![Richard Clarkson](https://profiles-cardiff.imgix.net/attachments/971?w=200&h=200&auto=format&crop=faces&fit=crop&q=90")
Yr Athro Richard Clarkson
Senior Lecturer
Ysgol y Biowyddorau
- Sylwebydd y cyfryngau
- Ar gael fel goruchwyliwr ôl-raddedig
Trosolwyg
The Clarkson group focuses on identifying novel therapeutic strategies to eliminate or modify the cancer cells responsible for the spread of tumours around the body.
According to the cancer stem cell hypothesis, only a limited proportion of tumour cells with stem-like properties are capable of seeding new tumours at distal sites. These cells also appear to be highly adaptable and are resistant to conventional therapeutic agents.
Using breast, prostate, pancreatic and colorectal cancer as their principal platforms, the Clarkson lab aims to understand the mechanisms of this cellular plasticity and drug resistance in order to identify new therapeutic strategies to target this minority cell population within cancers.
Roles
Academic Team Leader
Assessment Leader: BI3352 Cancer: Molecular mechanisms, diagnostics and therapeutics
Human Tissue Officer – Research.
Research Integrity Lead for the School of Biosciences
Theme lead for the Wales Cancer Research Centre
Science Director of the Wales Cancer Bank
Cyhoeddiad
2024
- Turnham, D. J. et al. 2024. Development and characterisation of a new patient-derived Xenograft model of AR-negative metastatic asctration-resistant prostate cancer. Cells 13(8), article number: 673. (10.3390/cells13080673)
- Turnham, D. J., Smith, H. and Clarkson, R. W. E. 2024. Suppression of Bcl3 disrupts viability of breast cancer cells through both p53-dependent and p53-independent mechanisms via loss of NF-κB signalling. Biomedicines 12(1), article number: 143. (10.3390/biomedicines12010143)
- Seaton, G., Smith, H., Brancale, A., Westwell, A. D. and Clarkson, R. 2024. Multifaceted roles for BCL3 in cancer: a proto-oncogene comes of age. Molecular Cancer 23(1), article number: 7. (10.1186/s12943-023-01922-8)
2021
- Soukupova, J. et al. 2021. The discovery of a novel anti-metastatic Bcl3 inhibitor. Molecular Cancer Therapeutics 10(5), pp. 775-786. (10.1158/1535-7163.MCT-20-0283)
- Davies, J. A. et al. 2021. Efficient intravenous tumor targeting using the αvβ6 integrin-selective precision virotherapy Ad5NULL-A20. Viruses 13(5), article number: 864. (10.3390/v13050864)
2020
- Turnham, D. J., Yang, W. W., Davies, J., Varnava, A., Ridley, A. J., Conlan, R. S. and Clarkson, R. W. E. 2020. Bcl-3 promotes multi-modal tumour cell migration via NF-kB1 mediated regulation of Cdc42. Carcinogenesis 41(10), pp. 1432-1443. (10.1093/carcin/bgaa005)
- Kiraga, L. et al. 2020. Biodistribution PET/CT study of hemoglobin-DFO-89Zr complex in healthy and lung tumor-bearing mice. International Journal of Molecular Sciences 21(14), article number: 4991. (10.3390/ijms21144991)
2019
- Healey, G. D. et al. 2019. Antibody drug conjugates against the receptor for advanced glycation end products (RAGE), a novel therapeutic target in endometrial cancer. Journal for ImmunoTherapy of Cancer 7(1), article number: 280. (10.1186/s40425-019-0765-z)
- Legge, D. N. et al. 2019. BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells. Disease Models and Mechanisms 12(3), article number: 37697. (10.1242/dmm.037697)
2018
- Pearson, H. B. et al. 2018. Identification of Pik3ca mutation as a genetic driver of prostate cancer that cooperates with Pten loss to accelerate progression and castration-resistant growth. Cancer Discovery 8(6), pp. 764-779. (10.1158/2159-8290.CD-17-0867)
- Piggott, L. et al. 2018. Acquired resistance of ER-positive breast cancer to endocrine treatment confers an adaptive sensitivity to TRAIL through post-translational downregulation of c-FLIP. Clinical Cancer Research 24(10), pp. 2452-2463. (10.1158/1078-0432.CCR-17-1381)
2017
- Chen, H. et al. 2017. Synergistic targeting of breast cancer stem-like cells by human γδ T cells and CD8+ T cells. Immunology and Cell Biology 95(7), pp. 620-629. (10.1038/icb.2017.21)
- Yeo, S. K., French, R., Filomena, S. and Clarkson, R. 2017. Opposing roles of Nfkb2 gene products p100 and p52 in the regulation of breast cancer stem cells. Breast Cancer Research and Treatment 162(3), pp. 465-477. (10.1007/s10549-017-4149-0)
2016
- Yeo, S. K., Ali, A. Y., Hayward, O. A., Turnham, D., Jackson, T., Bowen, I. D. and Clarkson, R. 2016. Bisabolene, a sesquiterpene from the essential oil extract of opoponax (Commiphora guidottii), exhibits cytotoxicity in breast cancer cell lines. Phytotherapy Research 30(3), pp. 418-425. (10.1002/ptr.5543)
2015
- French, R., Hayward, O., Jones, S., Yang, W. and Clarkson, R. 2015. Cytoplasmic levels of cFLIP determine a broad susceptibility of breast cancer stem/progenitor-like cells to TRAIL. Molecular Cancer 14, article number: 209. (10.1186/s12943-015-0478-y)
- Ali, A. Y. et al. 2015. Anti-metastatic and cytotoxic properties of frankincense and scented myrrh. Anticancer Research 35(7), pp. 4310-4311.
- Piggott, L., Omidvar, N., Martí Pérez, S., French, R., Eberl, M. and Clarkson, R. W. E. 2015. Erratum to: Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL. Breast Cancer Research 17(1), pp. 96. (10.1186/s13058-015-0597-9)
2014
- Cowley, M. et al. 2014. Developmental programming mediated by complementary roles of imprinted Grb10 in mother and pup. PLoS Biology 12(2), pp. e1001799. (10.1371/journal.pbio.1001799)
2013
- Wakefield, A. M., Soukupová, J., Montagne, A., Ranger, J., French, R., Muller, W. and Clarkson, R. W. E. 2013. Bcl3 selectively promotes metastasis of ErbB2-driven mammary tumors. Cancer Research 73(2), pp. 745-755. (10.1158/0008-5472.CAN-12-1321)
- Smalley, M. J., Piggott, L. and Clarkson, R. W. E. 2013. Breast cancer stem cells: obstacles to therapy. Cancer Letters 338(1), pp. 57-62. (10.1016/j.canlet.2012.04.023)
2012
- Soukupova, J., Brancale, A., Westwell, A. D. and Clarkson, R. W. E. 2012. Inhibitors of Bcl-3 as a novel therapeutic strategy for HER2+ breast cancer. European Journal of Cancer 48(5), pp. S225-S225.
2011
- Piggott, L., Omidvar, N., Marti-Perez, S., Eberl, M. and Clarkson, R. W. E. 2011. Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL. Breast Cancer Research 13(5), article number: R88. (10.1186/bcr2945)
- Kreuzaler, P. A. et al. 2011. Stat3 controls lysosomal-mediated cell death in vivo. Nature Cell Biology 13(3), pp. 303-309. (10.1038/ncb2171)
- Knight, J. C., Hallett, A. J., Brancale, A., Paisey, S. J., Clarkson, R. W. E. and Edwards, P. G. 2011. Evaluation of a fluorescent derivative of AMD3100 and its interaction with the CXCR4 chemokine receptor. ChemBioChem 12(17), pp. 2692-2698. (10.1002/cbic.201100441)
2009
- Jasani, B., Gee, J. M. W., Hutcheson, I. R., Clarkson, R. W. E., Bartlett, J. and Barrett-Lee, P. 2009. Resistance to HER2-directed trastuzumab therapy in breast cancer. Advances in Breast Cancer 6(3), pp. 11-18.
2008
- Wakefield, A., Piggott, L., Croston, D., Jiang, W. G. and Clarkson, R. W. E. 2008. Suppression of the NF-kappa B cofactor Bcl3 inhibits mammary epithelial cell apoptosis and, in breast tumours, correlates with poor prognosis. Breast Cancer Research 10(S2), article number: O4. (10.1186/bcr1884)
- Tiffen, P., Omidvar, N., Marquez, N., Croston, D., Watson, C. and Clarkson, R. W. E. 2008. A dual role for Oncostatin M signalling in the differentiation and death of mammary epithelial cells in vivo. Molecular Endocrinology 22(12), pp. 2677-2688. (10.1210/me.2008-0097)
2007
- Sykacek, P., Clarkson, R. W. E., Print, C., Furlong, R. and Micklem, G. 2007. Bayesian modelling of shared gene function. Bioinformatics 23(15), pp. 1936-1944. (10.1093/bioinformatics/btm280)
2006
- Clarkson, R. W. E., Boland, M. P., Kritikou, E. A., Lee, J. M., Freeman, T. C., Tiffen, P. G. and Watson, C. J. 2006. The genes induced by signal transducer and activators of transcription (STAT)3 and STAT5 in mammary epithelial cells define the roles of these STATs in mammary development. Molecular Endocrinology 20(3), pp. 675-685. (10.1210/me.2005-0392)
2005
- Abell, K. et al. 2005. Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition. Nature Cell Biology Vol. 7(4), pp. 392-398. (10.1038/ncb1242)
- Sorrell, D. A. et al. 2005. Regulation of genes encoding proteolytic enzymes during mammary gland development. Journal of Dairy Research 72(4), pp. 433-441. (10.1017/S0022029905001202)
2004
- Clarkson, R. W. E., Wayland, M. T., Lee, J., Freeman, T. and Watson, C. J. 2004. Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression. Breast Cancer Research 6(2), pp. R92-R109.
2003
- Clarkson, R. W. E., Corti, C., Ferraguti, F. and Xuereb, J. 2003. Gene structure of the human metabotropic glutamate receptor 5 and functional analysis of its multiple promoters in neuroblastoma and astroglioma cells. Journal of Biological Chemistry Vol. 2(No.35), pp. 33105-33119. (10.1074/jbc.M212380200)
- Kritikou, E. A., Sharkey, A., Abell, K., Came, P. J., Anderson, E., Clarkson, R. W. E. and Watson, C. J. 2003. A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland. Development 130(15), pp. 3459-3468. (10.1242/dev.00578)
- Clarkson, R. W. E. and Watson, C. J. 2003. Microarray analysis of the involution switch. Journal of Mammary Gland Biology and Neoplasia 8(3), pp. 309-319. (10.1023/B:JOMG.0000010031.53310.92)
2002
- Clarkson, R. W. E. 2002. lkB kinase alpha: a link in the chain of the mammary cycle. Breast Cancer Research 4, article number: 173. (10.1186/bcr446)
2000
- Gordon, K. et al. 2000. A novel cell culture model for studying differentiation and apoptosis in the mouse mammary gland. Breast Cancer Research 2, pp. 222-235. (10.1186/bcr57)
- Clarkson, R. W. E., Heeley, J., Chapman, R., Aillet, F., Hay, R. T., Wyllie, A. and Watson, C. J. 2000. NF-kappa B inhibits apoptosis in murine mammary epithelia. Journal of Biological Chemistry 275(17), pp. 12737-12742. (10.1074/jbc.275.17.12737)
Articles
- Turnham, D. J. et al. 2024. Development and characterisation of a new patient-derived Xenograft model of AR-negative metastatic asctration-resistant prostate cancer. Cells 13(8), article number: 673. (10.3390/cells13080673)
- Turnham, D. J., Smith, H. and Clarkson, R. W. E. 2024. Suppression of Bcl3 disrupts viability of breast cancer cells through both p53-dependent and p53-independent mechanisms via loss of NF-κB signalling. Biomedicines 12(1), article number: 143. (10.3390/biomedicines12010143)
- Seaton, G., Smith, H., Brancale, A., Westwell, A. D. and Clarkson, R. 2024. Multifaceted roles for BCL3 in cancer: a proto-oncogene comes of age. Molecular Cancer 23(1), article number: 7. (10.1186/s12943-023-01922-8)
- Soukupova, J. et al. 2021. The discovery of a novel anti-metastatic Bcl3 inhibitor. Molecular Cancer Therapeutics 10(5), pp. 775-786. (10.1158/1535-7163.MCT-20-0283)
- Davies, J. A. et al. 2021. Efficient intravenous tumor targeting using the αvβ6 integrin-selective precision virotherapy Ad5NULL-A20. Viruses 13(5), article number: 864. (10.3390/v13050864)
- Turnham, D. J., Yang, W. W., Davies, J., Varnava, A., Ridley, A. J., Conlan, R. S. and Clarkson, R. W. E. 2020. Bcl-3 promotes multi-modal tumour cell migration via NF-kB1 mediated regulation of Cdc42. Carcinogenesis 41(10), pp. 1432-1443. (10.1093/carcin/bgaa005)
- Kiraga, L. et al. 2020. Biodistribution PET/CT study of hemoglobin-DFO-89Zr complex in healthy and lung tumor-bearing mice. International Journal of Molecular Sciences 21(14), article number: 4991. (10.3390/ijms21144991)
- Healey, G. D. et al. 2019. Antibody drug conjugates against the receptor for advanced glycation end products (RAGE), a novel therapeutic target in endometrial cancer. Journal for ImmunoTherapy of Cancer 7(1), article number: 280. (10.1186/s40425-019-0765-z)
- Legge, D. N. et al. 2019. BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells. Disease Models and Mechanisms 12(3), article number: 37697. (10.1242/dmm.037697)
- Pearson, H. B. et al. 2018. Identification of Pik3ca mutation as a genetic driver of prostate cancer that cooperates with Pten loss to accelerate progression and castration-resistant growth. Cancer Discovery 8(6), pp. 764-779. (10.1158/2159-8290.CD-17-0867)
- Piggott, L. et al. 2018. Acquired resistance of ER-positive breast cancer to endocrine treatment confers an adaptive sensitivity to TRAIL through post-translational downregulation of c-FLIP. Clinical Cancer Research 24(10), pp. 2452-2463. (10.1158/1078-0432.CCR-17-1381)
- Chen, H. et al. 2017. Synergistic targeting of breast cancer stem-like cells by human γδ T cells and CD8+ T cells. Immunology and Cell Biology 95(7), pp. 620-629. (10.1038/icb.2017.21)
- Yeo, S. K., French, R., Filomena, S. and Clarkson, R. 2017. Opposing roles of Nfkb2 gene products p100 and p52 in the regulation of breast cancer stem cells. Breast Cancer Research and Treatment 162(3), pp. 465-477. (10.1007/s10549-017-4149-0)
- Yeo, S. K., Ali, A. Y., Hayward, O. A., Turnham, D., Jackson, T., Bowen, I. D. and Clarkson, R. 2016. Bisabolene, a sesquiterpene from the essential oil extract of opoponax (Commiphora guidottii), exhibits cytotoxicity in breast cancer cell lines. Phytotherapy Research 30(3), pp. 418-425. (10.1002/ptr.5543)
- French, R., Hayward, O., Jones, S., Yang, W. and Clarkson, R. 2015. Cytoplasmic levels of cFLIP determine a broad susceptibility of breast cancer stem/progenitor-like cells to TRAIL. Molecular Cancer 14, article number: 209. (10.1186/s12943-015-0478-y)
- Ali, A. Y. et al. 2015. Anti-metastatic and cytotoxic properties of frankincense and scented myrrh. Anticancer Research 35(7), pp. 4310-4311.
- Piggott, L., Omidvar, N., Martí Pérez, S., French, R., Eberl, M. and Clarkson, R. W. E. 2015. Erratum to: Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL. Breast Cancer Research 17(1), pp. 96. (10.1186/s13058-015-0597-9)
- Cowley, M. et al. 2014. Developmental programming mediated by complementary roles of imprinted Grb10 in mother and pup. PLoS Biology 12(2), pp. e1001799. (10.1371/journal.pbio.1001799)
- Wakefield, A. M., Soukupová, J., Montagne, A., Ranger, J., French, R., Muller, W. and Clarkson, R. W. E. 2013. Bcl3 selectively promotes metastasis of ErbB2-driven mammary tumors. Cancer Research 73(2), pp. 745-755. (10.1158/0008-5472.CAN-12-1321)
- Smalley, M. J., Piggott, L. and Clarkson, R. W. E. 2013. Breast cancer stem cells: obstacles to therapy. Cancer Letters 338(1), pp. 57-62. (10.1016/j.canlet.2012.04.023)
- Soukupova, J., Brancale, A., Westwell, A. D. and Clarkson, R. W. E. 2012. Inhibitors of Bcl-3 as a novel therapeutic strategy for HER2+ breast cancer. European Journal of Cancer 48(5), pp. S225-S225.
- Piggott, L., Omidvar, N., Marti-Perez, S., Eberl, M. and Clarkson, R. W. E. 2011. Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL. Breast Cancer Research 13(5), article number: R88. (10.1186/bcr2945)
- Kreuzaler, P. A. et al. 2011. Stat3 controls lysosomal-mediated cell death in vivo. Nature Cell Biology 13(3), pp. 303-309. (10.1038/ncb2171)
- Knight, J. C., Hallett, A. J., Brancale, A., Paisey, S. J., Clarkson, R. W. E. and Edwards, P. G. 2011. Evaluation of a fluorescent derivative of AMD3100 and its interaction with the CXCR4 chemokine receptor. ChemBioChem 12(17), pp. 2692-2698. (10.1002/cbic.201100441)
- Jasani, B., Gee, J. M. W., Hutcheson, I. R., Clarkson, R. W. E., Bartlett, J. and Barrett-Lee, P. 2009. Resistance to HER2-directed trastuzumab therapy in breast cancer. Advances in Breast Cancer 6(3), pp. 11-18.
- Wakefield, A., Piggott, L., Croston, D., Jiang, W. G. and Clarkson, R. W. E. 2008. Suppression of the NF-kappa B cofactor Bcl3 inhibits mammary epithelial cell apoptosis and, in breast tumours, correlates with poor prognosis. Breast Cancer Research 10(S2), article number: O4. (10.1186/bcr1884)
- Tiffen, P., Omidvar, N., Marquez, N., Croston, D., Watson, C. and Clarkson, R. W. E. 2008. A dual role for Oncostatin M signalling in the differentiation and death of mammary epithelial cells in vivo. Molecular Endocrinology 22(12), pp. 2677-2688. (10.1210/me.2008-0097)
- Sykacek, P., Clarkson, R. W. E., Print, C., Furlong, R. and Micklem, G. 2007. Bayesian modelling of shared gene function. Bioinformatics 23(15), pp. 1936-1944. (10.1093/bioinformatics/btm280)
- Clarkson, R. W. E., Boland, M. P., Kritikou, E. A., Lee, J. M., Freeman, T. C., Tiffen, P. G. and Watson, C. J. 2006. The genes induced by signal transducer and activators of transcription (STAT)3 and STAT5 in mammary epithelial cells define the roles of these STATs in mammary development. Molecular Endocrinology 20(3), pp. 675-685. (10.1210/me.2005-0392)
- Abell, K. et al. 2005. Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition. Nature Cell Biology Vol. 7(4), pp. 392-398. (10.1038/ncb1242)
- Sorrell, D. A. et al. 2005. Regulation of genes encoding proteolytic enzymes during mammary gland development. Journal of Dairy Research 72(4), pp. 433-441. (10.1017/S0022029905001202)
- Clarkson, R. W. E., Wayland, M. T., Lee, J., Freeman, T. and Watson, C. J. 2004. Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression. Breast Cancer Research 6(2), pp. R92-R109.
- Clarkson, R. W. E., Corti, C., Ferraguti, F. and Xuereb, J. 2003. Gene structure of the human metabotropic glutamate receptor 5 and functional analysis of its multiple promoters in neuroblastoma and astroglioma cells. Journal of Biological Chemistry Vol. 2(No.35), pp. 33105-33119. (10.1074/jbc.M212380200)
- Kritikou, E. A., Sharkey, A., Abell, K., Came, P. J., Anderson, E., Clarkson, R. W. E. and Watson, C. J. 2003. A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland. Development 130(15), pp. 3459-3468. (10.1242/dev.00578)
- Clarkson, R. W. E. and Watson, C. J. 2003. Microarray analysis of the involution switch. Journal of Mammary Gland Biology and Neoplasia 8(3), pp. 309-319. (10.1023/B:JOMG.0000010031.53310.92)
- Clarkson, R. W. E. 2002. lkB kinase alpha: a link in the chain of the mammary cycle. Breast Cancer Research 4, article number: 173. (10.1186/bcr446)
- Gordon, K. et al. 2000. A novel cell culture model for studying differentiation and apoptosis in the mouse mammary gland. Breast Cancer Research 2, pp. 222-235. (10.1186/bcr57)
- Clarkson, R. W. E., Heeley, J., Chapman, R., Aillet, F., Hay, R. T., Wyllie, A. and Watson, C. J. 2000. NF-kappa B inhibits apoptosis in murine mammary epithelia. Journal of Biological Chemistry 275(17), pp. 12737-12742. (10.1074/jbc.275.17.12737)
Ymchwil
Targeting metastatic disease
The spread of malignant tumours around the body, termed metastasis, is the principal cause of death in patients with solid tumours. The Clarkson lab has identified two intra-cellular mechanisms that appear to contribute to this process in models of breast cancer. Now situated in the European Cancer Stem Cell Research Institute, the research group has focused its attentions on identifying molecular strategies to target these mechanisms and thus prevent malignant disease progression.
The first of these pathways affects the viability of cancer stem cells through regulation of TRAIL mediated apoptosis, targeting an innate inhibitor of this pathway, cFLIP. Inhibition of this mechanism sensitizes these cells to cytotoxic agents. The second pathway focuses on Bcl-3 which impinges on the ability of tumour cells to migrate through tissues and has a direct effect on the ability of tumours to metastasise. Ongoing studies are aimed at characterizing these mechanisms in more detail, determining their efficacy in primary cancer tissues obtained from local cancer clinics and establishing their involvement in the biology of cancers arising from a variety of tissue types including breast, ovarian, prostate and pancreatic.
Targeting apoptosis and the cancer stem cell
The Clarkson lab has a long-standing interest in how genes that have presumptive roles in the removal / reorganization of supernumerary cells from adult tissues could play a role in breast and other forms of cancer.
Having initially focused on identifying genes that control apoptosis in mouse mammary tissues (Clarkson, 2003) the lab subsequently used conditional transgenics to modify gene activity in normal and cancer cells in vitro and in vivo to observe the effects of these changes on tumour behaviour with mammary (breast) cancer as the primary model.
Much of the ongoing work in the lab stems from two microarray-based studies of mammary involution and epithelial apoptosis (Clarkson 2000; 2003; 2006). Thus, in a global analysis of the mammary transcriptome during the pregnancy cycle it was deduced from gene expression profiles that two distinct cell-death pathways were sequentially activated during involution, the first characterized by the activation of members of the TNF superfamily, a cytokine activated pathway implicated in extrinsic (death receptor mediated) apoptosis and the second associated with remodeling enzymes. We also identified a possible molecular link between these two phases of involution, involving the transition from LIF-STAT3 to OSM-STAT1 signalling in mammary epithelial cells (Tiffen, 2008).
However, in a recent study using a conditional inhibitor of caspase activity (baculovirus p35 protein) in murine mammary tissues, the Clarkson lab provided evidence to support the proposal that apoptosis was redundant during mammary involution (Kreuzaler, 2011).
The identification of TNF-related signaling components in the mammary gland led to the investigation of the role of TNFR-associated inhibitory molecule c-FLIP in the maintenance of breast stem cancer cells (Piggott, 2011, French, 2015). More recently the lab showed that this c-FLIP/TRAIL axis was perturbed in ER-positive breast tumours that develop acquired resistance to endocrine therapy, making the cancer stem cells hypersensitive to TRAIL mediated killing (Piggott, 2018). This has led the group to propose that clinically approved TRAIL agonists could be an effective second line therapy for breast cancer patients who relapse on endocrine therapy.
In a separate microarray study, conditionally active forms of two STAT transcription factors, STAT3 and STAT5 were used to identify the genes responsible for their known roles in mammary cell apoptosis and differentiation respectively (Clarkson, 2006). This has led to the identification of a number of gene targets that are likely to play important roles in the maintenance of tissue homeostasis in the mammary gland, one of which, Bcl3, is the subject of ongoing studies within the lab due to its surprising role in disease progression in vivo (Wakefield, 2013; Turnham, 2020). The lab has shown that Bcl3 plays a novel and non-redundant role in the migration and metastasis of breast tumour cells and colorectal cancer stem cells (Legge, 2019) mediated through Bcl3-NF-kB complexes (Yeo, 2017, Turnham, 2020).
Pharmacological targeting of cancer stem cells
Based on the evidence of Bcl3 and c-FLIP involvement in cancer stem cell maintenance and metastasis the Clarkson lab has collaborated with Prof Andrea Brancale and Prof Andrew Westwell of the Cardiff University School of Pharmaceutical Sciences to develop novel pharmacological agents targeting these intra-cellular pathways. Thus, using state-of-art molecular modelling and in silico compound screening they have identified potent first-in-class inhibitors of both Bcl3 and c-FLIP (Soukupova, 2021, French, 2021, manuscript in preparation). These agents are currently undergoing further pre-clinical evaluation to determine their suitability for clinical trials in breast, colorectal and other cancer patients. The candidate small-molecule inhibitor of Bcl3 is in late-stage pre-clinical development, having completed toxicology in several species and with large scale API awaiting formulation.
Future work in the Clarkson lab will increasingly focus on the mechanisms underlying the dissemination of cancer stem cells and the propagation of metastatic disease, and working with their collaborators (below) to continue to develop novel therapeutic strategies that target these cancer stem cell-related pathways.
Current grant support
- Cancer Research Wales
- Sêr Cymru – Welsh Government
- Health Care Research Wales
- Pancreatic Cancer Research Fund
Collaborators
- Andrew Westwell, Andrea Brancale – School of Pharmacy, Cardiff University
- Jen Morton – Beatson Institute, Glasgow
- Erin Hertlein – OSUCCC, James, OHIO State University
- Blake Peterson – OHIO University, College of Pharmacy
- Rob Jones MRCP, PHD – Phase 1 clinical trial lead, Velindre Cancer Centre, Cardiff
- Stephen Paisey, Chris Marshall - Wales Research and Diagnostic Positron Emission Tomography Imaging Centre (PETIC), Medical School, Cardiff University
- Matthias Eberl – Dept Infection, Immunity and Biochemistry, Cardiff School of Medicine
- Julia Gee – School of Pharmacy, Cardiff University
- Peter Barrett-Lee - Medical Director, Velindre Cancer Centre, Cardiff
- Dr Philippa Young - Consultant Radiologist, Cardiff Breast Clinic
- Dr Luke Piggott - Debiopharm, Switzerland
Staff members
Postgraduate research students
- Anna Richards
- Kok Yung Lee
Meysydd goruchwyliaeth
Mae ein grŵp ymchwil wedi cydweithio ag ymchwilwyr blaenllaw o'r Ysgol Fferylliaeth i ddatblygu atalyddion ffarmacolegol bôn-gelloedd canser. Mae'r celloedd prin hyn o fewn tiwmorau solet yn gyfrifol am ledaenu canserau o amgylch y corff (metastasis) ac am ailwaelu clefydau ac ailadrodd tiwmorau ar ôl therapïau traddodiadol. Mae ein labordy yn ymchwilio i fioleg celloedd celloedd hyn a'r llwybrau moleciwlaidd/cellog sy'n dylanwadu ar eu hymddygiad a'u hyfywedd. Rydym yn canolbwyntio'n benodol ar sefydlu apoptosis a gallu'r celloedd hyn i ledaenu a chytrefu safleoedd distal o fewn y corff.
Technegau: diwylliant celloedd a meinwe, bioleg llygoden a xenografts canser, profion apoptosis. Trasncriptomics, RNAseq, siRNA, shRNA anorchfygol a fflworoleuedd / ymoleuedd celloedd canser trwy ficrosgopeg cydfocal a fflworoleuedd amser.
Contact Details
+44 29208 70249
Adeilad Hadyn Ellis, Ystafell European Cancer Stem Cell Research Institute, Cardiff School of Biosciences, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff CF24 4HQ, Heol Maendy, Caerdydd, CF24 4HQ
