title: Inhibition of Aurora-B kinase activity confers antitumor efficacy in preclinical mouse models of early and advanced gastrointestinal neoplasia.
abstract: The Aurora family of kinases, play a fundamental role in cell division and are overexpressed in several cancers including colon. The activity of barasertib-hQPA, a selective inhibitor of Aurora-B kinase (ABK) was investigated in a range of preclinical models of gastrointestinal cancer. Treatment with barasertib-hQPA produced anti-proliferative and cytotoxic effects across a panel of human colorectal cancer (CRC) cell lines in vitro. Prodrug, barasertib [48-h subcutaneous (s.c.) infusion; 150 mg/kg/day] inhibited the growth of SW620, Colo205, HCT116 human colorectal tumor xenografts in nude mice significantly (Student's t-test, P<0.05, n=10-12 per group). Flow cytometric analysis of single cells from disaggregated barasertib-treated SW620 tumors revealed a decrease in phosphorylated histone H3 (phH3) and an increase in tumor cells with ≥4N DNA content P<0.05). The activity of barasertib was then examined in ApcMin/+ mice, a spontaneous model of early intestinal neoplasia. Macroscopic evaluation of the small intestine revealed that barasertib treatment [25 mg/kg intra-peritoneal (i.p.) Q1Dx4 each week for 3 weeks] of 8-week old ApcMin/+ mice produced a 39% reduction in macroadenoma number (P=0.02) and a 43% reduction in overall adenoma burden (P=0.02) compared with vehicle-treated controls. Quantification of microscopic adenomas revealed a >64% reduction in the number of adenomas spanning more than one villus. Histological analysis of these adenomas revealed a number of distinct changes in barasertib-treated ApcMin/+ mice, including a 94% reduction in the proportion of phospho-histone H3-positive cells (P<0.001) and a 53% reduction in the number of cells per adenoma (P=0.001). These results provide a scientific rationale for investigating ABK inhibitors as a treatment for intestinal cancer.
authors.affiliation: Histopathology Unit, London Research Institute, Cancer Research UK, Lincoln's Inn Fields, London, UK.
authors.forename: Denis G
authors.initials: DG
authors.lastname: Alferez
authors.forename: Robert A
authors.initials: RA
authors.lastname: Goodlad
authors.forename: Rajesh
authors.initials: R
authors.lastname: Odedra
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sini
authors.forename: Claire
authors.initials: C
authors.lastname: Crafter
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ryan
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Wedge
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Wright
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Anderson
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
mesh_terms: D000818:Animals; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006657:Histones / Q000235:genetics; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011799:Quinazolines / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D006657:Histones; D011799:Quinazolines; C531556:AZD 1152-HQPA; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B