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01.08.2012 | Leading Article

PARP Inhibitors

Mechanism of Action and Their Potential Role in the Prevention and Treatment of Cancer

verfasst von: Bristi Basu, Shahneen K. Sandhu, Professor Johann S. de Bono, MBChB, MSc, PhD, FRCP

Erschienen in: Drugs | Ausgabe 12/2012

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Abstract

The use of poly(ADP-ribose) polymerase (PARP) inhibitors provided proof-of-concept for a synthetic lethal anticancer strategy as a result of their efficacy and favourable toxicity profile in BRCA1/2 mutation carriers. Efforts are underway to identify a broader group of patients with genomic susceptibility that may benefit from these agents. In an endeavour to enhance anti-tumour effects, PARP inhibitors have been combined with traditional cytotoxic therapy and radiotherapy; however, optimization of dosing schedules for these combination regimens remains key to maximizing benefit whilst mitigating the potential for increased toxicity. With ongoing clinical experience of PARP inhibition, mechanisms of resistance to these therapies are being elucidated and specific challenges to long-term administration of these drugs will need to be addressed. Development of robust predictive biomarkers of response for optimal patient selection and rational combination strategies must be pursued if the full potential of these agents is to be realized.

Chambon P, Weill JD, Mandel P. Nicotinamide mononucleotide activation of new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochem Biophys Res Commun 1963 Apr 2; 11: 39–43PubMedCrossRef

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: 139PubMedCrossRef

de la Lastra CA, Villegas I, Sanchez-Fidalgo S. Poly(ADP-ribose) polymerase inhibitors: new pharmacological functions and potential clinical implications. Curr Pharm Des 2007; 13 (9): 933–62PubMedCrossRef

Langelier MF, Planck JL, Roy S, et al. Crystal structures of poly(ADP-ribose) polymerase-1 (PARP-1) zinc fingers bound to DNA: structural and functional insights into DNA-dependent PARP-1 activity. J Biol Chem 2011 Mar 25; 286 (12): 10690–701PubMedCrossRef

Chalmers A, Johnston P, Woodcock M, et al. PARP-1, PARP-2, and the cellular response to low doses of ionizing radiation. Int J Radiat Oncol Biol Phys 2004 Feb 1; 58 (2): 410–9PubMedCrossRef

Curtin NJ. PARP inhibitors for cancer therapy. Expert Rev Mol Med 2005 Mar 15; 7 (4): 1–20PubMedCrossRef

Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature 2001 May 17; 411 (6835): 366–74PubMedCrossRef

Ratnam K, Low JA. Current development of clinical inhibitors of poly(ADP-ribose) polymerase in oncology. Clin Cancer Res 2007 Mar 1; 13 (5): 1383–8PubMedCrossRef

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 Aug 1; 26 (22): 3785–90PubMedCrossRef

10.

Yap TA, Sandhu SK, Carden CP, et al. Poly(ADP-ribose) polymerase (PARP) inhibitors: exploiting a synthetic lethal strategy in the clinic. CA Cancer J Clin 2011 Jan-Feb; 61 (1): 31–49PubMedCrossRef

11.

D’Amours D, Desnoyers S, D’Silva I, et al. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J 1999 Sep 1; 342 (Pt 2): 249–68PubMedCrossRef

12.

Rankin PW, Jacobson EL, Benjamin RC, et al. Quantitative studies of inhibitors of ADP-ribosylation in vitro and in vivo. J Biol Chem 1989 Mar 15; 264 (8): 4312–7PubMed

13.

Southan GJ, Szabo C. Poly(ADP-ribose) polymerase in-hibitors. Curr Med Chem 2003 Feb; 10 (4): 321–40PubMedCrossRef

14.

Papeo G, Forte B, Orsini P, et al. Poly(ADP-ribose) poly-merase inhibition in cancer therapy: are we close to maturity?. Exp Opin Ther Patents 2009 Oct; 19 (10): 1377–400CrossRef

15.

Moore J, Keyt B, Burnler J, et al. Treatment of cancer. US patent application publication US2008/0103104 A1. 2008

16.

Liu X, Shi Y, Maag DX, et al. Iniparib non-selectively modifies cysteine-containing proteins in tumor cells and is not a bona fide PARP inhibitor. Clin Cancer Res 2012 Jan 15; 18 (2): 510–23PubMedCrossRef

17.

Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009 Jul 9; 361 (2): 123–34PubMedCrossRef

18.

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 Jun 1; 27 (16): 2705–11PubMedCrossRef

19.

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 Dec 1; 14 (23): 7917–23PubMedCrossRef

20.

Kaelin Jr WG. The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer 2005 Sep; 5 (9): 689–98PubMedCrossRef

21.

Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005 Apr 14; 434 (7035): 913–7PubMedCrossRef

22.

Helleday T, Bryant HE, Schultz N. Poly(ADP-ribose) poly-merase (PARP-1) in homologous recombination and as a target for cancer therapy. Cell Cycle 2005 Sep; 4 (9): 1176–8PubMedCrossRef

23.

Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005 Apr 14; 434 (7035): 917–21PubMedCrossRef

24.

Audeh MW, Carmichael J, Penson RT, et al. Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 2010 Jul 24; 376 (9737): 245–51PubMedCrossRef

25.

Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 2010 Jul 24; 376 (9737): 235–44PubMedCrossRef

26.

Plummer ER. Inhibition of poly(ADP-ribose) polymerase in cancer. Curr Opin Pharmacol 2006 Aug; 6 (4): 364–8PubMedCrossRef

27.

Kummar S, Chen A, Ji J, et al. Phase I study of PARP in-hibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. Cancer Res 2011 Sep 1; 71 (17): 5626–34PubMedCrossRef

28.

Giaccone G, Rajan A, Kelly R, et al. A phase I combination study of olaparib (AZD2281; KU-0059436) and cisplatin (C) plus gemcitabine (G) in adults with solid tumors [abstract]. J Clin Oncol 2010; 28 (15S): 3027A

29.

O’Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 2011 Jan 20; 364 (3): 205–14PubMedCrossRef

30.

AstraZeneca. AstraZeneca updates on olaparib and TC-5214 development programmes [media release]. 2011 Dec 20 [online]. Available from URL: http://www.astrazeneca.com/Media/Press-releases/Article/20111220-az-updates-olaparib-TC5214-development [Accessed 2012 Jul 16]

31.

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 Jan 7; 96 (1): 56–67PubMedCrossRef

32.

Nowsheen S, Bonner JA, Yang ES. The poly(ADP-Ribose) polymerase inhibitor ABT-888 reduces radiation-induced nuclear EGFR and augments head and neck tumor response to radiotherapy. Radiother Oncol 2011 Jun; 99 (3): 331–8PubMedCrossRef

33.

Senra JM, Telfer BA, Cherry KE, et al. Inhibition of PARP-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft. Mol Cancer Ther 2011 Oct; 10 (10): 1949–58PubMedCrossRef

34.

Wang L, Mason KA, Ang KK, et al. MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation. Invest New Drugs. Epub 2011 Nov 30

35.

Blakeley J, Ye X, Grossman S, et al. Poly (ADP-ribose) polymerase-1 (PARP1) inhibitor BSI-201 in combination with temozolomide (TMZ) in malignant glioma [abstract]. J Clin Oncol 2010; 28 (15S): 2012A

36.

Dungey FA, Loser DA, Chalmers AJ. Replication-dependent radiosensitization of human glioma cells by inhibition of poly(ADP-Ribose) polymerase: mechanisms and therapeutic potential. Int J Rad Oncol Biol Phys 2008 Nov 15; 72 (4): 1188–97CrossRef

37.

Chalmers AJ. Overcoming resistance of glioblastoma to conventional cytotoxic therapies by the addition of PARP inhibitors. Anticancer Agents Med Chem 2010 Sep; 10 (7): 520–33PubMedCrossRef

38.

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 Aug 15; 66 (16): 8109–15PubMedCrossRef

39.

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

40.

Weston VJ, Oldreive CE, Skowronska A, et al. The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Blood 2010 Nov 25; 116 (22): 4578–87PubMedCrossRef

41.

Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000 Aug 17; 406 (6797): 747–52PubMedCrossRef

42.

Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 2004 Aug 15; 10 (16): 5367–74PubMedCrossRef

43.

Turner NC, Reis-Filho JS. Basal-like breast cancer and the BRCA1 phenotype. Oncogene 2006 Sep 25; 25 (43): 5846–53PubMedCrossRef

44.

Turner NC, Reis-Filho JS, Russell AM, et al. BRCA1 dys-function in sporadic basal-like breast cancer. Oncogene 2007 Mar 29; 26 (14): 2126–32PubMedCrossRef

45.

Thompson ME, Jensen RA, Obermiller PS, et al. Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet 1995 Apr; 9 (4): 444–50PubMedCrossRef

46.

Byrski T, Gronwald J, Huzarski T, et al. Pathologic com-plete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol 2010 Jan 20; 28 (3): 375–9PubMedCrossRef

47.

Gelmon K, Hirte H, Robidoux A, et al. Can we define tu-mors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer [abstract no. 3002]. J Clin Oncol 2010; 28 (15 Suppl.)

48.

Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differ-entiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011 Sep; 12 (9): 852–61PubMedCrossRef

49.

Bouwman P, Aly A, Escandell JM, et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol 2010 Jun; 17 (6): 688–95PubMedCrossRef

50.

Bunting SF, Callen E, Wong N, et al. 53BP1 inhibits homo-logous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 2010 Apr 16; 141 (2): 243–54PubMedCrossRef

51.

Cheung HW, Cowley GS, Weir BA, et al. Systematic in-vestigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer. Proc Natl Acad Sci U S A 2011 Jul 26; 108 (30): 12372–7PubMedCrossRef

52.

Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011 Jun 29; 474 (7353): 609–15CrossRef

53.

Ledermann J, Harter P, Gourley et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 2012 Apr 12; 366 (15): 1382–92PubMedCrossRef

54.

Zhao W, Duan W, Leon M, et al. Targeting fanconi anemia (FA) repair pathway deficiency for treatment with PARP inhibitors [abstract]. J Clin Oncol 2010; 28 (15S): TPS168A

55.

Sanchez EV, Chow A, Raskin L, et al. Preclinical testing of the PARP inhibitor ABT-888 in microsatellite instable colorectal cancer [abstract]. J Clin Oncol 2009; 27 (15S): 11028A

56.

Williamson CT, Muzik H, Turhan AG, et al. ATM defi-ciency sensitizes mantle cell lymphoma cells to poly(ADP-ribose) polymerase-1 inhibitors. Mol Cancer Ther 2010 Feb; 9 (2): 347–57PubMedCrossRef

57.

Gaymes TJ, Shall S, Farzaneh F, et al. Chromosomal in-stability syndromes are sensitive to poly ADP-ribose polymerase inhibitors. Haematologica 2008 Dec; 93 (12): 1886–9PubMedCrossRef

58.

Dedes KJ, Wetterskog D, Mendes-Pereira AM, et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med 2010 Oct 13; 2 (53): 53ra75

59.

Fraser M, Zhao H, Luoto KR, 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 Feb 15; 18 (4): 1015–27PubMedCrossRef

60.

Brenner JC, Ateeq B, Li Y, et al. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell 2011 May 17; 19 (5): 664–78PubMedCrossRef

61.

Brenner JC, Feng FY, Han S, et al. PARP-1 inhibition as a targeted strategy to treat Ewing’s sarcoma. Cancer Res 2012 Apr 1; 72 (7): 1608–13PubMedCrossRef

62.

Iorns E, Lord CJ, Turner N, et al. Utilizing RNA inter-ference to enhance cancer drug discovery. Nat Rev Drug Disc 2007 Jul; 6 (7): 556–68CrossRef

63.

Graeser M, McCarthy A, Lord CJ, et al. A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer. Clin Cancer Res 2010 Dec 15; 16 (24): 6159–68PubMedCrossRef

64.

Asakawa H, Koizumi H, Koike A, et al. Prediction of breast cancer sensitivity to neoadjuvant chemotherapy based on status of DNA damage repair proteins. Breast Cancer Res 2010; 12 (2): R17PubMedCrossRef

65.

Mukhopadhyay A, Elattar A, Cerbinskaite A, et al. Devel-opment of a functional assay for homologous recombination status in primary cultures of epithelial ovarian tumor and correlation with sensitivity to poly(ADP-ribose) polymerase inhibitors. Clin Cancer Res 2010 Apr 15; 16 (8): 2344–51PubMedCrossRef

66.

Gottipati P, Vischioni B, Schultz N, et al. Poly(ADP-ribose) polymerase is hyperactivated in homologous recombination-defective cells. Cancer Res 2010 Jul 1; 70 (13): 5389–98PubMedCrossRef

67.

de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 2008 Oct 1; 14 (19): 6302–9PubMedCrossRef

68.

Bednarz N, Eltze E, Semjonow A, et al. BRCA1 loss pre-existing in small subpopulations of prostate cancer is associated with advanced disease and metastatic spread to lymph nodes and peripheral blood. Clin Cancer Res 2010 Jul 1; 16 (13): 3340–8PubMedCrossRef

69.

Wang LH, Pfister TD, Parchment RE, et al. Monitoring drug-induced gammaH2AX as a pharmacodynamic bio-marker in individual circulating tumor cells. Clin Cancer Res 2010 Feb 1; 16 (3): 1073–84PubMedCrossRef

70.

Norquist B, Wurz KA, Pennil CC, et al. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol 2011 Aug 1; 29 (22): 3008–15PubMedCrossRef

71.

Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 2010 May 20; 28 (15): 2512–9PubMedCrossRef

72.

Edwards SL, Brough R, Lord CJ, et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 2008 Feb 28; 451 (7182): 1111–5PubMedCrossRef

73.

Sakai W, Swisher EM, Karlan BY, et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 2008 Feb 28; 451 (7182): 1116–20PubMedCrossRef

74.

Rottenberg S, Jaspers JE, Kersbergen A, et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A 2008 Nov 4; 105 (44): 17079–84PubMedCrossRef

75.

Chiarugi A. A snapshot of chemoresistance to PARP in-hibitors. Trends Pharmacol Sci 2012 Jan; 33 (1): 42–8PubMedCrossRef

76.

Schild D. Wiese Overexpression of RAD51 suppresses recombination defects: a possible mechanism to reverse genomic instability. Nucleic Acids Res 2010 Mar; 38 (4): 1061–70PubMedCrossRef

77.

Lord CJ, Ashworth A. Targeted therapy for cancer using PARP inhibitors. Curr Opin Pharmacol 2008 Aug; 8 (4): 363–9PubMedCrossRef

78.

Hay T, Matthews JR, Pietzka L, et al. Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res 2009 May 1; 69 (9): 3850–5PubMedCrossRef

79.

Drew Y, Plummer R. PARP inhibitors in cancer therapy: two modes of attack on the cancer cell widening the clinical applications. Drug Resist Updat 2009 Dec; 12 (6): 153–6PubMedCrossRef

80.

Tong WM, Ohgaki H, Huang H, et al. Null mutation of DNA strand break-binding molecule poly(ADP-ribose) polymerase causes medulloblastomas in p53(-/-) mice. Am J Pathol 2003 Jan; 162 (1): 343–52PubMedCrossRef

81.

Devalaraja-Narashimha K, Padanilam BJ. PARP1 deficiency exacerbates diet-induced obesity in mice. J Endocrinol 2010 Jun; 205 (3): 243–52PubMedCrossRef

Titel: PARP Inhibitors
Mechanism of Action and Their Potential Role in the Prevention and Treatment of Cancer
verfasst von: Bristi Basu
Shahneen K. Sandhu
Professor Johann S. de Bono, MBChB, MSc, PhD, FRCP
Publikationsdatum: 01.08.2012
Verlag: Springer International Publishing
Erschienen in: Drugs / Ausgabe 12/2012
Print ISSN: 0012-6667
Elektronische ISSN: 1179-1950
DOI: https://doi.org/10.2165/11635510-000000000-00000

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

PARP Inhibitors

Mechanism of Action and Their Potential Role in the Prevention and Treatment of Cancer

Abstract

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

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