Abstract P5-03-03: Antitumor Activity and Cancer Stem Cells Effect of Cetuximab in Combination with Ixabepilone in Triple Negative Breast Cancers (TNBC)

Abstract

Abstract Purpose: The ErbB family, including EGFR, has been demonstrated to play key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSCs) which are believed to be responsible for tumor initiation and maintenance. Ixabepilone is the microtubule-stabilizing agent has been expected to be more sensitive than the conventional taxanes. The aim of this study was to investigate whether the EGFR monoclonocal antibody cetuximab, in combination with ixabepilone is a more effective treatment, and kill cancer stem cells more effectively as compared to chemotherapy alone in TNBC. Experimental Design and Results: Breast CSC populations were evaluated with FACS analysis (CD44+ and CD24−/low, or Aldefluor+) and mammosphere formation efficiency (MSFE). In vitro, we demonstrated that in triple negative cell lines (MDA-MB-231 and SUM159), cancer stem cell populations were decreased after treatment of cetuximab, or cetuximab plus ixabepilone. In vivo, cetuximab in combination with ixabepilone treatment caused significant tumor regression (cetuximab vs. cetuximab+ ixabepilone; tumor volume fold change P <0.05 (MDA-MB-231), P <0.0001 (SUM159) in triple negative breast cancer xenografts. Thus, cetuximab decreased CSC population in xenograft tumors. Decrease in autophagy (LC3b, p62 and autophagosomes) were seen in cetuximab-treated tumors. Conclusions: These studies demonstrate that cetuximab in combination with ixabepilone is more effective than chemotherapy alone in TNBC by affecting CSCs, as well as bulk tumor. These data support a neoadjuvant phase II study comparing ixabepilone vs. ixabepilone +cetuximab in TNBC patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-03.