Abstract A226: Identification of new synergistic compounds for the treatment of NOTCH-driven T-ALL.

Abstract

Abstract T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy that accounts for 15% of childhood and 25% of adult ALLs. Constitutive activation of NOTCH signaling as result of activating mutations in the NOTCH1 gene is a hallmark of this disease and small molecule gamma-secretase inhibitors, which effectively block activation of the NOTCH1 receptor, have been proposed as targeted therapy. However, the progress of NOTCH1-blocking agents such as in the clinic has been limited. Here we hypothesized that detailed transcriptional profiling of T-ALL lymphoblasts upon inhibition of NOTCH1 signaling would uncover major effector pathways downstream of NOTCH1. Moreover, we proposed that these signatures would facilitate the identification of new drugs and drug combinations for the treatment of T-ALL. Gene expression profiling of NOTCH1 induced leukemias treated with DBZ, a highly active gamma-secretase inhibitor, identified numerous genes regulated by NOTCH1 in human leukemia. Notably these signatures were enriched in NOTCH1 direct target genes such as Hes1 and revealed a prominent role of NOTCH signaling in the control of cellular metabolic pathways. Following on these results we performed Connectiviy map analysis to identify drugs whose transcriptional effects could antagonize those of oncogenic NOTCH1 in human leukemia. This analysis identified HDAC inhibitors, anti-psychotic agents, anti-malarials and compounds targeting the PI3K and NFKB signaling pathways. Detailed analysis of the effects of these drugs alone and in combination with DBZ demonstrated strong antileukemic activity and strong synergism when combined with inhibition of NOTCH signaling with a gamma-secretase inhibitor. Moreover, biochemical and transcriptional profiling of these drugs identifies agents with unique and related mechanisms of action. Overall these results identify new antileukemic drugs with strongly synergistic activity in combination with NOTCH1 inhibition for the treatment of T-ALL Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A226. Citation Format: Marta Sanchez Martin, Alberto Ambesi, Daniel Herranz, Adolfo Ferrando. Identification of new synergistic compounds for the treatment of NOTCH-driven T-ALL. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A226.