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Combining PARP inhibitors with radiation therapy for the treatment of glioblastoma: Is PTEN predictive of response?

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Abstract

Glioblastoma (GBM) is fatal. The standard radiotherapy and chemotherapy (temozolomide) followed by an adjuvant phase of temozolomide provide patients with, on average, a 2.5 months benefit. New treatments that can improve sensitivity to the standard treatment are urgently needed. Herein, we review the mechanisms and utility of poly (ADP-ribose) polymerase inhibitors in combination with radiation therapy as a treatment option for GBM patients and the role of phosphatase and tensin homologue mutations as a biomarker of response.

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References

  1. De Vos M, Schreiber V, Dantzer F. The diverse roles and clinical relevance of PARPs in DNA damage repair: current state of the art. Biochem Pharmacol. 2012;84(2):137–46.

    Article  PubMed  Google Scholar 

  2. Gibson BA, Kraus WL. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol. 2012;13(7):411–24.

    Article  CAS  PubMed  Google Scholar 

  3. El-Khamisy SF, Masutani M, Suzuki H, Caldecott KW. A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage. Nucleic Acids Res. 2003;31(19):5526–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mortusewicz O, Amé J-C, Schreiber V, Leonhardt H. Feedback-regulated poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells. Nucleic Acids Res. 2007;35(22):7665–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Godon C, Cordelières FP, Biard D, Giocanti N, Mégnin-Chanet F, Hall J, et al. PARP inhibition versus PARP-1 silencing: different outcomes in terms of single-strand break repair and radiation susceptibility. Nucleic Acids Res. 2008;36(13):4454–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ström CE, Johansson F, Uhlén M, Szigyarto CA-K, Erixon K, Helleday T. Poly (ADP-ribose) polymerase (PARP) is not involved in base excision repair but PARP inhibition traps a single-strand intermediate. Nucleic Acids Res. 2011;39(8):3166–75.

    Article  PubMed  Google Scholar 

  7. Beck C, Robert I, Reina-San-Martin B, Schreiber V, Dantzer F. Poly (ADP-ribose) polymerases in double-strand break repair: focus on PARP1, PARP2 and PARP3. Exp Cell Res. 2014;329(1):18–25.

    Article  CAS  PubMed  Google Scholar 

  8. Balvers RK, Lamfers ML, Kloezeman JJ, Kleijn A, Pont LMB, Dirven CM, et al. ABT-888 enhances cytotoxic effects of temozolomide independent of MGMT status in serum free cultured glioma cells. J Transl Med. 2015;13(1):74–83.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Murai J, Shar-yin NH, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;72(21):5588–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–7.

    Article  CAS  PubMed  Google Scholar 

  11. Donawho CK, Luo Y, Luo Y, Penning TD, Bauch JL, Bouska JJ, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007;13(9):2728–37.

    Article  CAS  PubMed  Google Scholar 

  12. Lupo B, Trusolino L. Inhibition of poly(ADP-ribosyl)ation in cancer: old and new paradigms revisited. Biochim Biophys Acta (BBA) Rev Cancer. 2014;1846(1):201–15.

    Article  CAS  Google Scholar 

  13. Dungey FA, Löser DA, Chalmers AJ. Replication-dependent radiosensitization of human glioma cells by inhibition of poly(ADP-ribose) polymerase: mechanisms and therapeutic potential. Int J Radiat Oncol Biol Phys. 2008;72(4):1188–97.

    Article  CAS  PubMed  Google Scholar 

  14. Russo AL, Kwon H-C, Burgan WE, Carter D, Beam K, Weizheng X, et al. In vitro and In vivo Radiosensitization of Glioblastoma Cells by the Poly (ADP-Ribose) Polymerase Inhibitor E7016. Clin Cancer Res. 2009;15(2):607–12.

    Article  CAS  PubMed  Google Scholar 

  15. Curtin NJ, Szabo C. Therapeutic applications of PARP inhibitors: anticancer therapy and beyond. Mol Asp Med. 2013;34(6):1217–56.

    Article  CAS  Google Scholar 

  16. Alexander BM, Ligon KL, Wen PY. Enhancing radiation therapy for patients with glioblastoma. Expert Rev Anticancer Ther. 2013;13(5):569–81.

    Article  CAS  PubMed  Google Scholar 

  17. Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA. DNA repair pathways as targets for cancer therapy. Nat Rev Cancer. 2008;8(3):193–204.

    Article  CAS  PubMed  Google Scholar 

  18. Noël G, Godon C, Fernet M, Giocanti N, Mégnin-Chanet F, Favaudon V. Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis. Mol Cancer Ther. 2006;5(3):564–74.

    Article  PubMed  Google Scholar 

  19. Dungey FA, Caldecott KW, Chalmers AJ. Enhanced radiosensitisation of human glioma cells by combining inhibition of PARP with inhibition of Hsp90. Mol Cancer Ther. 2009;8(8):2243–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Löser DA, Shibata A, Shibata AK, Woodbine LJ, Jeggo PA, Chalmers AJ. Sensitization to radiation and alkylating agents by inhibitors of poly(ADP-ribose) polymerase is enhanced in cells deficient in DNA double-strand break repair. Mol Cancer Ther. 2010;9(6):1775–87.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chan N, Koritzinsky M, Zhao H, Bindra R, Glazer PM, Powell S, et al. Chronic hypoxia decreases synthesis of homologous recombination proteins to offset chemoresistance and radioresistance. Cancer Res. 2008;68(2):605–14.

    Article  CAS  PubMed  Google Scholar 

  22. Barazzuol L, Jena R, Burnet NG, Meira LB, Jeynes JCG, Kirkby KJ, et al. Evaluation of poly (ADP-ribose) polymerase inhibitor ABT-888 combined with radiotherapy and temozolomide in glioblastoma. Radiat Oncol (Lond Engl). 2013;8:65–75.

    Article  CAS  Google Scholar 

  23. Venere M, Hamerlik P, Wu Q, Rasmussen R, Song L, Vasanji A, et al. Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells. Cell Death Differ. 2014;21(2):258–69.

    Article  CAS  PubMed  Google Scholar 

  24. Brescia P, Richichi C, Pelicci G. Current strategies for identification of glioma stem cells: adequate or unsatisfactory? J Oncol. 2012;2012:10.

    Article  Google Scholar 

  25. Clarke MJ, Mulligan EA, Grogan PT, Mladek AC, Carlson BL, Schroeder MA, et al. Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines. Mol Cancer Ther. 2009;8(2):407–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Majuelos-Melguizo J, Rodríguez MI, López-Jiménez L, Rodríguez-Vargas JM, Martí Martín-Consuegra JM, Serrano-Sáenz S, et al. PARP targeting counteracts gliomagenesis through induction of mitotic catastrophe and aggravation of deficiency in homologous recombination in PTEN-mutant glioma. Oncotarget. 2015;6(7):4790–803.

    Article  PubMed  Google Scholar 

  27. Javle M, Curtin NJ. The role of PARP in DNA repair and its therapeutic exploitation. Br J Cancer. 2011;105(8):1114–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yin Y, Shen WH. PTEN: a new guardian of the genome. Oncogene. 2008;27(41):5443–53.

    Article  CAS  PubMed  Google Scholar 

  29. Chalhoub N, Baker SJ. PTEN and the PI3-Kinase pathway in cancer. Annu Rev Pathol. 2009;4:127–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Baker SJ, McKinnon PJ. Tumour-suppressor function in the nervous system. Nat Rev Cancer. 2004;4(3):184–96.

    Article  CAS  PubMed  Google Scholar 

  31. Hunt CR, Gupta A, Horikoshi N, Pandita TK. Does PTEN loss impair DNA double-strand break repair by homologous recombination? Clin Cancer Res. 2012;18(4):920–2.

    Article  CAS  PubMed  Google Scholar 

  32. Wick W, Furnari FB, Naumann U, Cavenee WK, Weller M. PTEN gene transfer in human malignant glioma: sensitization to irradiation and CD95L-induced apoptosis. Oncogene. 1999;18(27):3936–43.

    Article  CAS  PubMed  Google Scholar 

  33. Kao GD, Jiang Z, Fernandes AM, Gupta AK, Maity A. Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation. J Biol Chem. 2007;2007:21206–12.

    Article  Google Scholar 

  34. McEllin B, Camacho CV, Mukherjee B, Hahm B, Tomimatsu N, Bachoo RM, et al. PTEN loss compromises homologous recombination repair in astrocytes: implications for GBM therapy with temozolomide or PARP inhibitors. Cancer Res. 2010;70(13):5457–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pappas G, Zumstein LA, Munshi A, Hobbs M, Meyn RE. Adenoviral-mediated PTEN expression radiosensitizes non-small cell lung cancer cells by suppressing DNA repair capacity. Cancer Gene Ther. 2007;14(6):543–9.

    Article  CAS  PubMed  Google Scholar 

  36. Rosser CJ, Tanaka M, Pisters LL, Tanaka N, Levy LB, Hoover DC, et al. Adenoviral-mediated PTEN transgene expression sensitizes Bcl-2-expressing prostate cancer cells to radiation. Cancer Gene Ther. 2004;11(4):273–9.

    Article  CAS  PubMed  Google Scholar 

  37. Fraser M, Zhao H, Luoto KR, Lundin C, Coackley C, Chan N, et al. PTEN deletion in prostate cancer cells does not associate with loss of RAD51 function: implications for radiotherapy and chemotherapy. Clin Cancer Res. 2012;18(4):1015–27.

    Article  CAS  PubMed  Google Scholar 

  38. Shen WH, Balajee AS, Wang J, Wu H, Eng C, Pandolfi PP, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell. 2007;2007:157–70.

    Article  Google Scholar 

  39. Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS, et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med. 2009;1(6–7):315–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mukherjee A, Karmakar P. Attenuation of PTEN perturbs genomic stability via activation of Akt and down-regulation of Rad51 in human embryonic kidney cells. Mol Carcinog. 2013;52(8):611–8.

    Article  CAS  PubMed  Google Scholar 

  41. Minami D, Takigawa N, Takeda H, Takata M, Ochi N, Ichihara E, et al. Synergistic effect of olaparib with combination of cisplatin on PTEN-deficient lung cancer cells. Mol Cancer Res. 2013;11(2):140–8.

    Article  CAS  PubMed  Google Scholar 

  42. He J, Kang X, Yin Y, Chao KSC, Shen WH. PTEN regulates DNA replication progression and stalled fork recovery. Nat Commun. 2015;2015:6.

    Google Scholar 

  43. Gupta A, Yang Q, Pandita RK, Hunt CR, Xiang T, Misri S, et al. Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair. Cell Cycle. 2009;8(14):2198–210.

    Article  CAS  PubMed  Google Scholar 

  44. Ming M, He Y-Y. PTEN in DNA damage repair. Cancer Lett. 2012;319(2):125–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Miyasaka A, Oda K, Ikeda Y, Wada-Hiraike O, Kashiyama T, Enomoto A, et al. Anti-tumor activity of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in cultured endometrial carcinoma cells. BMC Cancer. 2014;14(1):1–10.

    Article  Google Scholar 

  46. Gong L, Govan JM, Evans EB, Dai H, Wang E, Lee S-W, et al. Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure. Cell Cycle. 2015;14(14):2323–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sun Z, Huang C, He J, Lamb Kristy L, Kang X, Gu T, et al. PTEN C-terminal deletion causes genomic instability and tumor development. Cell Reports. 2014;6(5):844–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Godoy PRDV, Mello SS, Magalhães DAR, Donaires FS, Nicolucci P, Donadi EA, et al. Ionizing radiation-induced gene expression changes in TP53 proficient and deficient glioblastoma cell lines. Mutat Res, Genet Toxicol Environ Mutagen. 2013;756(1–2):46–55.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. University of NSW, Kensington, NSW, Australia

    A. Lester, R. Rapkins, S. Nixdorf & K. McDonald

  2. University of Sydney, NHMRC Clinical Trials Centre, Camperdown, NSW, Australia

    M. Khasraw

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  1. A. Lester
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  2. R. Rapkins
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  3. S. Nixdorf
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  5. K. McDonald
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Correspondence to K. McDonald.

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Lester, A., Rapkins, R., Nixdorf, S. et al. Combining PARP inhibitors with radiation therapy for the treatment of glioblastoma: Is PTEN predictive of response?. Clin Transl Oncol 19, 273–278 (2017). https://doi.org/10.1007/s12094-016-1547-4

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  • DOI: https://doi.org/10.1007/s12094-016-1547-4

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