213 A phase I dose-finding study of BI 853520, a potent and selective inhibitor of focal adhesion kinase (FAK), in Japanese and Taiwanese patients with advanced or metastatic solid tumors

Abstract

Lysine specific demethylase 1 (LSD1) is a histone H3K4me1/2 demethylase found in various transcriptional co-repressor complexes. LSD1 mediated H3K4 demethylation can result in repressive chromatin environment that silences gene expression and has been shown to play a role in development and hematopoietic differentiation. LSD1 is overexpressed in multiple tumor types, including acute myeloid leukemia (AML). Together, these studies suggest LSD1 is an important regulator of the epigenome that modulates gene expression through modification of histones and its presence in transcriptional complexes. The current study describes the anti-tumor effects of a novel, potent, irreversible, GSK LSD1 inhibitor (GSK2879552) in AML and small cell lung cancer (SCLC). Screening of over 150 cancer cell lines revealed that SCLC and AML cells have a unique requirement for LSD1. While LSD1 inhibition did not affect the global levels of H3K4me1 or H3K4me2, local changes in these histone marks were observed near transcriptional start sites of putative LSD1 target genes. This increase in the transcriptionally activating histone modification correlates with increased gene expression. Treatment of AML cells with GSK2879552 promotes the expression of cell surface markers associated with a differentiated immunophenotype, including CD11b and CD86. In an MV-4−11 engraftment model, increases in CD86 and CD11b were observed as early as 8 hours post dosing. GSK2879552 treatment resulted in a potent anti-proliferative growth effect in a subset of SCLC cell lines tested and all AML cell lines tested. Potent growth inhibition was also observed on AML blast colony forming ability of bone marrow samples derived from primary AML patient samples. The effects of LSD1 inhibition were further characterized in vivo using a mouse model of AML induced by transduction of mouse hematopoietic progenitor cells with a retrovirus encoding MLL-AF9 and GFP. Primary AML cells were transplanted into secondary recipient mice that were treated with an LSD1 tool molecule inhibitor for 17 days. Control mice succumbed to AML by 45 days post transplant, while treated mice showed prolonged survival. GSK2879552 treatment of mice engrafted with SCLC cell lines resulted in greater than 80% tumor growth inhibition. Studies using patient derived primary SCLC showed similar efficacy demonstrating the growth inhibition of SCLC with an LSD1 inhibitor extended beyond cell lines. Together, these data demonstrate that pharmacological inhibition of LSD1 may provide a promising treatment for AML and SCLC. A Phase I clinical trial using GSK2879552 was initiated in March, 2014. All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed.