P1-04-09: Biphasic Effects of Docetaxel and Hedgehog Signaling Antagonists on Breast Cancer Tumor-Initiating Cells In Vivo.

Abstract

Abstract Recent data suggest the existence of a subset of breast cancer cells variously termed cancer stem cells, tumor-initiating, or tumor-propagating cells, that are capable of self-renewal and of regenerating tumors upon transplantation that are biologically consistent with the tumor of origin. These cells appear to be intrinsically resistant to systemic chemo- and radiation therapies and may therefore be responsible for treatment resistance, and disease recurrence. Several signal transduction networks have been implicated in normal and malignant stem cell self-renewal. These include those of the Hedgehog, Notch, Wnt, EGF, FGF families of ligands. Antagonists of these networks have become attractive targeted therapeutic agents. In this study, we evaluated two different Hedgehog signaling antagonists, one targeting Smoothened (the main membrane effector of activated signaling) and one targeting GLI1/2 (the two transcription factors mediating ligand response), for their ability to shrink patient-derived xenograft tumors and to affect the number or function of breast tumor-initiating cells in vivo. Both antagonists showed little effect as single agents, but could augment tumor shrinkage by docetaxel. However, these effects were only observed in those models showing evidence of canonical SMO/GLI-mediated signaling. In dilutional transplantation assays, both SMO or GLI targeted agents have a biphasic effect on the behavior of the tumor-initiating population such that large cell numbers yielded few tumors while intermediate cell numbers yielded tumors at a comparable rate as controls. These data suggest that combination therapy alters the functional state of stem cells in the context of larger cell numbers rather than targeting the tumor-initiating cell directly. These data therefore have significant relevance for the interpretation of ongoing clinical trials of hedgehog signaling inhibitors in solid tumors, including breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-04-09.