Abstract A29: Discovery and preclinical to clinical evaluation of biomarkers for Anti-DLL4, a monoclonal antibody targeting cancer stem cells

Abstract

Abstract Blockade of DLL4 signaling reduces tumor growth in preclinical human xenograft models by disrupting productive angiogenesis and reducing proliferation of tumor cells. Importantly in these models, blocking DLL4 also reduces cancer stem cell (CSC) frequency in multiple solid tumor types. Currently, there exists an important need to identify and evaluate pharmacodynamic biomarkers that indicate the biological activity of agents, such as anti-DLL4, that are in clinical studies. Towards this aim, we used numerous human xenograft models derived from primary human tumors to identify and characterize biomarkers for anti-DLL4. Here, we present data from these studies and describe anti-DLL4 biomarkers in tumors, in hair follicles, and in blood. We show that several vascular-related genes are significantly upregulated by anti-DLL4 in tumors including, Egfl7, Apln, Cldn5, and Notch4. We also demonstrate significant downregulation of CSC gene signatures and modulation of differentiation genesets. A subset of the identified markers were validated at the protein level and also tested in a human skin graft model, where the human tumor is engrafted in a human microenvironment/vasculature. Finally, a DLL4-Notch gene signature was identified that showed a significant association with breast cancer survival using publicly available cancer gene sets. In surrogate tissues, we identified anti-DLL4 biomarkers in blood and in hair follicles. These markers from surrogate tissues were translated into a phase I trial of Anti-DLL4 antibody (OMP-21M18), and an interim analysis of this data demonstrates that OMP-21M18 affects the Notch pathway in patient samples. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A29.