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Novel targeted agents in Her-2 positive and triple negative breast cancer
Tryfonopoulos, Dimitrios
The development of Her-2 targeted therapies has improved the prognosis for patients with Her-2 positive breast cancer. However, not all Her-2 positive tumours respond to treatment with Her-2 antagonists. Triple negative cancers are resistant to hormone and Her-2 targeted therapies. This project focused on improving response in Her-2 overexpressing breast cancer and on developing effective targeted therapy strategies for triple negative breast cancer. We tested a number of multi-target kinase inhibitors (imatinib, sunitinib, pazopanib and dasatinib) in Her-2 positive and triple negative breast cancer cell lines, alone and in combination with other agents. Two of the Her-2 positive cell lines showed moderate sensitivity to sunitinib malate. Combined treatment with sunitinib and trastuzumab showed improved response compared to either drug alone, in the four Her-2 positive cell lines tested. Dasatinib inhibited growth in 3 of the 5 triple negative but in only 1 of the 4 Her-2 positive cell lines tested. Based on response to the other multi-target kinase inhibitors, which have overlapping target specificities, and the Src,PP2, our results suggest that sensitivity to dasatinib in triple negative breast cancer is due to inhibition of ephrin type A receptors. Consistent with this hypothesis, neither Src expression nor phosphorylation predicted sensitivity to dasatinib, but high levels of Ephrin type A receptor 2 protein correlated with dasatinib sensitivity. High levels of caveolin 1 and caveolin 2 also correlated with dasatinib sensitivity in the panel of cell lines. Dasatinib combined with cisplatin was synergistic in the three dasatinib-sensitive cell lines. Dasatinib, in combination with 5’-deoxy-5’-fluoruridine, displayed synergy or additivity. Moderate synergy was observed with docetaxel in two triple negative cell lines. In conclusion, we have identified dasatinib with cisplatin as a rational combination for testing in triple-negative breast cancer, and have identified a panel of putative predictive biomarkers for dasatinib sensitivity (EphA2, CAV1 and CAV2).
Keyword(s): Cell biology; Cancer; HER2 positive; triple negative; breast cancer; dasatinib
Publication Date:
2013
Type: Other
Peer-Reviewed: Unknown
Language(s): English
Contributor(s): O'Donovan, Norma
Institution: Dublin City University
Citation(s): Tryfonopoulos, Dimitrios (2013) Novel targeted agents in Her-2 positive and triple negative breast cancer. Master of Science thesis, Dublin City University.
Publisher(s): Dublin City University. School of Biotechnology; Dublin City University. National Institute for Cellular Biotechnology (NICB)
File Format(s): application/pdf
Related Link(s): http://doras.dcu.ie/18334/1/Dimitrios_Tryfonopoulos_MSc.pdf
First Indexed: 2013-11-23 05:06:02 Last Updated: 2019-02-09 06:35:13