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Volume 10 Supplement 2

Breast Cancer Research 2008

PARP-1 inhibitor monotherapy and combination therapy in a preclinical mouse model of Brca2 mutant breast cancer

Background

Women who inherit a germline mutation in the BRCA2 gene are predisposed to breast cancer [1]. Therapies targeted specifically at these cancers have so far remained elusive. Recently, inhibition of poly-ADP-(ribose)-polymerase-1 (PARP-1) was shown to cause high levels of death in cells and xenografts deficient in BRCA2 [24].

Methods

We have conditionally deleted Brca2 and p53 within murine mammary epithelium, resulting in the development of naturally arising tumours from 6 months of age. These tumours have been treated in situ with a highly potent inhibitor of PARP-1, either alone or in combination with carboplatin. The tumour size was followed by regular measurement with calipers.

Results

Daily exposure to 50 mg/kg PARP-1 inhibitor caused significant regression or growth inhibition in the majority of Brca2/p53-deficient tumours, in comparison with p53-deficient or pten-deficient control tumours. Combination treatment with carboplatin did not enhance initial tumour regression compared with carboplatin treatment alone. However, prolonged treatment with PARP-1 inhibitor, after an initial 28-day combination therapy, increased the time to tumour relapse compared with 28 days of carboplatin monotherapy or combination therapy.

Conclusion

This is the first preclinical study to show in vivo hypersensitivity of naturally arising Brca2-deficient mammary tumours to PARP-1 inhibition monotherapy and combination therapy.

References

  1. 1.

    Boulton SJ: Cellular functions of the BRCA tumour-suppressor proteins. Biochem Soc Trans. 2006, 34: 633-645. 10.1042/BST0340633.

  2. 2.

    Farmer H, et al: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005, 434: 917-921. 10.1038/nature03445.

  3. 3.

    Bryant HE, et al: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose)polymerase. Nature. 2005, 434: 913-917. 10.1038/nature03443.

  4. 4.

    Hay T, et al: Efficient deletion of normal Brca2-deficient intestinal epithelium by PARP inhibition models potential prophylactic therapy. Cancer Res. 2005, 65: 10145-10148. 10.1158/0008-5472.CAN-05-1186.

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Acknowledgements

TH is funded by the Association for International Cancer Research and LP is funded by AstraZeneca.

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Keywords

  • Breast Cancer
  • Carboplatin
  • Germline Mutation
  • Ribose
  • BRCA2 Gene