Stephen Taylor#
Laudatio by Martin Humphries#
Biography
Prof Stephen Taylor’s scientific interests were initiated while studying for his undergraduate degree in Manchester. For his industrial placement he joined Alex Markham’s group at AstraZeneca where he worked on a genome mapping project using yeast artificial chromosomes as cloning vectors. He was inspired by the way that yeast chromosomes had been dissected and reassembled in order to identify the DNA sequences which defined the major functional elements, namely origins of replication, telomeres and in particular centromeres. This prompted him to join Professor Ed Southern’s lab in Oxford where Stephen’s PhD work focussed on trying to define the sequences required for Centromere function in human cells. This in tum started his fascination with the molecular mechanisms that ensure accurate chromosome segregation during mitosis.
After obtaining his PhD in 1995, Stephen moved to Harvard Medical School, as a Wellcome Trust Travelling Fellow, as a post-doc with Professor Frank McKeon. There, he saw an opportunity to identify several mammalian spindle checkpoint proteins, resulting in publications in Cell and the Journal of Cell Biology. These discoveries launched his independent career, allowing Stephen to return to the UK in 1998, funded by a BBSRC David Phillips Fellowship. Over the next five years Stephen built a small and productive research team in the Faculty of Life Sciences at the University of Manchester, focussed on the "basic biology" of the spindle checkpoint. During this time, Stephen established what would turn out to be a very productive collaboration with AstraZeneca, helping them characterise an Aurora kinase inhibitor which was being developed as a novel anti-cancer agent. The first part of this work was published in 2003, in the Journal of Cell Biology, and has already been cited over 400 times.
This experience inspired Stephen to be become actively interested in exploiting the spindle checkpoint and mitosis vis-a-vis developing novel anti-cancer strategies. Based on these interests, Stephen secured a CR-UK Senior Fellowship in 2004. This in turn allowed him to expand his research program and pursue a number of more "translational" projects. Stephen’s group has always been productive and in the last few years he has published important papers in Current Biology, Developmental Cell, the Journal of Cell Biology, Chemistry & Biology and Cancer Cell. His efforts have been recognised on several occasions. In 2004 he was awarded the Translation Research Award by the British Association for Cancer Research. ln 2008, the Faculty of Life Sciences awarded him Best Collaboration with Industry Prize, then in 2009, the University of Manchester awarded him the Kilburn-Williams medal which recognises the Faculty of Life Sciences’ Researcher of the Year. In August 2009 he was promoted to Professor and successfully renewed his CR-UK Fellowship.
Exemplars of Research Achievements
Prof. Taylor’s research focuses on mitosis, and spans both basic and translational issues. Rather then summarising his contributions to the field in toto, below two recent projects of significant biomedical impact are highlighted. The first relates to understanding how existing anti-mitotic chemotherapy agents kill cancer cells. The second relates to efforts to develop novel anti-mitotic drugs, namely inhibitors of the Aurora kinases.
How do anti-mitotic drugs kill cancer cells?
In terms of global sales, Taxol remains the most successful anti-cancer chemotherapy agent in
use, A natural compound originally isolated from the bark of the Pacific Yew tree, Taxol was
shown to have anti-tumour activity in mouse models shortly after it was first isolated. In cells,
Taxol stabilizes microtubules which disrupts mitotic spindle assembly thereby activating the
spindle assembly checkpoint causing a prolonged mitotic delay which eventually induces cell
death. Our understanding of the underlying cell death mechanisms is however very limited.
Efforts have been hampered because commonly used population-based approaches generate
indirect and confusing data. Therefore, to understand how human tumour cells respond to anti-mitotic agents, Prof. Taylor’s lab took a new approach. Using automated time-lapse light
microscopy, they used a single cell based assay to analyze >l0,000 individual cells from 15 lines in response to 3 classes of anti—mitotic drug. The aim was to generate a sufhciently large data set with which to formulate hypotheses that could then be tested with more focused experiments.
The study revealed a level of complexity that was at first overwhelming. While variation
between different cell lines was anticipated, it was striking that cells within a line exhibited
multiple fates. This intraline variation turned out not to be genetically pre-determined because
sister cells underwent different fates. This phenomenon does not appear to be restricted to anti-mitotic drugs; a similar observation was recently published in Nature regarding TRAIL-induced apoptosis. Despite the complexity, they formulated and tested a new model. This turned out to be very informative and they are now using it to dissect the nature ofthe death signal. This is not just of academic interest; manipulation of the relevant death pathways, may make it possible to sensitise cancer cells to existing anti-mitotic agents.
Will patients develop resistance to Aurora B inhibitors?
Despite Taxol’s clinical success, it is far from perfect. In particular, the side effects are limiting, not all patients respond and many acquire resistance. Therefore much effort is being directed towards developing second generation anti-mitotic agents, and in particular, drugs targeting mitotic kinases including the Auroras. To generate Aurora A inhibitors, AstraZeneca developed, ZM447439. Early studies indicated that this compound inhibited Aurora A and was potently cytotoxic. However, Stephen’s lab showed that the ZM447439-phenotypes were more consistent with inhibition of Aurora B, not Aurora A, suggesting that Aurora B might be the relevant target.
Indeed, his lab went on to show that inhibition of Aurora B by molecular-genetic means
phenocopied ZM447439, while inhibition of Aurora A was rather benign, Consistently, in vitro kinase assays showed that ZM447439 was ~20-fold selective for Aurora B over A. Based on this, AstraZeneca then developed AZDl 152, a potent and selective Aurora B inhibitor which is now in clinical trials. Protein kinases are attractive as drug targets because they are druggable.
This enthusiasm has been fuelled by the success of BCR~ABL inhibitors such as imatinib (aka Gleevec) in the treatment of Chronic Myelogenous Leukaemia. However, a sobering lesson has emerged; patients can rapidly become resistant due to mutations in the Abl kinase domain.
Indeed, over 50 mutations in Abl have been implicated in imatinib-resistance, indicating that Abl is a remarkably plastic enzyme. However, whether other kinases of therapeutic interest have similar capacities for drug-resistance is unclear. To determine whether Aurora B can become drug-resistant, Stephen’s lab set up a screen to identify colon cancer cells which developed resistance to ZM447439. They indentified 7 lines and subsequent sequencing of cDNAs demonstrated that all of them harboured mutations in Aurora B, three in the active site and one near the activation loop. These mutations render Aurora B resistant to ZM447439 and several other Aurora inhibitors. This demonstrates that like BCR-Abl, it is indeed mechanistically possible for Aurora B to become drug resistant, thus predicting that if these inhibitors demonstrate clinical efficacy then resistance will emerge in patients. In order to pre-empt resistance, one possibility is that that these mutants should be considered as de novo drug targets.
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