Abstract 5584: Finding predictive markers for tumor response to classical cytotoxic drugs.

Abstract

Abstract As attempts to find predictive markers for cytotoxic drugs have been relatively unsuccessful using patient tumor samples (1), we are using a mouse model for BRCA1-deficient mammary tumors to search for such markers. Although these tumors originate in inbred mice from an inactivating deletion of the Brca1 and p53 genes, their response to doxorubicin (2), docetaxel (2), topotecan (3) and PARP inhibitors (4) varies. We have shown that in this tumor model 5 of the 22 tumors respond poorly to docetaxel, because of upregulated drug-transporting P-glycoproteins (5). These 5 were not found by standard gene expression analytical tools, such as significance analysis of microarrays (SAM), and we have shown that SAM only detects resistance markers if present in more than half the tumor samples (5). Better algorithms for the detection of resistance determinants in a subfraction of tumors are being developed by De Ronde and Wessels (5). We are still searching for the cause of the poor docetaxel response in 17 of the 22 tumors. 1. Borst,P. and Wessels,L. (2010). Do predictive signatures really predict response to cancer chemotherapy? Cell Cycle 9, 4836-4840. 2. Rottenberg,S., et al (2007). Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc. Natl. Acad. Sci. U. S. A. 104, 12117-12122. 3. Zander,S., et al (2010). Sensitivity and acquired resistance of BRCA1; -53-deficient mouse mammary tumors to the topoisomerase I inhibitor topotecan. Cancer Res. 70, 1700-1710. 4. Rottenberg,S., et al (2008). 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 105, 17079-17084. 5. Rottenberg,S., et al (2012). Impact of intertumoral heterogeneity on predicting chemotherapy response of BRCA1-deficient mammary tumors. Cancer Res 72, 2350-2361. Citation Format: Piet Borst, Sven Rottenberg. Finding predictive markers for tumor response to classical cytotoxic drugs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5584. doi:10.1158/1538-7445.AM2013-5584