Identifying Rgulators of Mitotic Catastrophe and Resistance to Anti-microtubule Agents by RNA Interf

• 作 者: CharlesSwanton;
• 机 构: Department of Medicine Royal Marsden Hospital CR-UK London Research Institute Signal Transduction La
• 出 处: BIT Life Sciences' 1st Annual World Cancer Congess-2008(
• 发表日期: 2008年期

　　The taxanes are amongst the most effective cytotoxics used in the management of ovarian and breast cancer.Despite their proven efficacy, taxane resistance is associated with significant patient morbidity and remains a major economic health burden.Using high throughput RNA interference screening techniques, we have identified that regulators of mitotic arrest and ceramide metabolism influence sensitivity to the microtubule stabilising agent, Paclitaxel.Many of these genes also promote aneuploidy without drug treatment when targeted by RNA interference, supporting the connection between spindle checkpoint activation, chromosomal instability (CIN) and taxane resistance.Further data support the existence of an aneuploid checkpoint, initiated by taxane treatment which may be de-regulated in tumours with chromosomal instability.This work has led to the development of a clinical trial at the Royal Marsden Hospital investigating the activity of a novel microtubule stabilising agent, Epothilone 906 in advanced CIN+ and CIN-colorectal cancer to attempt to establish a microtubule stabiliser-sensitive patient cohort.