European Journal of Cancer
Volume 46, Issue 1 , Pages 9-20 , January 2010

Poly(ADP-ribose) polymerase inhibitors in cancer treatment: A clinical perspective

  • Shahneen K. Sandhu
  • ,
  • Timothy A. Yap
  • ,
  • Johann S. de Bono

      Affiliations

    • Corresponding Author InformationCorresponding author: Address: Section of Medicine, The Institute of Cancer Research, Drug Development Unit, The Royal Marsden NHS Foundation Trust, Downs Road Sutton, Surrey SM2 5PT, UK. Tel.: +44 20 8722 4302; fax: +44 20 8642 7979.

Received 9 September 2009 ,Revised 9 October 2009 ,Accepted 15 October 2009.

References 

  1. Ames BN, Gold LS. Endogenous mutagens and the causes of aging and cancer. Mutat Res. 1991;250(1–2):3–16
  2. Fortini P, Pascucci B, Parlanti E, et al. The base excision repair: mechanisms and its relevance to cancer susceptibility. Biochimie. 2003;85(11):1053–1071
  3. Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature. 2001;411(6835):366–374
  4. Bernstein C, Bernstein H, Payne CM, Garewal H. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutat Res. 2002;511(2):145–178
  5. Hansen K, Kelly M. Review of mammalian DNA repair and translational implications. J Pharmacol Exp Ther. 2000;295(1):1–9
  6. Andreassen P, Ho GP, D’Andrea AD. DNA damage responses and their many interactions with the replication fork. Carcinogenesis. 2006;27(5):883–892
  7. Ashworth A. A synthetic lethal therapeutic approach: Poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol. 2008;26(22):3785–3790
  8. Chambon P, Weill JD, Mandel P. Nicotinamide mononucleotide activation of new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochem Biophys Res Commun. 1963;11:39–43
  9. Otto H, Reche PA, Bazan F, et al. In silico characterization of the family of PARP-like poly(ADP-ribosyl)transferases(pARTs). BMC Genomics. 2005;6:139
  10. De Murcia JM, Ricoul M, Tartier L, et al. Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse. EMBO J. 2003;22(9):2255–2263
  11. Huber A, Bai P, de Murcia JM, de Murcia G. PARP-1, PARP-2 and ATM in the DNA damage response: functional synergy in mouse development. DNA Repair (Amst). 2004;3(8–9):1103–1108
  12. Plummer ER, Calvert H. Targeting poly(ADP-ribose) polymerase: a two-armed strategy for cancer treatment. Clin Cancer Res. 2007;13(21):6252–6256
  13. Peralta-Leal A, Rodriguez MI, Oliver FJ. Poly(ADP-ribose) polymerase-1(PARP-1) in carcinogenesis: potential role of PARP inhibitors in cancer treatment. Clin Transl Oncol. 2008;10(6):318–323
  14. Ratman K, Low JA. Current development of clinical inhibitors of Poly(ADP-ribose) polymerase in oncology. Clin Cancer Res. 2007;13(5):1383–1388
  15. Yang YG, Cortes U, Patnaik S, Jasin M, Wang ZQ. Ablation of PARP-1 does not interfere with the repair of DNA double-strand breaks, but compromises the reactivation of stalled replication forks. Oncogene. 2004;23(21):3972–3982
  16. Schultz N, Lopez E, Saleh-Gohari N, Helleday T. Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination. Nucleic Acids Res. 2003;31(17):4959–4964
  17. Wang M, Wu W, Rosidi B, et al. PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Res. 2006;34(21):6170–6182
  18. Durkacz BW, Omidiji O, Gray DA, Shall S. (ADP-ribose)n participates in DNA excision repair. Nature. 1980;283(5747):593–596
  19. Thomas HD, Calabrese CR, Batey MA, et al. Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial. Mol Cancer Ther. 2007;6(3):945–956
  20. Southan GJ, Szabo C. Poly(ADP-ribose)polymerase inhibitors. Curr Med Chem. 2003;10(4):321–340
  21. Donawho CK, Luo Y, Luo Y, Penning TD, 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):2728–2737
  22. Kummar S, Kinders R, Gutierrez ME, et al. Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol. 2009;27(16):2705–2711
  23. Cockcroft XL, Dillon KJ, Dixon L. Phthalazinones 2: Optimisation and synthesis of novel potent inhibitors of poly(ADP-ribose)polymerase. Bioorg Med Chem Lett. 2006;16(4):1040–1044
  24. Fong PC, Boss DS, Yap TA, et al. Inhibition of Poly(ADP-Ribose) polymerase in tumors from brca mutation carriers. New Engl J Med. 2009;361(2):123–134
  25. Fong PC, Boss DS, Carden CP, et al. AZD2281(KU-0059436), a PARP (poly ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA deficient ovarian cancer. Results form a Phase I study. J Clin Oncol. 2008;26(Suppl.):[abstract 5510]
  26. Jagtap PG, Baloglu E, Southan GJ, et al. Discovery of potent poly(ADP-ribose) polymerase-1 inhibitors from the modification of indeno[1, 2-c]isoquinolinone. J Med Chem. 2005;48(16):5100–5103
  27. Bedikian AY, Papadopoulos NE, Kim KB. A phase IB trial of intravenous INO-1001 plus oral temozolomide in subjects with unresectable stage-III or IV melanoma. Cancer Invest. 2009;27(7):756–763
  28. Curtin NJ. PARP inhibitors for cancer therapy. Expert Rev Mol Med. 2005;7(4):1–20
  29. Plummer R, Jones C, Middleton M, et al. Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res. 2008;14(23):7917–7923
  30. Plummer ER, Lorigan P, Evans J, et al. First and final report of a phase II study of poly(ADP-ribose) polymerase (PARP) inhibitor AG014699 in combination with temozolomide (TMZ) in patients with metastatic melanoma (MM). Proc Am Soc Clin Oncol. 2006;[abstract: 8013]
  31. Kopetz S, Mita MM, Mok I, et al. First in human Phase I study of BSI-201, a small molecule inhibitor of poly ADP-ribose polymerase (PARP) in subjects with advanced solid tumours. J Clin Oncol. 2008;26(Suppl.):[abstract 3577]
  32. Mahany JJ, Lewis N, Heath EI, et al. A Phase IB study evaluating BSI-201 in combination with chemotherapy in subjects with advanced solid tumors. Proc. Am. Soc. Clin. Oncol. 2008;26(Suppl.):[abstr 3579]
  33. O’Shaughnessy J, Osborne C, Pippen J, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II trial. ASCO J Clin Oncol. 2009;27:18s;[abstract 3]
  34. <www.clinicaltrials.gov>.
  35. Yoshida K, Miki Y. Role of BRCA1 and BRCA 2 as regulators of DNA repair, transcription, and cell cycle response to DNA damage. Cancer Sci. 2004;95(11):866–871
  36. Gudmundsdottir K, Ashworth A. The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene. 2006;25(43):5864–5874
  37. Venkitaraman A. Cancer susceptibility and functions of BRCA1 and BRCA2. Cell. 2002;108(2):171–182
  38. Lord CJ, Ashworth A. RAD 51, BRCA2 and DNA repair: a partial resolution. Nat Struct Mol Biol. 2007;14(6):475–483
  39. Lord CJ, Garrett MD, Ashworth A. Targeting the double-strand DNA break repair pathway as a therapeutic strategy. Clin Cancer Res. 2006;12(15):4463–4468
  40. Tutt A, Bertwistle D, Valentine J, et al. Mutations in BRCA2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences. EMBO J. 2001;20(17):4704–4716
  41. Wooster R, Weber BL. Breast and ovarian cancer. New Engl J Med. 2003;348(23):2339–2347
  42. Brose MS, Rebbeck TR, Calzone KA, et al. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst. 2002;94(18):1365–1372
  43. Ford D, Easton DF, Bishop DT, Narod SA, Goldga DE. Risks of cancer in BRCA-1 mutation carriers: Breast Cancer Linkage Consortium. Lancet. 1994;343(8899):692–695
  44. Evans DG, Shenton A, Woodward E, et al. Penetrance estimates for BRCA1 and BRCA2 based on genetic testing in a Clinical Cancer Genetics service setting: risks of breast/ovarian cancer quoted should reflect the cancer burden in the family. BMC Cancer. 2008;30(8):155
  45. Tutt AN, Lord CJ, McCabe N, et al. Exploiting the DNA repair defect in BRCA mutant cells in the design of new therapeutic strategies for cancer. Cold Spring Harb Symp Quant Biol. 2005;70:139–148
  46. Dobzhansky T. Genetics of natural populations. Xiii. Recombination and variability in populations of Drosophila pseudoobscura. Genetics. 1946;31(3):269–290
  47. Kaelin WG. The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer. 2005;5(9):689–698
  48. Kyle S, Thomas HD, Mitchell J, Curtin NJ. Exploiting the Achilles heel of cancer: the therapeutic potential of poly(ADP-ribose) polymerase inhibitors in BRCA2-defective cancer. Br J Radiol. 2008;81(Spec. No. 1):S6–S11
  49. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2–deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–917
  50. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–921
  51. Haber JE. DNA recombination: the replication connection. Trends Biochem Sci. 1999;24(7):271–275
  52. Arnaudeu C, Lundin C, Helleday C. DNA double-strand breaks associated with replication forks are predominantly repaired by homologous recombination involving an exchange mechanism in mammalian cells. J Mol Biol. 2001;307:1235–1245
  53. McCabe N, Lord CJ, Tutt AN, et al. BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of Poly(ADP-ribose)polymerase: an issue of potency. Cancer Biol Ther. 2005;4(9):934–936
  54. Gallmeier E, Kern SE. Absence of specific cell killing of the BRCA2- deficient human cancer cell line CAPAN1 by poly(ADP-ribose) polymerase inhibition. Cancer Biol Ther. 2005;4(7):703–706
  55. Turner N, Tutt A, Ashworth A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat. Rev Cancer. 2004;4(10):814–819
  56. McCabe N, Turner NC, Lord CJ, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66(16):8109–8115
  57. Turner NC, Reis-Filho JS. Basal-like breast cancer and BRCA1 phenotype. Oncogene. 2006;25(43):5846–5853
  58. Saal LH, Gruvberger-Saal SK, Persson C, et al. Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair. Nat Genet. 2008;40(1):102–107
  59. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 2003;100(14):8418–8423
  60. Foulkes WD, Stefansson IM, Chappuis PO, et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst. 2003;95(19):1482–1485
  61. Jacinto FV, Esteller M. Mutator pathways unleashed by epigenetic silencing in human cancer. Mutagenesis. 2007;22(4):247–253
  62. Taniguchi T, Tischkowitz M, Ameziane N, et al. Disruption of the Fanconi anaemia-BRCA pathway in cisplatin-sensitive ovarian tumours. Nat Med. 2003;9(5):568–574
  63. Catteau A, Harris WH, Xu CF, Solomon E. Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer: correlation with disease characteristics. Oncogene. 1999;18(11):1957–1965
  64. Esteller M, Silva JM, Dominguez G, et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst. 2000;92(7):564–569
  65. Rice JC, Ozcelik H, Maxeiner P, Andrulis I, Futscher BW. Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens. Carcinogenesis. 2000;21(9):1761–1765
  66. Baldwin RL, Nemeth E, Tran H, et al. BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study. Cancer Res. 2000;60(19):5329–5333
  67. Collins N, Wooster R, Stratton MR. Absence of methylation of CpG dinucleotides within the promoter of the breast cancer susceptibility gene BRCA2 in normal tissues and in breast and ovarian cancers. B J Cancer. 1997;76(9):1150–1156
  68. Huges-Davies L, Huntsman D, Ruas M, et al. EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell. 2003;115(5):523–535
  69. Drew YC, Vong WT, Khan S, et al. Investigating the DNA double-strand break formation and repair in response to PARP inhibitor AGO14699 in cell lines defective in Homologous Recombination: a role for PARP inhibitors in sporadic cancers? In: 99th AACR annual meeting 2008 [abstract 859].
  70. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998;396(6712):643–649
  71. Memisoglu A, Samson L. Base excision repair in yeast and mammals. Mutat Res. 2000;451(1–2):39–51
  72. Calabrese CR, Almassy R, Barton S, et al. Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst. 2004;96(1):56–67
  73. Miknyoczki SJ, Jones-Bolin S, Pritchard S, et al. Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor. Mol Cancer Ther. 2003;2(4):371–382
  74. Mason KA, Valdecanas D, Hunter NR, Milas L. INO-1001, a novel inhibitor of poly(ADP-ribose) polymerase, enhances tumor response to doxorubicin. Invest New Drugs. 2008;26(1):1–5
  75. Bowman KJ, White A, Golding BT, Griffin RJ, Curtin NJ. Potentiation of anti-cancer agent cytotoxicity by the potent poly(ADP-ribose) polymerase inhibitors NU1025 and NU1064. Br J Cancer. 1998;78(10):1269–1277
  76. Delaney CA, Wang LZ, Kyle S, et al. Potentiation of temozolomide and topotecan growth inhibition and cytotoxicity by novel poly(adenosine diphosphoribose) polymerase inhibitors in a panel of human tumor cell lines. Clin Cancer Res. 2000;6(7):2860–2867
  77. Chalmers A, Johnston P, Woodcock M, Joiner M, Marples B. PARP-1, PARP-2, and the cellular response to low doses of ionizing radiation. Int J Radiat Oncol Biol Phys. 2004;58(2):410–419
  78. Albert JM, Cao C, Kim KW, et al. Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Clin Cancer Res. 2007;13(10):3033–3042
  79. Cheng CL, Johnson SP, Keir ST, et al. Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft. Mol Cancer Ther. 2005;4(9):1364–1368
  80. Tentori L, Leonetti C, Scarsella M. Systemic administration of GPI 15427, a novel poly(ADP-ribose) polymerase-1 inhibitor, increases the antitumor activity of temozolomide against intracranial melanoma, glioma, lymphoma. Clin Cancer Res. 2003;9(14):5370–5379
  81. Veuger SJ, Curtin NJ, Richardson CJ, Smith GC, Durkacz BW. Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1. Cancer Res. 2003;63(18):6008–6015
  82. Chalmers AJ. Poly(ADP-ribose) polymerase-1 and ionizing radiation: sensor, signaller and therapeutic target. Clin Oncol (R Coll Radiol). 2004;16(1):29–39
  83. Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18(1):158–166
  84. Tutt A, Robson M, Garber JE, et al. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. J Clin Oncol. 2009;27:18s;[Suppl.; abstr CRA501]
  85. Audeh MW, Penson RT, Friedlander M, et al. Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. J Clin Oncol. 2009;27:15s;[Suppl.; abstr 5500]
  86. Sirohi B, Arnedos M, Popat S, et al. Platinum-based chemotherapy in triple-negative breast cancer. Ann Oncol. 2008;19(11):1847–1852
  87. Yi S, Uhm J, Cho E, et al. Clinical outcomes of metastatic breast cancer patients with triple-negative phenotype who received platinum-containing chemotherapy. J Clin Oncol. 2008;26;[suppl; abstr 1008]
  88. Ashworth A. Drug resistance caused by reversion mutation. Cancer Res. 2008;68(24):10021–10023
  89. Edwards SL, Brough R, Lord CJ, et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature. 2008;451(7182):1111–1115
  90. Yang H, Jeffrey PD, Miller J, et al. BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science. 2002;297(5588):1837–1848
  91. Esashi F, Galkin VE, Yu X, Egelman EH, West SC. Stabilization of RAD51 nucleoprotein filaments by the C-terminal region of BRCA2. Nat Struct Mol Biol. 2007;14(6):468–474
  92. Davies OR, Pellegrini L. Interaction with the BRCA2 C terminus protects RAD51-DNA filaments from disassembly by BRC repeats. Nat Struct Mol Biol. 2007;14:475–483
  93. Spain BH, Larson CJ, Shihabuddin LS, Gage FH, Verma IM. Truncated BRCA2 in cytoplasmic: implications for cancer linked mutations. Proc Natl Acad Sci USA. 1999;96(24):13920–13925
  94. Sakai W, Swisher EM, Karlan BY, et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature. 2008;451(7182):1116–1120
  95. Swisher EM, Sakai W, Karlan BY, et al. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res. 2008;68(8):2581–2586
  96. Plummer ER, Middleton MR, Jones C, et al. Temozolomide pharmacodynamics in patients with metastatic melanoma: dna damage and activity of repair enzymes O6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1. Clin Cancer Res. 2005;11(9):3402–3409
  97. Lord CJ, McDonald S, Swift S, Turner NC, Ashworth A. A high-throughput RNA interference screen for DNA repair determinants of PARP inhibitor sensitivity. DNA Repair (Amst). 2008;7(12):2010–2019
  98. Domchek SM, Weber BL. Clinical management of BRCA1 and BRCA2 mutation carriers. Oncogene. 2006;25(43):5825–5831
  99. Lord CJ, Ashworth A. Targeted therapy for cancer using PARP inhibitors. Curr Opin Pharmacol. 2008;8(4):363–369
  100. Hay T, Jenkins H, Sansom OJ, Martin NM, Smith GC, Clarke AR. Efficient deletion of normal BRCA2-deficient intestinal epithelium by poly(ADP-ribose) polymerase inhibition models potential prophylactic therapy. Cancer Res. 2005;65(22):10145–10148
  101. Tong WM, Yang YG, Cao WH, et al. Poly(ADP-ribose) polymerase-1 plays a role in suppressing mammary tumourigenesis in mice. Oncogene. 2007;26(26):3857–3867
  102. Martin SA, Lord CJ, Ashworth A. DNA repair deficiency as a therapeutic target in cancer. Curr Opin Genet Dev. 2008;18(1):80–86
  103. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. New Engl J Med. 2005;352(10):997–1003
  104. Lord RV, Brabender J, Gandara D, et al. Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res. 2002;8(7):2286–2291
  105. Boulton S, Kyle S, Durkacz BW. Interactive effects of inhibitors of poly(ADP-ribose) polymerase and DNA-dependent protein kinase on cellular responses to DNA damage. Carcinogenesis. 1999;20(2):199–203
  106. Damia G, D’Incalci M. Targeting DNA repair as a promising approach in cancer therapy. Eur J Cancer. 2007;43(12):1791–1801
  107. Hickson I, Zhao Y, Richardson CJ, et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 2004;64(24):9152–9159

PII: S0959-8049(09)00779-5

doi: 10.1016/j.ejca.2009.10.021

European Journal of Cancer
Volume 46, Issue 1 , Pages 9-20 , January 2010