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GBM radiosensitizers: dead in the water…or just the beginning?

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Abstract

The finding that most GBMs recur either near or within the primary site after radiotherapy has fueled great interest in the development of radiosensitizers to enhance local control. Unfortunately, decades of clinical trials testing a wide range of novel therapeutic approaches have failed to yield any clinically viable radiosensitizers. However, many of  the previous radiosensitizing strategies were not based on clear pre-clinical evidence, and in many cases blood-barrier penetration was not considered. Furthermore, DNA repair inhibitors have only recenly arrived in the clinic, and likely represent potent agents for glioma radiosensitization. Here, we present recent progress in the use of small molecule DNA damage response inhibitors as GBM radiosensitizers. In addition, we discuss the latest progress in targeting hypoxia and oxidative stress for GBM radiosensitization.

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References

  1. Chang JE, Khuntia D, Robins HI, Mehta MP (2007) Radiotherapy and radiosensitizers in the treatment of glioblastoma multiforme. Clin Adv Hematol Oncol 5(894–902):894–902

    PubMed  Google Scholar 

  2. Flatmark K, Ree AH (2010) Radiosensitizing drugs: lessons to be learned from the oxaliplatin story. J Clin Oncol 28:e577–e578

    Article  PubMed  Google Scholar 

  3. Awasthi P, Foiani M, Kumar A (2015) ATM and ATR signaling at a glance. J Cell Sci 128:4255–4262

    Article  CAS  PubMed  Google Scholar 

  4. Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40:179–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Roy R, Chun J, Powell SN (2012) BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer 12:68–78

    Article  CAS  Google Scholar 

  6. Meek K, Dang V, Lees-Miller SP (2008) DNA-PK: the means to justify the ends? Adv Immunol 99:33–58

    Article  CAS  PubMed  Google Scholar 

  7. Taverna P, Hwang HS, Schupp JE, Radivoyevitch T, Session NN, Reddy G, Zarling DA, Kinsella TJ (2003) Inhibition of base excision repair potentiates iododeoxyuridine-induced cytotoxicity and radiosensitization. Cancer Res 63:838–846

    CAS  PubMed  Google Scholar 

  8. Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG (2010) PARP inhibition: PARP1 and beyond. Nat Rev Cancer 10:293–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kastan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432:316–323

    Article  CAS  PubMed  Google Scholar 

  10. Russell P, Nurse P (1987) Negative regulation of mitosis by wee1+, a gene encoding a protein kinase homolog. Cell 49:559–567

    Article  CAS  PubMed  Google Scholar 

  11. Wang Y, Decker SJ, Sebolt-Leopold J (2004) Knockdown of Chk1, Wee1 and Myt1 by RNA interference abrogates G2 checkpoint and induces apoptosis. Cancer Biol Ther 3:305–313

    Article  CAS  PubMed  Google Scholar 

  12. Benafif S, Hall M (2015) An update on PARP inhibitors for the treatment of cancer. OncoTargets Ther 8:519–528

    CAS  Google Scholar 

  13. Chalmers AJ (2010) Overcoming resistance of glioblastoma to conventional cytotoxic therapies by the addition of PARP inhibitors. Anticancer Agents Med Chem 10:520–533

    Article  CAS  PubMed  Google Scholar 

  14. Dungey FA, Loser DA, Chalmers AJ (2008) Replication-dependent radiosensitization of human glioma cells by inhibition of poly(ADP-Ribose) polymerase: mechanisms and therapeutic potential. Int J Radiat Oncol Biol Phys 72:1188–1197

    Article  CAS  PubMed  Google Scholar 

  15. Parrish KE, Cen L, Murray J, Calligaris D, Kizilbash S, Mittapalli RK, Carlson BL, Schroeder MA, Sludden J, Boddy AV et al (2015) Efficacy of PARP inhibitor rucaparib in orthotopic glioblastoma xenografts is limited by ineffective drug penetration into the central nervous system. Mol Cancer Ther 14:2735–2743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chalmers AJ (2014) Results of stage 1 of the oparatic trial: a phase I study of olaparib in combination with temozolomide in patients with relapsed glioblastoma. J Clin Oncol 32:5s

    Google Scholar 

  17. Mehta MP, Wang D, Wang F, Kleinberg L, Brade A, Robins HI, Turaka A, Leahy T, Medina D, Xiong H et al (2015) Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study. J Neurooncol 122:409–417

    Article  CAS  PubMed  Google Scholar 

  18. Carruthers R, Ahmed SU, Strathdee K, Gomez-Roman N, Amoah-Buahin E, Watts C, Chalmers AJ (2015) Abrogation of radioresistance in glioblastoma stem-like cells by inhibition of ATM kinase. Mol Oncol 9:192–203

    Article  CAS  PubMed  Google Scholar 

  19. Biddlestone-Thorpe L, Sajjad M, Rosenberg E, Beckta JM, Valerie NC, Tokarz M, Adams BR, Wagner AF, Khalil A, Gilfor D et al (2013) ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation. Clin Cancer Res 19:3189–3200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Moding EJ, Lee CL, Castle KD, Oh P, Mao L, Zha S, Min HD, Ma Y, Das S, Kirsch DG (2014) Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium. J Clin Invest 124:3325–3338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fokas E, Prevo R, Pollard JR, Reaper PM, Charlton PA, Cornelissen B, Vallis KA, Hammond EM, Olcina MM, Gillies McKenna W et al (2012) Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis 3:e441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ahmed SU, Carruthers R, Gilmour L, Yildirim S, Watts C, Chalmers A.J. (2015) Selective inhibition of parallel DNA damage response pathways optimizes radiosensitization of glioblastoma stem-like cells. Cancer Res 75:4416–4428

    Article  CAS  PubMed  Google Scholar 

  23. McNeely S, Beckmann R, Bence Lin AK (2014) CHEK again: revisiting the development of CHK1 inhibitors for cancer therapy. Pharmacol Ther 142:1–10

    Article  CAS  PubMed  Google Scholar 

  24. Lv W, Budke B, Pawlowski M, Connell PP, Kozikowski AP (2016) Development of small molecules that specifically inhibit the D-loop activity of RAD51. J Med Chem 59:4511–4525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Berte N, Piee-Staffa A, Piecha N, Wang M, Borgmann K, Kaina B, Nikolova T (2016) Targeting homologous recombination by pharmacological inhibitors enhances the killing response of glioblastoma cells treated with alkylating drugs. Mol Cancer Ther 15(11):2665–2678

    Article  CAS  PubMed  Google Scholar 

  26. Balbous A, Cortes U, Guilloteau K, Rivet P, Pinel B, Duchesne M, Godet J, Boissonnade O, Wager M, Bensadoun RJ et al (2016) A radiosensitizing effect of RAD51 inhibition in glioblastoma stem-like cells. BMC Cancer 16:604

    Article  PubMed  PubMed Central  Google Scholar 

  27. Davidson D, Amrein L, Panasci L, Aloyz R (2013) Small molecules, inhibitors of DNA-PK, targeting DNA repair, and beyond. Front Pharmacol 4:5

    Article  PubMed  PubMed Central  Google Scholar 

  28. Jette N, Lees-Miller SP (2015) The DNA-dependent protein kinase: a multifunctional protein kinase with roles in DNA double strand break repair and mitosis. Prog Biophys Mol Biol 117:194–205

    Article  CAS  PubMed  Google Scholar 

  29. Frit P, Barboule N, Yuan Y, Gomez D, Calsou P (2014) Alternative end-joining pathway(s): bricolage at DNA breaks. DNA Repair 17:81–97

    Article  CAS  PubMed  Google Scholar 

  30. Goglia AG, Delsite R, Luz AN, Shahbazian D, Salem AF, Sundaram RK, Chiaravalli J, Hendrikx PJ, Wilshire JA, Jasin M et al (2015) Identification of novel radiosensitizers in a high-throughput, cell-based screen for DSB repair inhibitors. Mol Cancer Ther 14(2):326–342

    Article  CAS  PubMed  Google Scholar 

  31. Sheehan JP, Xu Z, Popp B, Kowalski L, Schlesinger D (2013) Inhibition of glioblastoma and enhancement of survival via the use of mibefradil in conjunction with radiosurgery. J Neurosurg 118:830–837

    Article  CAS  PubMed  Google Scholar 

  32. Goglia AG, Delsite R, Luz AN, Shahbazian D, Salem AF, Sundaram RK, Chiaravalli J, Hendrikx PJ, Wilshire JA, Jasin M et al (2015) Identification of novel radiosensitizers in a high-throughput, cell-based screen for DSB repair inhibitors. Mol Cancer Ther 14:326–342

    Article  CAS  PubMed  Google Scholar 

  33. Keir ST, Friedman HS, Reardon DA, Bigner DD, Gray LA (2013) Mibefradil, a novel therapy for glioblastoma multiforme: cell cycle synchronization and interlaced therapy in a murine model. J Neurooncol 111:97–102

    Article  CAS  PubMed  Google Scholar 

  34. Bridges KA, Hirai H, Buser CA, Brooks C, Liu H, Buchholz TA, Molkentine JM, Mason KA, Meyn RE (2011) MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clin Cancer Res 17:5638–5648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mueller S, Hashizume R, Yang X, Kolkowitz I, Olow AK, Phillips J, Smirnov I, Tom MW, Prados MD, James CD et al (2014) Targeting Wee1 for the treatment of pediatric high-grade gliomas. Neuro-oncol 16:352–360

    Article  CAS  PubMed  Google Scholar 

  36. Do K, Wilsker D, Ji J, Zlott J, Freshwater T, Kinders RJ, Collins J, Chen AP, Doroshow JH, Kummar S (2015) Phase I study of single-agent AZD1775 (MK-1775), a Wee1 kinase inhibitor, in patients with refractory solid tumors. J Clin Oncol 33:3409–3415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pokorny JL, Calligaris D, Gupta SK, Iyekegbe DO Jr, Mueller D, Bakken KK, Carlson BL, Schroeder MA, Evans DL, Lou Z et al (2015) The efficacy of the Wee1 inhibitor MK-1775 combined with temozolomide is limited by heterogeneous distribution across the blood-brain barrier in glioblastoma. Clin Cancer Res 21:1916–1924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sanai N, Li J, Boerner J, Dhruv H, Berens M, LoRusso P (2016) Phase 0 trial of AZD1775 in patients with first-recurrence glioblastoma. J Clin Oncol 34(suppl; abstr 2008)

  39. Brown JM, William WR (2004) Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 4:437–447

    Article  CAS  PubMed  Google Scholar 

  40. Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor-1 is a basic-helix-loop-helix-pas heterodimer regulated by cellular o-2 tension. Proc Natl Acad Sci USA 92:5510–5514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, FujiiKuriyama Y (1997) A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1 alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA 94:4273–4278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE et al (2009) Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15:501–513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Overgaard J (2011) Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck–a systematic review and meta-analysis. Radiother Oncol 100:22–32

    Article  PubMed  Google Scholar 

  44. Stone HB, Brown JM, Phillips TL, Sutherland RM (1993) Oxygen in human tumors: correlations between methods of measurement and response to therapy. Summary of a workshop held November 19–20, 1992, at the National Cancer Institute, Bethesda, Maryland. Radiat Res 136:422–434

    Article  CAS  PubMed  Google Scholar 

  45. Dewhirst MW, Birer SR (2016) Oxygen-enhanced MRI is a major advance in tumor hypoxia imaging. Cancer Res 76:769–772

    Article  CAS  PubMed  Google Scholar 

  46. Vaupel P (2001) Tumor hypoxia: Definitions and current clinical, biologic, and molecular targets. J Natl Cancer Inst 93:266–276

    Article  PubMed  Google Scholar 

  47. Collingridge DR, Piepmeier JM, Rockwell S, Knisely JPS (1999) Polarographic measurements of oxygen tension in human glioma and surrounding peritumoural brain tissue. Radiother Oncol 53:127–131

    Article  CAS  PubMed  Google Scholar 

  48. Evans SM, Judy KD, Dunphy I, Jenkins WT, Nelson PT, Collins R, Wileyto EP, Jenkins K, Hahn SM, Stevens CW et al (2004) Comparative measurements of hypoxia in human brain tumors using needle electrodes and EF5 binding. Cancer Res 64:1886–1892

    Article  CAS  PubMed  Google Scholar 

  49. Lee CT, Boss MK, Dewhirst MW (2014) Imaging tumor hypoxia to advance radiation oncology. Antioxid Redox Signal 21:313–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Neeman M, Dafni H, Bukhari O, Braun RD, Dewhirst MW (2001) In vivo BOLD contrast MRI mapping of subcutaneous vascular function and maturation: validation by intravital microscopy. Magn Reson Med 45:887–898

    Article  CAS  PubMed  Google Scholar 

  51. O’Connor, J.P.B., Boult, J.K.R., Jamin Y, Babur M, Finegan KG, Williams KJ, Little RA, Jackson A, Parker, G.J.M., Reynolds AR et al (2016) Oxygen-enhanced MRI accurately identifies, quantifies, and maps tumor hypoxia in preclinical cancer models. Cancer Res 76:787–795

    Article  PubMed  Google Scholar 

  52. Linnik IV, Scott, M.L.J., Holliday KF, Woodhouse N, Waterton JC, O’Connor, J.P.B., Barjat H, Liess C, Ulloa J, Young H et al (2014) Noninvasive tumor hypoxia measurement using magnetic resonance imaging in murine U87 glioma xenografts and in patients with glioblastoma. Magn Reson Med 71:1854–1862

    Article  CAS  PubMed  Google Scholar 

  53. Boxerman JL, Ellingson BM (2015) Response assessment and magnetic resonance imaging issues for clinical trials involving high-grade gliomas. Top Magn Reson Imaging 24:127–136

    Article  PubMed  Google Scholar 

  54. Spence AM, Muzi M, Swanson KR, O’Sullivan F, Rockhill JK, Rajendran JG, Adamsen TC, Link JM, Swanson PE, Yagle KJ et al (2008) Regional hypoxia in glioblastoma multiforme quantified with [18F] fluoromisonidazole positron emission tomography before radiotherapy: correlation with time to progression and survival. Clin Cancer Res 14:2623–2630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Koch CJ, Evans SM (2003) Non-invasive PET and SPECT imaging of tissue hypoxia using isotopically labeled 2-nitroimidazoles. Adv Exp Med Biol 510:285–292

    Article  CAS  PubMed  Google Scholar 

  56. Dolbier WR, Li AR, Koch CJ, Shiue CY, Kachur AV (2001) [18F]-EF5, a marker for PET detection of hypoxia: synthesis of precursor and a new fluorination procedure. Appl Radiat Isot 54:73–80

    Article  CAS  PubMed  Google Scholar 

  57. Tateishi K, Tateishi U, Sato M, Yamanaka S, Kanno H, Murata H, Inoue T, Kawahara N (2013) Application of 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) PET imaging to predict highly malignant tumor grades and hypoxia-inducible factor-1alpha expression in patients with glioma. AJNR Am J Neuroradiol 34:92–99

    Article  CAS  PubMed  Google Scholar 

  58. Dische S (1985) Chemical sensitizers for hypoxic cells—a decade of experience in clinical radiotherapy. Radiother Oncol 3:97–115

    Article  CAS  PubMed  Google Scholar 

  59. Mayer R, Hamilton-Farrell MR, van der Kleij AJ, Schmutz J, Granstrom G, Sicko Z, Melamed Y, Carl UM, Hartmann KA, Jansen EC et al (2005) Hyperbaric oxygen and radiotherapy. Strahlentherapie Onkologie 181:113–123

    Article  Google Scholar 

  60. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D et al (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370:709–722

    Article  CAS  PubMed  Google Scholar 

  61. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M et al (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699–708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E et al (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metal loproteinases. Cancer Cell 6:553–563

    CAS  PubMed  Google Scholar 

  63. Batinic-Haberle I, Tovmasyan A, Spasojevic I (2015) An educational overview of the chemistry, biochemistry and therapeutic aspects of Mn porphyrins—from superoxide dismutation to H2O2-driven pathways. Redox Biol 5:43–65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ashcraft KA, Boss M-K, Tovmasyan A, Choudhury KR, Fontanella AN, Young KH, Palmer GM, Birer SR, Landon CD, Park W et al (2015) Novel manganese-porphyrin superoxide dismutase-mimetic widens the therapeutic margin in a preclinical head and neck cancer model. Int J Radiat Oncol Biol Phys 93:892–900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Weitzel DH, Tovmasyan A, Ashcraft KA, Rajic Z, Weitner T, Liu C, Li W, Buckley AF, Prasad MR, Young KH et al (2015) Radioprotection of the brain white matter by Mn(III) N-butoxyethylpyridylporphyrin-based superoxide dismutase mimic MnTnBuOE-2-PyP5+. Mol Cancer Ther 14:70–79

    Article  CAS  PubMed  Google Scholar 

  66. Weitzel DH, Tovmasyan A, Ashcraft KA, Boico A, Birer SR, Roy Choudhury K, Herndon JE II, Rodriguiz RM, Wetsel WC, Peters KB et al (2016) Neurobehavioral radiation mitigation to standard brain cancer therapy regimens by byMn(III)n-butoxyethylpyridylporphyrin-based RedoxModifier. Environ Mol Mutagen 57(5):372–381

    Article  CAS  PubMed  Google Scholar 

  67. Moeller BJ, Cao YT, Li CY, Dewhirst MW (2004) Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: Role of reoxygenation, free radicals, and stress granules. Cancer Cell 5:429–441

    Article  CAS  PubMed  Google Scholar 

  68. Dewhirst MW, Cao Y, Moeller B (2008) Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 8:425–437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, 06520, USA

    Ranjit S. Bindra

  2. Institute of Cancer Sciences & Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK

    Anthony J. Chalmers

  3. Department of Radiation Oncology, University of Pennsylvania, School of Medicine, Philadelphia, PA, 19081, USA

    Sydney Evans

  4. Radiation Oncology Department, Duke University School of Medicine, Durham, NC, USA

    Mark Dewhirst

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  1. Ranjit S. Bindra
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  2. Anthony J. Chalmers
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  3. Sydney Evans
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  4. Mark Dewhirst
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Correspondence to Ranjit S. Bindra.

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Bindra, R.S., Chalmers, A.J., Evans, S. et al. GBM radiosensitizers: dead in the water…or just the beginning?. J Neurooncol 134, 513–521 (2017). https://doi.org/10.1007/s11060-017-2427-7

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