Abstract 5218: γ-secretase inhibitor PF-03084014 impairs Notch signaling and induces antiangiogenic and antitumor effects in breast cancer models

PF-03084014, a small molecule γ-secretase inhibitor (GSI), has previously been shown to inhibit Notch signaling and demonstrated antitumor efficacy. The aim of this report is to gain insights into the mechanism PF-03084014-induced activity. The cell-based evaluation of PF-03084014 across 30 breast cancer (BC) cell lines indicated significant growth inhibition in only a subset of cell lines (3/30). In contrast, PF-03084014 demonstrated cell cycle arrest and induction of apoptosis by FACS analysis across the majority of a panel of T-acute lymphoblastic leukemia (T-ALL) cell lines. In vivo BrdU uptake of tumor and [ 18 F]FLT-PET imaging studies demonstrated that PF-03084014 at an efficacious dose (120 mg/kg) caused cell cycle arrest in Sup T1 tumors but not in MDA-MB-231 xenografts, although PF-03084014 suppressed the expression of Notch target genes and tumor growth in both models. These results suggest that the primary mechanism(s) for PF-03084014-induced efficacy in T-ALL and BC models may be different, possibly because the tumor-host microenvironment in the BC model plays an important role during Notch signaling activation. IHC analysis in a panel of solid tumors demonstrated that Notch ligands including jagged 1, 2 and Dll4 were predominately expressed in the host vasculature and stromal cells. To investigate the potential antiangiogenic activity of PF-03084014, an in vitro endothelial cell/fibroblast co-culture tube formation assay was utilized. PF-03084014 disrupted the multicellular lumen-like structures at 100 nM, indicating defective differentiation of endothelial cells in early stage angiogenesis. Ultrasound imaging was utilized to further investigate the antiangiogenic properties of PF-03084014 including both the quantitative measurement of the total tumor vessel volume using 3-D scanning methods and an assessment tumor blood vessel function by measuring blood flow after iv injection of microbubble contrast agents. When MDA-MB-231 tumor bearing mice were administered with an efficacious dose of PF-03084014 consecutively for 4 days, ultrasound imaging revealed a significant (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5218.