Researchers of the Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital used the novel inhibitor AZD2281 to target breast cancer, in which the BRCA1-gene plays a role, in a genetically engineered mouse model. Treatment resulted in tumor regression and a strong increase in survival without signs of toxicity. The inhibitor, which recently entered trials in human cancer patients, thus seems to have therapeutic potential for BRCA-defective tumors.
Long-term treatment with AZD2281 in the mouse model did result in the development of drug resistance. This could however be reversed by coadministration of an other type of inhibitor, tariquidar. Furthermore, the researchers studied the effect of combined treatment with AZD2281 and cisplatin or carboplatin. This increased the recurrence-free and overall survival, suggesting that AZD2281 potentiates the effect of these DNA-damaging agents.
The researchers previously developed the mouse model to study BRCA1-associated breast tumors. BRCA1 defects are often observed in so called triple-negative tumors. No targeted therapy exists yet for this type of breast cancer, which account for about 15% of all breast tumors. The researchers now use the mouse model for preclinical evaluation of potential therapeutics that target tumors with BRCA1 defects and that might be useful for treatment of triple-negative cancers.
The results with AZD2281 show that the mouse model is not only useful for the investigation of the efficacy and toxicity of chemical compounds. Also the development, prevention and circumvention of drug resistance can be tested in the model. Hence, intervention studies in the mouse model may help to predict the basis of resistance to novel therapeutics well in advance of the human experience.
Ultimately, this may improve the clinical success rate for novel anticancer drugs.
- Sven Rottenberg, Janneke E. Jaspers, Ariena Kersbergen, Eline van der Burg, Anders O. H. Nygren, Serge A. L. Zander, Patrick W. B. Derksen, Michiel de Bruin, John Zevenhoven, Alan Lau, Robert Boulter, Aaron Cranston, Mark J. O'Connor, Niall M. B. Martin, Piet Borst, and Jos Jonkers. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. PNAS Online Early Edition, October 29, 2008
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