After completing his Bachelors degree in Biochemistry at the University of Manchester, Stephen moved to the Department of Biochemistry in Oxford to pursue his doctoral studies, working in Prof. Ed Southern’s lab. His graduate work focused on developing mammalian artificial chromosomes in order to define the DNA sequences required for human centromere function. After completing his PhD in 1995, Stephen moved to Harvard Medical School funded by a Wellcome Trust Traveling post-doctoral fellowship. There, he worked with Prof. Frank McKeon in the Department of Cell Biology, where he discovered several components of the mammalian spindle assembly checkpoint. In 1998, Stephen moved back to Manchester, funded by a BBSRC David Phillips Fellowship. In 2004 he was awarded a Senior Research Fellowship from Cancer Research UK. In 2009 Stephen renewed his CR-UK Senior Fellowship and was promoted to Professor of Cell Biology. He won the Translational Research Award from the British Association for Cancer Research in 2004, the University of Manchester’s Kilburn-Williams Medal in 2009, and was elected to Academia Europaea in 2010. In 2015, Stephen was awarded the Leech Chair of Pharmacology. During his time in Manchester, Stephen continued to be a pioneer in the spindle checkpoint field, and in collaboration with AstraZeneca described the first inhibitors targeting the Aurora B and Mps1 protein kinases. More recently his research has focused on understanding cell fate in response to anti-mitotic chemotherapy agents.

Chromosome segregation, aneuploidy, anti-mitotic drugs and cancer

Antimitotic agents, e.g. paclitaxel, are used extensively to treat breast and ovarian cancer. Also, at ASCO 2015, the STAMPEDE clinical trial showed that docetaxel significantly extends survival in men with prostate cancer. Despite the proven efficacy of these drugs, there are a number of issues. Not every cancer responds and we cannot predict which cancers will/not respond. Resistance is a problem, but the mechanisms are obscure. Also, neurotoxicity due to disrupting microtubule function in non-dividing cells can be problematic. To address these issues, ~€10bn has been spent developing 2nd generation antimitotics, resulting in excellent drugs targeting mitotic kinesins and mitotic kinases. However, these agents have thus far been disappointing in the clinic, further highlighting our inability to identify which tumour genotypes to target. Following a genome-wide siRNA screen for taxol sensitizers, we recently identified the oncogenic transcription factor c-Myc as a major determinant of mitotic cell fate. We showed that Myc sensitizes cells to various antimitotics by upregulating a cluster of redundant pro-apoptotic BH3-only proteins and suppressing pro-survival Bcl-xL. Pharmacological inhibition of Bcl-xL restores apoptosis in Myc-deficient cells, and gene expression analysis of breast cancers indicates that taxane responses correlate positively with Myc and negatively with Bcl-xL. We are now translating these findings into a clinically relevant context to explore opportunities for biomarkers and combination therapies that could enhance traditional and 2nd generation antimitotic agents.

For more information see www.bub1.com.

After completing his Bachelors degree in Biochemistry at the University of Manchester, Stephen moved to the Department of Biochemistry in Oxford to pursue his doctoral studies, working in Prof. Ed Southern’s lab. His graduate work focused on developing mammalian artificial chromosomes in order to define the DNA sequences required for human centromere function. After completing his PhD in 1995, Stephen moved to Harvard Medical School funded by a Wellcome Trust Traveling post-doctoral fellowship. There, he worked with Prof. Frank McKeon in the Department of Cell Biology, where he discovered several components of the mammalian spindle assembly checkpoint. In 1998, Stephen moved back to Manchester, funded by a BBSRC David Phillips Fellowship. In 2004 he was awarded a Senior Research Fellowship from Cancer Research UK. In 2009 Stephen renewed his CR-UK Senior Fellowship and was promoted to Professor of Cell Biology. He won the Translational Research Award from the British Association for Cancer Research in 2004, the University of Manchester’s Kilburn-Williams Medal in 2009, and was elected to Academia Europaea in 2010. In 2015, Stephen was awarded the Leech Chair of Pharmacology. During his time in Manchester, Stephen continued to be a pioneer in the spindle checkpoint field, and in collaboration with AstraZeneca described the first inhibitors targeting the Aurora B and Mps1 protein kinases. More recently his research has focused on understanding cell fate in response to anti-mitotic chemotherapy agents. For more information see the lab website at www.bub1.com.

Chromosome segregation, aneuploidy, anti-mitotic drugs and cancer

Antimitotic agents, e.g. paclitaxel, are used extensively to treat breast and ovarian cancer. Also, at ASCO 2015, the STAMPEDE clinical trial showed that docetaxel significantly extends survival in men with prostate cancer. Despite the proven efficacy of these drugs, there are a number of issues. Not every cancer responds and we cannot predict which cancers will/not respond. Resistance is a problem, but the mechanisms are obscure. Also, neurotoxicity due to disrupting microtubule function in non-dividing cells can be problematic. To address these issues, ~€10bn has been spent developing 2nd generation antimitotics, resulting in excellent drugs targeting mitotic kinesins and mitotic kinases. However, these agents have thus far been disappointing in the clinic, further highlighting our inability to identify which tumour genotypes to target. Following a genome-wide siRNA screen for taxol sensitizers, we recently identified the oncogenic transcription factor c-Myc as a major determinant of mitotic cell fate. We showed that Myc sensitizes cells to various antimitotics by upregulating a cluster of redundant pro-apoptotic BH3-only proteins and suppressing pro-survival Bcl-xL. Pharmacological inhibition of Bcl-xL restores apoptosis in Myc-deficient cells, and gene expression analysis of breast cancers indicates that taxane responses correlate positively with Myc and negatively with Bcl-xL. We are now translating these findings into a clinically relevant context to explore opportunities for biomarkers and combination therapies that could enhance traditional and 2nd generation antimitotic agents.

For more information see www.bub1.com.

Key papers:

Topham, C., Tighe, A., Ly, P., Bennett, A., Sloss, O., Nelson, L., Ridgway, R.A., Huels, D.H., Littler, S., Schandl, C., et al. (2015). Myc is a major determinant of mitotic cell fate. Cancer Cell 28, 129-140.

Hewitt, L., Tighe, A., Santaguida, S., White, A.M., Jones, C.D., Musacchio, A., Green, S., and Taylor, S.S. (2010). Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1-C-Mad2 core complex. J Cell Biol 190, 25-34.

Gascoigne, K.E., and Taylor, S.S. (2008). Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell 14, 111-122.

Girdler, F., Gascoigne, K.E., Eyers, P.A., Hartmuth, S., Crafter, C., Foote, K.M., Keen, N.J., and Taylor, S.S. (2006). Validating Aurora B as an anti-cancer drug target. J Cell Sci 119, 3664-3675.

Morrow, C.J., Tighe, A., Johnson, V.L., Scott, M.I., Ditchfield, C., and Taylor, S.S. (2005). Bub1 and aurora B cooperate to maintain BubR1-mediated inhibition of APC/CCdc20. J Cell Sci 118, 3639-3652.

Johnson, V.L., Scott, M.I.F., Holt, S.V., Hussein, D., and Taylor, S.S. (2004). Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression. J Cell Sci 117, 1577-1589.

Ditchfield, C., Johnson, V., Tighe, A., Ellston, R., Haworth, C., Johnson, T., Mortlock, A., Keen, N., and Taylor, S. (2003). Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J Cell Biol 161, 267-280.

Taylor, S.S., and McKeon, F. (1997). Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell 89, 727-735.

Cytotoxic drugs targeting mitosis, including the taxanes and vinca alkaloids, are used widely as chemotherapy agents. For example, in the UK, ~70% of women with ovarian cancer are prescribed the microtubule stabilizer Taxol®. In addition, taxanes and Herceptin® synergise, dramatically improving clinical outcomes among women with HER2-positive breast cancer. However, it is still unclear how exactly these anti-mitotic drugs result in patient benefit. What is clear is that in cell culture, disrupting mitosis activates the spindle assembly checkpoint causing prolonged mitotic arrest. Our research is focused on understanding how this then leads to cell death, with an overall aim of trying to improve the efficacy of these drugs.