li F, Jiang Y, Jiang S, et al. Switch telomerase to ALT mechanism by inducing telomeric DNA damages and dysfunction of ATRX and DAXX. Sci Rep. 2016;6:32280. https://doi.org/10.1038/srep32280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors would like to thank The Ben and Catherine Ivy Foundation for their financial support.

Author information

Authors and Affiliations

  1. Division of Cancer and Cell Biology, Translational Genomics Research Institute, 445 N 5th Street, Phoenix, AZ, 85004, USA

    Saumya R. Bollam, Michael E. Berens & Harshil D. Dhruv

Authors
  1. Saumya R. Bollam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael E. Berens
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Harshil D. Dhruv
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Harshil D. Dhruv.

Ethics declarations

Conflict of Interest

Saumya R. Bollam, Michael E. Berens, and Harshil D. Dhruv declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Neuro-Oncology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bollam, S.R., Berens, M.E. & Dhruv, H.D. When the Ends Are Really the Beginnings: Targeting Telomerase for Treatment of GBM. Curr Neurol Neurosci Rep 18, 15 (2018). https://doi.org/10.1007/s11910-018-0825-7

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-018-0825-7

Keywords

Search

Navigation