Start dates for incoming postgraduate research students
1 October 2020 is the preferred date to start your PhD [or the date on your offer letter].
We will run a full on-line induction and training programme that may be taken remotely for the first month. Most of our doctoral researcher training programme will also be available online and we will offer many remote opportunities to help you become part of the Graduate School and wider University community.
Research that involves laboratory work may start following the completion of induction (all labs are currently up and running).
Some types of research (such as non-laboratory work) and supervision can be carried out entirely remotely and this may be the most appropriate way for you to work at the moment. Contact your supervisor, if you believe this applies to your research to discuss requirements for home/remote working. You may also require the agreement of the subject, school or institute convener if you wish to carry out your PhD remotely for a fixed period. You may not continue remotely unless an adequate plan is agreed to ensure sufficient work can be undertaken prior to starting the experimental work. It is important that starting remotely does not affect the overall PhD timescale.
Delayed start dates
We understand there may be good reasons to delay:
- If it is necessary to travel to Glasgow to begin your research, but there are restrictions preventing travel at this time, then a delay to 5 January 2021 is encouraged [when we will run full on-line induction and training programme]. You may also delay to another start time with the agreement of your supervisor and Graduate School.
- For subjects where laboratory work is required to commence immediately following on-line induction and training and you are unable to come to Glasgow, you should consider delaying your start-date. Contact your supervisor or the Graduate School in this instance.
- If your research involves objects, artefacts, archives or fieldwork, you should discuss this with your supervisor. Some kinds of work may be able to be started remotely; in other cases, it may be advisable to delay the start-date.
- External government sponsors may prefer a delay and the University is happy to support this.
From our point of view, there is no disadvantage in deferring your PhD to a later agreed start date. Scholarship holders should check that this can still be provided with a delayed start.
Office and study space
At present, current staff and research students are not using office spaces on campus. We do not have a confirmed date for the return to office use, but all work that can be undertaken off-campus (ie is not lab-based) should be done at home or remotely at present.
Some study spaces are becoming available on campus with a booking system in place, such as the postgraduate study space in the University Library.
International/EU students remotely starting a funded PhD
You should check with your funder that you can be paid a stipend if you are not in the UK. If you are in receipt of a scholarship, you should contact the Graduate School for advice on opening a bank account to allow stipend payments.
The Institute of Cancer Sciences (ICS) is a broad-based, research intensive institution with a global reach. We span fundamental cancer biology, translational and clinical cancer research with a major focus on cancer genomics and disease-specific research. Our primary goal is to deliver world-class research that can be translated to patient benefit and to provide a leading-edge environment for research and training.
Self-funded PhD opportunities
Investigation of new therapeutic approaches to combat viral-associated cancer
Background: Epstein-Barr virus (EBV) is a human Herpesvirus that is associated with several forms of human cancer. The virus leads to a life long infection, avoiding eradication by the immune system and has evolved intriguing tricks to do this. In the lab we investigate the role of key viral genes in disease processes, their mechanism of action at the molecular level and how they perturbate the immune system. Central to this are the mechanisms by which viral proteins disrupt normal cellular processes. New insights into viral action permit an exploration into novel therapeutic approaches to combat EBV-associated cancer.
Aims: To assess the efficiency of novel treatments in killing viral infected tumour cells and to explore the mechanism of action of such drugs in targeting the function of selected viral proteins
Techniques: The project will involve the use of several molecular biological and genetical techniques to examine protein, DNA, RNA and molecular interactions, as well as immunological and cell culture methods, also high resolution imaging.
- AlQarni, S., Al-Sheikh, Y., Campbell, D., Drotar, M., Hannigan, A., Boyle, S., Herzyk, P., Kossenkov, A., Armfield, K., Jamieson, L., Bailo, M., Lieberman, P., Tsimbouri, P. and Wilson, J.B. (2018) Lymphomas driven by Epstein-Barr virus nuclear antigen-1 (EBNA1) are dependant upon Mdm2. Oncogene (in the press)
- Gnanasundram, S.V., Pyndiah, S., Daskalogianni, C., Armfield, K., Nylander, K. , Wilson, J.B. and Fåhraeus,, R. (2017) PI3Kd activates E2F1 synthesis in response to EBNA1-induced mRNA translation stress. Nature Communications 8:2103, doi:10.1038/s41467-017-02282-w Gao, X., Lampraki, E., Al-Khalidi, S., Qureshi, M.A., Desai, R. and Wilson, J.B. (2017) N-acetyl cysteine (NAC) ameliorates Epstein-Barr virus latent membrane protein 1 induced chronic inflammation. PLoS-ONE 12 (12) e0189167
- Deschamps, T., Quentin, B, Leske, D.M., MacLeod, R., Mompelat, D., Tafforeau, L., Lotteau, V., Baillie, G.S., Gruffat, H., Wilson, J.B. and Manet, E. (2017) Epstein-Barr Virus Nuclear Antigen 1 (EBNA1) interacts with Regulator of Chromosome Condensation (RCC1) dynamically throughout the cell cycle. J. Gen. Virol. 98:251-265 PMID:28284242
- Hussain, M., Gatherer, D. and Wilson, J.B. (2014) Modelling the structure of full-length Epstein-Barr Virus Nuclear Antigen 1. Virus Genes 49:358-372 PMID: 25011696
Microenvironment in paediatric and adult acute myeloid leukaemia
Abstract: Acute myeloid leukaemia (AML) is a genetically and phenotypically heterogeneous disease that is characterized by a block in myeloid differentiation, as well as enhanced proliferation and survival. It affects people of all ages with an incidence of 2-3 per 100 000 per annum in children, increasing to 15 per 100 000 per annum in older adults. The relapse risk for childhood AML remains unacceptably high and relapse is the commonest cause of death. Multiple courses of chemotherapy remain the mainstay of treatment in adult and childhood AML but a ceiling of benefit has been reached and toxicity is significant (Chaudhury et al, 2015). There have been few, if any, new treatments in the past 30 years and there is a pressing need for novel effective therapies in AML.
The treatment of paediatric AML is in essence extrapolated from that of adults with AML. Our previous work (Chaudhury et al, 2015) in addition to recent timely publications (Beerman et al 2015) have questioned the appropriateness of this approach which assumes that a similar aetiology underlies AML in the young and old. There is additional evidence that disease characteristics differ between a paediatric and adult population with AML (Appelbaum 2006; Creutzig et al. 2008). Functional interplay between AML cells and the bone marrow microenvironment is a distinctive characteristic of AML disease. AML cells in the adult bone marrow BM reside in leukaemic niches (Colmone et al 2008) that support leukaemic cell survival and expansion. The importance of the microenvironment in paediatric versus adult AML (fetal liver, cord blood, bone marrow) and its role is disease characteristics has not been well explored. Our lab focuses on the proliferation and self-renewal capabilities of the leukaemic cell and the influence of the leukaemic niche. We hypothesize that the microenvironment influences the initiation, maintenance, and aggressiveness of paediatric and adult AML disease.
Methods & approaches: This project will investigate the role of the microenvironment in AML disease initiation and maintenance. We will focus on genetically distinct subtypes of paediatric and adult using a number of models and approaches including: Bone marrow transduction and transplantation (BMT) murine models: expression of AML oncogenes in viral constructs and using CRISPR/Cas9 gene editing approaches; assessments on disease in vivo; Stromal co-cultures and transcriptional profiling using haematopoietic stem cells; primary AML samples from paediatric and adult patients. The project will also employ flow cytometry, cellular and molecular biology technologies. This PhD studentship offers extensive dual training in both fundamental and translational biology of leukaemia, an environment encompassing clinical and basic researchers, and training opportunities as part of the college graduate program.
- Chaudhury SS, Morison JK, Gibson BES, Keeshan K. Insights into cell ontogeny, age and acute myeloid leukaemia. Experimental Hematology. 2015 Jun 4.
- Beerman I, Rossi DJ. Epigenetic Control of Stem Cell Potential during Homeostasis, Aging, and Disease. Cell Stem Cell. 2015 Jun;16(6):613–25.
- Appelbaum, F.R., 2006. Age and acute myeloid leukemia. Blood, 107(9), pp.3481–3485.
- Creutzig, U. et al., 2008. Significance of age in acute myeloid leukemia patients younger than 30 years: a common analysis of the pediatric trials AML-BFM 93/98 and the adult trials AMLCG 92/99 and AMLSG HD93/98A. Cancer, 112(3), pp.562–571.
- Colmone A, Amorim M, Pontier AL, Wang S, Jablonski E, Sipkins DA. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science. 2008;322(5909):1861-1865.
SWATH Proteomic analysis to identify putative biomarkers to predict disease related complications involved in Polycythaemia Vera
Abstract: Polycythaemia Vera (PV) is a haemopoietic stem cell disease, with ~95% of patients having the V617F JAK2 mutation, which results in constitutive activation of the JAK/STAT signalling pathway, leading to increased myelopoiesis and high erythrocyte counts. Patients also suffer from symptoms related to chronic inflammation, which is thought to explain, in part, the increased risk of thrombosis. Chronic inflammation is well recognised as a driver of atherosclerotic plaque formation and a risk for development of arterial and venous thromboembolism in patients with autoimmune conditions and other chronic medical illnesses, but the evidence for this in PV is only just starting to become available. It is known that an elevated white cell count in PV is associated with an increase in arterial events, and this appears to relate to inappropriate activation of the haemopoietic cells resulting in a pro-coagulation phenotype, however there is much that remains unclear about what drives these symptoms. One avenue worth exploring is the role of monocytes in PV related thrombotic and cardiovascular complications. Intermediate monocyte frequency has recently been identified as a positive predictor of cardiovascular events playing a significant role in inflammation through high secretion of TNFa and IL-1b. Intermediate monocytes also express CCR2 and CCR5, which are critical for monocyte homing and trans-endothelial migration into atherosclerotic plaques. Platelet activation and blood coagulation is also initiated at the site of injury by monocyte/macrophage secreted exosomes which contain tissue factor and P-selectin glycoprotein ligand-1 (PSGL-1) on their surface. Work from the Wheadon/Copland laboratory has recently identified significantly higher intermediate monocyte frequency in PV patients compared to normal aged matched control donors and high levels of pro-inflammatory cytokines/chemokines in PV patient serum. Recent interest has focused on the role that exosomes play in immune regulation, especially in neoplasms. Exosomes are homogenous membrane vesicles (40-150nm diameter), derived from the exocytosis of intraluminal vesicles and released into the extracellular space when fused to the plasma membrane. The majority of cells including haemopoietic cells release exosomes, with malignancy specific exosomes, expressing cell of origin cluster of differentiation (CD) antigens identified in leukaemia and PV. Exosomes are important for the extracellular transfer of proteins, lipids, mRNAs, microRNAs and DNAs to neighbouring cells where they can alter the function of the recipient cell. Tumour-derived exosomes (TEX) are released both locally and into the circulation to interact with a variety of cell types, including immune cells. TEX have been shown to alter immunoregulatory mechanisms such as; antigen presentation, immune activation, immune suppression, immune surveillance and cell communication. It is known that erythrocytes retain their microRNA content during maturation and that they secrete exosomes, however their functional role is still not clearly defined. One could postulate that the exosomes act as immunosuppressive signals given that erythrocyte homeostasis requires the constant removal of damaged or aged erythrocytes (2x106 per second)via phagocytes within the liver, spleen or lymph nodes. How erythrocyte exosomes modulate immune responses and whether this is altered in PV patients still remains to be investigated, as does the role of monocyte and erythrocyte derived TEX in PV related complications namely chronic inflammation and thrombotic events.
Hypothesis/research question: Are tumour-derived exosomes involved in the chronic inflammatory and pro-coagulation symptoms experienced by Polycythaemia Vera patients?
- Mathematical evaluation to determine cells of origin of exosomes in PV patients and normal aged matched donor plasma.
- SWATH profiling to identify novel biomarkers involved in PV pathophysiology
- Evaluate Ruxolitinib, hydroxycarbamide (HC), statins and aspirin treatment on TEX secretion & TEX effects on the inflammasome and coagulation.
- Hasselbalch, H.C., Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer? Blood, 2012. 119(14): p. 3219-25.
- Hulsmans, M. and P. Holvoet, MicroRNA-containing microvesicles regulating inflammation in association with atherosclerotic disease. Cardiovasc Res, 2013. 100(1): p. 7-18.
- Stansfield, B.K. and D.A. Ingram, Clinical significance of monocyte heterogeneity. Clin Transl Med, 2015. 4: p. 5.
- Caivano, A., et al., High serum levels of extracellular vesicles expressing malignancy-related markers are released in patients with various types of hematological neoplastic disorders. Tumour Biol, 2015.
- Greening, D.W., et al., Exosomes and their roles in immune regulation and cancer. Semin Cell Dev Biol, 2015. 40: p. 72-81.
Epigenetic profiling of blood and lung cancer stem cells for precision medicine
Abstract: Normal development of adult tissues relies on balanced self-renewal and differentiation of tissue stem and progenitor cells, whereas the abnormal activation of self-renewal or blockage of differentiation pathways, could lead to the malignant cell proliferation and oncogenesis. Leukaemia stem cells (LSCs) as a rare cell population present in Acute Myeloid Leukaemia (AML), confer chemotherapy resistance and are responsible for maintenance and relapse of the disease. Precision medicine requires eradication of LSCs for long term remission in AML, yet the detailed mechanism driving the oncogenic dysregulation in LSC still remains elusive. Epigenetic regulators play essential roles in cooperating with transcription factors to control gene expression required for LSC maintenance. The recent development of several pharmacological inhibitors targeting these regulators, such as BRD4 and Dot1L, highlights the great potential for them as promising anti-tumour targets. We have utilised a high throughput lentivirus shRNA screen to identify the critical epigenetic regulators, knock-down of which in human AML cells promoted AML LSC terminal myeloid differentiation and/or led to the loss of their self-renewal capacity, resulting in rapid cell death while sparing normal haemopoietic stem cell function. This suggests that targeting these candidates could represent rational novel therapeutic intervention in AML.
Hypothesis: In this project, we will focus on further validating the prioritised candidates from our previous screen, in primary AML patient samples and in our established human AML xenograft mice model. We hypothesise that these identified epigenetic regulators are required to sustain specific LSC centred epigenomic profiles, through association with distinct chromatin complex(es) in human AML cells compared to normal bone marrow cells, which are responsible for selectively maintaining LSC function.
Aims and Methodology: The PhD candidate will employ systems biology approaches utilising combined genomics/proteomics (such as SILAC-IP-MS, RNA-seq and ChIP-seq) and bioinformatics analysis with following aims:
- to determine epigenomic profiles in AML LSCs, which are associated with the specified candidate;
- to investigate the cellular and molecular mechanisms through which the specified candidate selectively targets human AML LSCs; i) to identify the components of the unique chromatin complex with which the candidate selectively associates in human AML ii) to identify the candidate’s downstream targets in human AML.
- to validate the use of the available epigenetic inhibitors in AML and provide information to facilitate and optimise the development of potent preclinical/clinical-grade drug(s).
Overall, this PhD project is expected to further consolidate our understanding underlying the important role of epigenetic regulators in human AML LSC. The information will be used to initiate the next stage of drug discovery and propose effective combination treatments with other standard AML therapies. The knowledge acquired in this study can also be applied to research of other cancer types. Our preliminary data indicate similar roles of particular epigenetic regulators in both blood and non-small cell lung carcinoma (NSCLC). The student will also be encouraged to use NSCLC cells as an alternative model for parallel studies in thisproject, and broaden our view on the role of epigenetic pathways in other stem cell derived solid tumours.
- Huang X et al. Enhancers of Polycomb EPC1 and EPC2 sustain the oncogenic potential of MLL leukaemia stem cells. Leukaemia (2014) 28: 1081-91.
- Harris WJ et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukamia stem cells. Cancer Cell (2012) 21: 473-487.
- Somerville TDD et al. Frequent depression of the mesenchymal transcription factor gene FOXC1 in acute myeloid leukemia. Cancer Cell (2015) 28:329-342.
- Lynch JT et al. TTC5 is required to preventapoptosis of acute myeloid leukemia stem cells. Cell Death and Disease (2013) 4, e573.
- Jude JG et al. A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival. Oncogene (2015) 34: 1253-1262.
Elucidating the role of APOBEC3B in CML stem cell survival
Abstract: Small molecule tyrosine kinase inhibitors (TKIs), such as imatinib, form the standard therapy for BCR-ABL1 driven chronic myeloid leukaemia (CML). However we have shown that CML leukaemia stem cells (LSC) are insensitive to these drugs, which cause cell cycle arrest rather than apoptosis resulting in disease persistence in patients that are very unlikely to be cured using TKI monotherapy. In the search for complementary targets to BCR-ABL1 in CML LSC, we have carried out global gene expression profiling between normal haematopoietic stem cells (HSC) and CML LSC. A key finding was that LSC, but not normal HSC, show up-regulation of several genes, including Apolipoprotein B mRNA editing enzyme (APOBEC3B). One of the major cellular functions of APOBEC3 proteins is the derepression of microRNA (miR)-mediated protein translation inhibition. Upregulation of miRs through targeted inhibition of APOBEC3B may have therapeutic effect in CML by re-enabling tumour suppressor functions of miRs, including down-regulation BCR-ABL1. In this project, miR signatures will be validated in CML, as they relate to APOBEC3B activity; the effect of APOBEC3B neutralisation on miR function, and the modulation of miR function on primary BCR-ABL1+ cell function will be investigated with a view to translating therapeutic targeting to the clinic.
- Holyoake T, Vetrie D, Cancer: Repositioned to kill stem cells. Nature 2015;525(7569):328.
- Hershkovitz-Rokah et al, Restoration of miR-424 suppresses BCR-ABL activity and sensitizes CML cells to imatinib treatment. Cancer Lett 2015;360:245.
- Huang et al, Derepression of microRNA-mediated protein translation inhibition by apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G) and its family members. J Biol Chem 2007;282:33632.?
- Swanton C et al, APOBEC Enzymes: Mutagenic fuel for cancer evolution and heterogeneity. Cancer Discov 2015;5(7):704.
- Jurkovicova D et al, microRNA expression profiling as supportive diagnostic and therapy prediction tool in chronic myeloid leukemia. Neoplasma 2015;62(6):949.
Identify Novel Drug Targets in Chronic Myeloid Leukaemia using a Genome-scale CRISPR-knockout Approach
Abstract: Chronic myeloid leukaemia (CML) is caused by a reciprocal translocation between chromosomes 9 and 22 leading to transcription of the fusion protein BCR-ABL, a constitutively active tyrosine kinase. The tyrosine kinase inhibitor (TKI) imatinib has significantly improved life expectancy in the majority of patients, however, TKI-treated CML patients continue to accumulate mutations over time and acquired TKI-resistance remains a significant problem for patients who currently need to continue TKI indefinitely1-3. While the mechanism of BCR-ABL dependent resistance has been thoroughly investigated (mainly caused by mutations in the tyrosine kinase domain of ABL4), relatively little is known about the mechanism(s) that drive BCR-ABL independent resistance and the therapeutic options for this group of patients are limited and expected survival short. It is therefore hoped that this patient population, that currently experiences rare responses to TKI treatment, may share an alternative drug target that can be inhibited with a novel compound.
So far, investigation into the mechanism(s) responsible for TKI resistance has been limited by the lack of availability of suitable cell line modes. We have therefore recently developed TKI-resistant CML cell lines with acquired BCR-ABL independent resistance (no mutation in kinase domain of BCR-ABL). To our knowledge this is the first time that TKI-resistant CML cell lines that continue to proliferate in the absence of BCR-ABL activity have been generated. This provides us with a unique opportunity to explore what drives BCR-ABL independent resistance in CML.
Aims: The aim of this project is to perform genome-scale CRISPR-knockout screens to identify mechanism(s) of BCR-ABL independent TKI-resistance and search for novel drug targets. We have already optimised all methods required to perform loss-of-function genetic screens using the genome-scale CRISPR-Cas9 knockout (GeCKO) v2 library5. Using this approach we will identify genes that are critical for survival of TKI-resistant CML cells in the presence of complete BCR-ABL inhibition. Positive hits will be validated on patient-derived CML cells (from patients not responding to TKI treatment) and the best pre-clinical murine models available. The ultimate aim is to facilitate the development of a pre-clinical package to be tested in future clinical trials for patients with CML, resistant to currently licensed TKIs through a BCR-ABL independent mechanism.
- Jiang, X., et al. Instability of BCR-ABL gene in primary and cultured chronic myeloid leukemia stem cells. Journal of the National Cancer Institute 99, 680-93 (2007).
- Holyoake, T.L., et al. Do we need more drugs for chronic myeloid leukemia? Immunological reviews 263, 106-23 (2015).
- Karvela, M., et al. Mechanisms and novel approaches in overriding tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Expert Rev Anticancer Ther 12, 381-92 (2012).
- Hochhaus, A., et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16, 2190-6 (2002).
- Sanjana, N.E., et al. Improved vectors and genome-wide libraries for CRISPR screening. Nature methods 11, 783-4 (2014).
Identification and characterisation of drug-able neurotransmitter signalling pathways in acute myeloid leukaemia (AML)
Abstract: Acute myeloid leukaemia (AML) is the most common form of acute leukaemia with an incidence in the U.K. of ≈ 4 cases/100,000 individuals and with 2250 cases diagnosed each year. It is characterised by a clonal hierarchy of malignant myeloid blast cells, and within each clone, a sub-population of cells known as leukaemia stem cells (LSCs) are considered to be the critical cells for maintenance and relapse of the disease. Standard AML chemotherapies such as daunorubicin and cytarabine, have evolved slowly since the 1970s and do not eradicate LSCs. Furthermore, AML is heterogeneous with sub-types characterised by different DNA mutations. DNA rearrangements of the mixed lineage leukaemia (MLL) gene are found in 70% of childhood and 10% of adult cases, and these forms of AML have particularly poor prognosis with 5 year survival rates between 11-38%.
Neurotransmitter signalling plays a role in haematopoiesis within the bone marrow and has been shown to be important for the maintenance of cancer cells in medulloneuroblastoma, myeloproliferative neoplasms and AML, among others. In AML, dopamine receptors have been shown to be important for the survival of leukaemic stem and progenitor cells. Treating AML cells with the dopaminergic antagonist thioridazine, a repurposed anti-psychotic drug (that is non-toxic to normal haematopoiesis), was shown to kill AML cells in combination with low dosages of cytarabine. This demonstrated that compounds targeting neurotransmitter signalling may provide novel therapeutic options for AML – and improve clinical outcome and reduce toxicity associated with standard chemotherapies. Recently we have demonstrated a role for neurotransmitter signalling in CML cells and that treatment with thioridazine can result in cell loss, particularly of primitive primary CD34+ cells. We have extended these observations to perform a compound screen in relevant cell lines and in primary CML and non-CML CD34+ cells and have identified neurotransmitter signalling antagonists and agonists that selectively kill CML cells in vitro. We are currently evaluating these compounds as potential novel therapeutics in CML.
For the reasons stated above, there is a significant unmet clinical need in AML that can only be addressed through the development of novel therapeutics, particularly for aggressive MLL-AML, and to eradicate LSCs. Based on previous work in AML and other cancers, and our ongoing complementary work in CML, we hypothesize that the identification and characterisation of compounds that modulate neurotransmitter signalling, will allow us to develop novel therapeutics that can target the selective loss of leukaemic stem and progenitor cells in AML. The aims of this project are:
- To identify compounds which modulate neurotransmitter signalling and selectively reduce the leukaemic stem and progenitor cell pool, when compared to normal stem and progenitor cells, in vitro, and in vivo using xenotransplantation.
- To validate the molecular mechanism of action (MOA) of compounds and identify specific genes/proteins which are differentially induced or repressed during modulation of neurotransmitter signalling in AML progenitor and stem cells LSCs when compared to HSCs.
- Passegue, E. et al. P.N.A.S. 30: 11842-11849. (2002).
- Bonnet, D & Dick, JE. Nat. Med. 3: 730-737 (1997).
- Diamandis, P., et al. Nature Chemical Biology 3: 268-273 (2007).
- Sachlos, E., et al. Cell 149: 1284-1297 (2012).
- Arranz, L., et al. Nature 512: 78-81 (2014).
Investigation of BET and MDM2 inhibitors as a candidate novel combination therapy for AML
Abstract: In 2015, there will be approximately 2400 new cases of AML in the United Kingdom (https://www.hmrn.org/statistics/survival). After diagnosis, five year survival is currently ~15.5%. Therefore, there remains a critical requirement for novel therapies for AML. Bromodomain and extra-terminal domain (BET) inhibitors are emerging as exciting therapeutic agents for hematopoietic malignancies, including AML . Pharmacological inhibition of BET bromodomains targets malignant cells by preventing reading of acetylated lysine residues, thus disrupting chromatin-mediated signal transduction, which reduces transcription at oncogenic loci, such as c-myc, Bcl-2 and cdk4/6 . Although a heterogeneous disease, most AML retains wild type p53 . However, p53 is often rendered functionally deficient by over-expression of MDM2 . Accordingly, we hypothesized that dual inhibition of MDM2 and BET would be synthetic lethal to p53 wild type AML. In extensive studies, we have confirmed this hypothesis both in vitro and in vivo.
Hypothesis: We hypothesize that BET inhibitors potentiate activation of p53 to promote cell cycle arrest and apoptosis. We will: 1) investigate the mechanism by which BET inhibitors potentiate activation of p53 by nutlin; 2) Investigate the mechanism of p53-dependent cell cycle arrest and cell killing.
- Investigate mechanism by which BET inhibitors potentiate activation of p53 by nutlin. We hypothesize that BET inhibitors potentiate activation of p53 by promoting binding of p53 to specific target gene regulatory sides and/or enhancing the activity of chromatin-bound p53. We further hypothesize that this depends on the ability of BET inhibitors to control p53 post-translational modification and/or interaction with associated proteins. We will dissect these hypotheses to elucidate the mechanism of p53 activation by BET inhibitors.
- Investigate mechanism of cell cycle arrest and cell killing. We hypothesize that marked G1 cell cycle arrest and apoptosis induced by the drug combination depends, at least in part, on expression of synergistically activated pro-apoptotic and cell cycle arrest p53 target genes, such as PUMA and CDKN1A (p21CIP1) respectively.
Completion of these studies will justify the testing of nutlin and BET inhibitors in a human clinical trial to be led from Glasgow.
- Gallipoli P, Giotopoulos G, Huntly BJ: Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia. Ther Adv Hematol 2015, 6:103-119.
- Hou HA, Chou WC, Kuo YY, Liu CY, Lin LI, Tseng MH, Chiang YC, Liu MC, Liu CW, Tang JL, et al: TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. Blood Cancer J 2015, 5:e331.
- Kojima K, Konopleva M, Samudio IJ, Shikami M, Cabreira-Hansen M, McQueen T, Ruvolo V, Tsao T, Zeng Z, Vassilev LT, Andreeff M: MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy. Blood 2005, 106:3150-3159.
Killing cancer cells - screen if you want to go faster
Abstract: Inhibition of cell death both promotes cancer and makes it more difficult to treat - consequently intense interest surrounds restoring cell death sensitivity to tumour cells in order to kill them. The major form of programmed cell death is apoptosis. Apoptosis requires a key event called mitochondrial outer membrane permeabilisation in order to kill the cell. Mitochondrial integrity is tightly controlled by pro- and anti-apoptotic members of the Bcl-2 protein family. Many cancers inhibit apoptosis by up-regulating anti-apoptotic Bcl-2 protein expression; this has led to development of potent new drugs - called BH3-mimetics - that neutralise anti-apoptotic Bcl-2 function thereby restoring apoptotic sensitivity to cancer cells.
While BH3-mimetics work very well as single agents in certain types of leukemia, their efficacy in other cancer types is less pronounced. Additionally, as with all targeted therapies, inherent or acquired resistance to BH3-mimetic treatment limits their effectiveness. Using this rationale, this project aims to identify regulators of sensitivity to BH3-mimetic induced killing. It will use genome-wide screens, applying CRISPR/Cas-9 genome editing, to identify sensitizing targets, followed by subsequent mechanistic basis of action studies. Finally, we will apply this knowledge to assess the impact of targeting selected hits on the effectiveness of BH3-mimetic treatment in vivo.
- Ichim G et al. Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. (2015) Molecular Cell 57:860.
- Haller M et al. Ubiquitination and proteasomal degradation of ATG12 regulates its pro- apoptotic activity. (2014) Autophagy 10:2269.
- Lopez J and Tait SW. Mitochondrial apoptosis: killing cancer using the enemy within. (2015) British Journal of Cancer 112:957.
- Tait SW et al. Widespread mitochondrial depletion via mitophagy does not compromise necroptosis. (2013) Cell Reports 5:878. ?
- Tait SW et al. Resistance to caspase-independent cell death requires persistence of intact mitochondria. (2010) Developmental Cell 18:802.
We are part of a national centre of excellence in the fight against cancer carrying out a programme of world-class science directed at understanding the molecular changes that cause cancer. We are working to translate scientific discoveries into new drugs or diagnostic and prognostic tools that benefit cancer patients, taking new therapies through preclinical and clinical trials.
The Institute of Cancer Sciences is a major component of the Cancer Research UK West of Scotland Cancer Centre. There are currently 51 research groups housed in magnificent new research buildings at the Beatson Institute for Cancer Research, the Paul O’Gorman Leukaemia Research Centre, the CRUK clinical trials unit (CTU) and the Wolfson Wohl Cancer Research Centre. Our facilities house a number of state-of-the-art technologies that underpin our key research themes.
Individual research projects are tailored around the expertise of principal investigators within the institute. Basic and clinical projects are also available for study.
A variety of approaches are used, including molecular biology, biochemistry, bioinformatics, genetics, cancer modelling and cell biology (including advanced in vitro and in vivo imaging), immunology and polyomics (genomics, transcriptomics, proteomics and metabolomics).
Specific areas of interest include:
- cancer biology and cell signalling
- cancer stem cell biology
- cancer imaging
- chemoresistance in cancer
- cancer and ageing
- regulation of cancer cell death processes
- genetics, genomics and systems medicine
- immunotherapy for cancer
- cancer clinical trials
- Duration: 3/4 years full-time; 5 years part-time
Individual research projects are tailored around the expertise of principal investigators.
Integrated PhD programmes (5 years)
Our integrated PhD allows you to combine Masters level teaching with your chosen research direction in a 1+3+1 format.
International students with MSc and PhD scholarships/funding do not have to apply for 2 Visas or exit and re-enter the country between programmes. International and UK/EU students may apply if your Masters was awarded a few years ago.
Taught masters level modules are taken alongside students on our masters programmes. Our research-led teaching supports you to fine tune your research ideas and discuss these with potential PhD supervisors. You will gain a valuable introduction to academic topics, research methods, laboratory skills and the critical evaluation of research data. Your grades must meet our requirements in order to gain entry on to a PhD research programme. If not, you will receive the Masters degree only.
Years 2, 3 and 4
PhD programme with research/lab work, completing an examinable piece of independent research in year 4.
Thesis write up.
All applicants must have full funding before starting their iPhD programme.
PhD applicants should have or expect to obtain a very good honours degree in Life Sciences. They should also have an aptitude for experimental work and be highly committed to pursuing a career in cancer research.
Integrated PhD programmes
Upper-Second-Class Honours degree or international equivalent in a relevant subject area.
English Language requirements for applicants whose first language is not English.
Fees and funding
- UK fee to be confirmed by ukri.org (2020/21 fee was £4,407)
- International & EU: £23,000
Prices are based on the annual fee for full-time study. Fees for part-time study are half the full-time fee.
Additional fees for all students:
- Re-submission by a research student £540
- Submission for a higher degree by published work £1,355
- Submission of thesis after deadline lapsed £350
- Submission by staff in receipt of staff scholarship £790
Depending on the nature of the research project, some students will be expected to pay a bench fee (also known as research support costs) to cover additional costs. The exact amount will be provided in the offer letter.
We offer a 10% discount to our alumni on all Postgraduate Research and full Postgraduate Taught Masters programmes. This includes University of Glasgow graduates and those who have completed Junior Year Abroad, Exchange programme or International Summer School with us. The discount is applied at registration for students who are not in receipt of another discount or scholarship funded by the University. No additional application is required.
- £4,407 UK/EU
- £21,920 outside EU
Prices are based on the annual fee for full-time study. Fees for part-time study are half the full-time fee.
Additional fees for all students:
- Re-submission by a research student £525
- Submission for a higher degree by published work £1,315
- Submission of thesis after deadline lapsed £340
- Submission by staff in receipt of staff scholarship £765
Depending on the nature of the research project, some students will be expected to pay a bench fee (also known as research support costs) to cover additional costs. The exact amount will be provided in the offer letter.
We offer a 20% discount to our alumni commencing study in Academic session 2020/21, on all Postgraduate Research and full Postgraduate Taught Masters programmes. This includes University of Glasgow graduates and those who have completed a Study Abroad programme or the Erasmus Programme at the University of Glasgow. This discount can be awarded alongside other University scholarships.
Funding for EU students
The Scottish Government has confirmed that fees for EU students commencing their studies 2020/21 will be at the same level as those for UK student.
The College of Medical, Veterinary and Life Sciences Graduate School provides a vibrant, supportive and stimulating environment for all our postgraduate students. We aim to provide excellent support for our postgraduates through dedicated postgraduate convenors, highly trained supervisors and pastoral support for each student.
Our overarching aim is to provide a research training environment that includes:
- provision of excellent facilities and cutting edge techniques
- training in essential research and generic skills
- excellence in supervision and mentoring
- interactive discussion groups and seminars
- an atmosphere that fosters critical cultural policy and research analysis
- synergy between research groups and areas
- extensive multidisciplinary and collaborative research
- extensive external collaborations both within and beyond the UK
- a robust generic skills programme including opportunities in social and commercial training
How to apply
Identify potential supervisors
All Postgraduate Research Students are allocated a supervisor who will act as the main source of academic support and research mentoring. You may want to identify a potential supervisor and contact them to discuss your research proposal before you apply. Please note, even if you have spoken to an academic staff member about your proposal you still need to submit an online application form.
You can find relevant academic staff members with our staff research interests search.
Gather your documents
Before applying please make sure you gather the following supporting documentation:
- Final or current degree transcripts including grades (and an official translation, if needed) – scanned copy in colour of the original document
- Degree certificates (and an official translation, if needed): scanned copy in colour of the original document
- Two references on headed paper (academic and/or professional).
- Research proposal, CV, samples of written work as per requirements for each subject area.
To complete your application we will need two references (one must be academic the other can be academic or professional).
There are two options for you to submit references as part of your application. You can upload a document as part of your application or you can enter in your referee’s contact details and we will contact them to request a reference.
Option 1 – Uploading as part of the application form
Your references should be on official headed paper. These should also be signed by the referee. You can then upload these via theOnline Application form with the rest your documents to complete the application process.
Please be aware that documents must not exceed 5MB in size and therefore you may have to upload your documents separately. The online system allow you to upload supporting documents only in PDF format. For a free PDF writer go to www.pdfforge.org.
Option 2 - Entering contact details as part of the application form
If you enter your referees contact details including email on the application form we will email them requesting they submit a reference once you have submitted the application form. When the referee responds and sends a reference you will be sent an email to confirm the university has received this.
After submitting your application form
Use our Applicant Self Service uploading documents function to submit a new reference. We can also accept confidential references direct to email@example.com, from the referee’s university or business email account.
I've applied. What next?
If you have any other trouble accessing Applicant Self-Service, please see Application Troubleshooting/FAQs.