2014 UALC
Arnaud Augert, PhD
Fred Hutchinson Cancer Research Center
Research Project:
Genetic models and targeted therapy for MLL2-mutant small cell lung cancer
Summary:
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer and there are as yet no approved targeted therapies available. In an effort to identify the genes and pathways that drive SCLC, we performed genomic analyses of SCLC tumors and cell lines and found frequent inactivating mutations in MLL2/KMT2D, a histone methyltransferase. Dr. Augert is now investigating roles for MLL2 in SCLC tumor suppression using cell-based studies and genetically engineered mouse models. He aims to develop a refined preclinical model to test a novel targeted therapeutic approach directed towards MLL2-mutant SCLC.
Update, 2019: Dr. Augert published a manuscript in 2019 based on this work. The authors assessed the anti-tumor properties of ORY-1001, a lysine-specific histone demethylase 1A (LSD1) inhibitor, in an ex vivo panel of SCLC patient derived xenografts (PDXs). Transcriptional analyses revealed an activation of NOTCH signaling which led to suppression of Achaete-scute homolog 1 (ASCL1) and SCLC tumorigenesis. Mechanistically, LSD1 was found to bind directly to regions of the NOTCH gene, repressing its expression and downstream signaling. Finally, complete and durable tumor regression occurred with ORY-1001 treatment in a chemoresistant PDX model. In summary, this study used a series of pharmacological and genetic approaches to show that targeting LSD1 impedes SCLC tumor growth via NOTCH signaling activation and loss of neuroendocrine differentiation. Read the full manuscript
Augert A, Eastwood E, Ibrahim AH, et al., 2019. Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition. Sci Signal. 12(567).