Abstract P6-15-10: Targeting Delta-Like 4 Ligand (DLL4)/Notch Signaling by a Novel Anti-DLL4 Antibody Inhibits Tumor Growth through Altering Cancer Stem Cell and Epithelial-to-Mesenchymal Transition-Associated Genes in Triple Negative Breast Cancer

Triple negative breast cancer (TNBC, ER-, PR-Her2-) accounts for 10% of all types of breast cancer and is known to be particularly aggressive and refractory to current therapies. Chemotherapeutic agents, such as taxanes, are currently the only treatment option for this type of breast cancer. However, these treatments often result in local and systemic relapse. While several promising targeted agents have improved the relapse rate in the combination with chemotherapy in patients with pathologic complete response, those who do not achieve pathologic complete response still have a poor prognosis. We previously demonstrated that interfering with Deltalike 4 ligand (DLL4)/Notch signaling by an anti-DLL4 antibody decreased tumor growth and delayed tumor recurrence following paclitaxel treatment through reducing breast cancer stem cell fraction and tumorigenicity (Proc Am Asso Cancer Res. 51:4, 2010). CD44+/CD24 low cells have been demonstrated to be highly tumorigenic in breast tumors and are associated with treatment resistance (PNAS U S A, 106: 13820-13825, 2009). To gain insights into the mechanism of action of anti-DLL4-mediated TNBC growth inhibition, we evaluated the effect of anti-DLL4 on breast cancer CD44+/CD24 low the expression patterns of a list of genes involved in sternness, differentiation, and key stem cell signaling pathways in TNBC xenograft tumors following paclitaxel with and without antibody treatment in vivo. Our data showed that paclitaxel treatment resulted in significant changes of gene expression patterns in the CD44 + /CD24 low cells in the residual tumors. We further analyzed these genes and identified several genes related to Notch signaling, stem cell maintenance and epithelial-to-mesenchymal transition that were modulated differentially by treatment with paclitaxel and/or anti-DLL4. In a metastatic TNBC orthotopic tumor model, the anti-DLL4 treatment resulted in tumor growth inhibition at the primary site and distant organs. Taken together, our findings suggest that targeting DLL4 may improve the efficacy of current treatments, delay tumor recurrence, and reduce metastatic growth in TNBC. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-10.