CRUK CoL Centre MBPhD supervisors
Potential CoL Centre MBPhD supervisors and project areas are provided below. Successful candidates may also be able to consider other CoL faculty as supervisors.
Research areas: Theranostic nanomedicine; early detection
Prof Khuloud Al-Jamal has extensive experience in design and development of novel nano-carriers specifically for drug, protein, nucleic acids and radionuclide delivery for cancer therapeutic or diagnostic applications. In brief there are three research focuses:
1. Development of cancer theranostic nanomedicines
2. Cancer immune modulation
3. Cancer early detection and prognosis
Research areas: Dendritic cell immunology and immunotherapy; skin immunology
The Bennett lab is an immunology lab with a strong and focused track record in studying the functions of dendritic cells (DC) and Langerhans cells (LC) in vivo. We have recently re-evaluated the role of LC in the skin, defining the importance of novel cellular interactions in peripheral tissues for the control of T cell function (Santos e Sousa JCI Insight 2018), and determining the cellular processes by which the LC network is repaired after damage in adults (Ferrer Sci Immune 2019). We apply this expertise to address key gaps in our understanding of the role of DC in cancer immunology, in particular by asking how plasticity of DC populations in vivo impacts on T cell activation in therapeutic settings. Recent key findings demonstrated the potency of lentiviral vectors to deliver antigen that may be cross-presented by DC to prime anti-tumour T cells and drive tumour rejection (Hotblack Mol Ther 2016). Guided by this work, we have also tested the importance of tumour DC in adoptive T cell therapy. This work has revealed the exciting potential of DC recruited into B16 melanomas, for stimulation of T cell receptor engineered T cells (Hotblack Mol Ther 2018). On-going CRUK-funded work in the lab is focused on addressing fundamental questions about the role of tumour DC in regulating T cell function for cancer immune surveillance, and how we can exploit DC to enhance T cell responses in patients that do not respond to immunotherapy.
Research areas: Protein kinases, in vivo models, tumour microenvironment, targeted therapy
The Cameron lab focuses on critical tumour associated protein kinases (including EGFR family, mTOR, PKC, Rhoregulated kinases) using a combination of in vivo models, cell biology, proteomics and drug discovery. We have identified critical roles for the Rho effector PKN kinases in pancreatic, breast and bowel cancer. An MBPhD student would address the therapeutic potential of PKN in the stroma and malignant epithelium of breast cancer, integrating drug and biomarker discovery with in vivo models of metastasis.
Research areas: Immune response to cancer; T cell receptor repertoire
T lymphocytes play a key role in controlling the growth and spread of cancer, and drugs which boost T cell function have achieved remarkable results in several cancer types. However, in many cases these drugs fail, for unknown reasons. The Chain Lab seeks students interested in combining computational and experimental systems level analysis of the T cell immune response in a variety of cancers, especially using TCRseq, a powerful new technology for analysing T cell receptors.
Research areas: Cancer genomics and evolution
The Ciccarelli lab is interested in studying the evolution of gastrointestinal cancer using systems biology. We are a multidisciplinary team of clinicians, wet-lab and computational scientists and collaborate tightly with gastrointestinal oncologists at UCLH. We have access to samples of cancer patients treated with targeted and systemic therapies from various clinical trials.
This project will study the molecular mechanisms triggering resistance to immunotherapy through the analysis of cancer genomes and the surrounding microenvironment using primary tissues and patient-derived organoids.
Research areas: Cancer Biology and Therapeutics in Myeloid Leukaemias.
The overall outcome of acute myeloid leukaemia (AML) patients remains dismal with most patients relapsing following initial responses to therapy. While genetic mutations are well described drivers of therapy resistance, less is known about the role of non-mutational adaptations in drug resistance. The proposed project in the Gallipoli lab will leverage an ongoing collaboration with Prof. Lo Celso group to study in vivo dynamics of therapy resistance in AML and will complement this by using AML cell lines and primary human samples to study the biology and molecular underpinnings of adaptive changes leading to therapy resistance with the aim to reduce relapses and improve AML patients’ outcomes.
Specifically ongoing projects in the lab are:
1) Validation of the role of genes identified from a drop-out genome-wide CRISPR/Cas9 screen in FLT3 mutated AML as sensitisers to targeted therapy in AML carrying FLT3 mutations (Blood 2018;131:1639-1653).
2) Dissecting the role of metabolic adaptations to targeted therapy in IDH2 mutant AML.
3) Studying the interplay between metabolic alterations and epigenetic in AML leukaemic stem cells.
4) Defining the role of antioxidant genes/pathways in determining resistance to several therapies across multiple subtypes of AML.
Research areas: Molecular and histological characterisation of genomic instability and immune responses in breast cancers
In breast cancers at the primary tumour site, the Grigoriadis lab investigates the chromosomal instability features indicative of (i) defects in DNA damage repair mechanisms, (ii) the presence of microbial communities, and (iii) their correlates to features in the tumour microenvironment. In parallel, we study local and systemic immune responses informative of cancer cell seeding in pre-metastatic lymph nodes of breast cancer patients and mouse models. Our ultimate aim is to decipher how the sum of these individual components influence treatment responses and disease progression.
Research areas: Developing oncolytic adenoviruses to target pancreatic and prostate cancers
Oncolytic adenoviruses selectively lyse cancer cells resulting in release of tumour antigens and induction of tumour-specific immune responses. Pancreatic ductal adenocarcinomas and metastatic prostate cancers have dismal treatment outcomes mainly because of dense impenetrable tumour microenvironments, preventing access of immune factors and drugs. Our engineered virus targets all cells in the microenvironment. The Hallden’s lab ongoing work is focused on further enhancement of viral efficacy by viral oncolysis that in turn activates the host anti-tumour immune response. We are also developing strategies that will enable systemic delivery of viruses for clinical translation.
Research areas: Cancer immunosurveillance by gamma delta T cells, immunological visibility of transformed epithelial cells, systemic immune dysregulation by local oncogenic events
Multiple independent lines of evidence argue that gamma delta T cells mount local immune surveillance that decreases susceptibility to carcinogenesis. The Hayday lab has begun to elucidate the mechanisms by which gamma delta T cells discriminate between normal and transformed tissue, but there is much more to learn before textbook descriptions of this fundamental biology can be provided. At the same time, we are keen to understand how local oncogene activation can induce systemic immune dysregulation.
Research areas: Cancer evolution and radiation resistance
Cancer evolution has been shown to be involved in resistance to cancer therapy both by cell intrinsic genomic evolution and also through longitudinal changes in the immune microenvironment. The Hiley lab focuses on resistance to immunotherapy in NSCLC through the TRACERx and DARWIN2 studies and is leveraging these methodologies and new technology platforms to study the cell intrinsic factors and tumour microenvironment changes associated with resistance to radiotherapy.
Research areas: Pancreatic cancer, stromal biology
The Kocher lab’s translational research interests include stromal biology of pancreatic cancer, biomarker discovery, and investigations into liver metastasis and duodenal cancers (<UKDCSG). Clinical interests include clinical trials and epidemiology in patients with hepato-biliary-pancreatic disorders, surgical development, innovative surgical techniques, risk-assessment and quality improvement. Dr Kocher’s clinical practice is at the Barts and the London HPB Centre at the Royal London Hospital of Barts Health NHS Trust.
Research areas: Translational research in the mechanism of resistance and biomarkers of ErbB inhibitors and the effect of radiotherapy with immunotherapy and/or other radiosensitizing agents in in head and neck and breast cancers. Clinical research to develop new clinical trials combining standard treatments with immunotherapy and/or other novel agents
Radiotherapy is one of the most important treatment modalities in many cancers and many studies have demonstrated a critical role for immune cells in mediating response to radiotherapy. However, there is uncertainty of how to combine anti-PD-1/PD-L1 antibody with radiotherapy in terms of dose fractionation as well as treatment schedule. In addition, there may be also other radio-sensitizing agents that could be combined with radiotherapy to enhance its effectiveness. The Kong lab aims to investigate the combination of radiotherapy with immunotherapy and/or other radio-sensitizing agents using a multidisciplinary approach using patients’ samples, animal models and patient-derived organoids, with an aim to translate the research findings to clinical trials.
Research areas: Targeting RNA modifications to eradicate cancer stem cells in acute myeloid leukaemia (AML)
Acute myeloid leukaemia is an aggressive clonal disorder of hematopoietic stem and progenitor cells, which acquire mutations and generate self-renewing leukemic stem cells (LSCs). LSCs initiate and propagate the disease, and given that they are treatment resistant, they fuel disease relapses. Therefore, identification of specific therapeutic targets for LSC elimination is an unmet clinical need. The Kranc lab aims to reveal the key RNA modifications, which govern LSC functions, investigate them and therapeutically target them to eliminate LSCs.
Research areas: Ovarian cancer, evolution of treatment resistance, biological therapies
The Lockley lab aims to improve treatments for women with ovarian cancer, particularly those that are resistant to treatment. We are developing personalised therapeutic strategies that respond to the evolution of therapy resistance over time. We are currently developing a clinical trial testing this novel approach.
The MBPhD student will be integrated within this ground-breaking study. They will exploit primary clinical samples to define the evolutionary dynamics of drug resistance in cancer patients. They will use this unique patient material, mathematical modelling and wet lab experiments to interrogate how these dynamics can be exploited for therapeutic gain.
Research areas: Cancer genetics (including impact on tumour microenvironment) and circulating biomarkers
With cancer genetics as a background, the Lu lab aims to improve cancer early detection and precision medicine through novel biomarker and therapeutic target development, with a recent research focus on ‘liquid biopsy’, particularly circulating biomarkers. We have identified prostate cancer hormone therapy resistance associated plasma exosome miRNAs by RNA-seq, which were validated at separate centres by q-RT-PCR, later observing their secretion by cancer. We are interested in investigating their prediction value of hormone therapy resistance and underlying biological mechanisms.
Research areas: Peptide and protein-targeted molecular imaging and radiotherapy with radionuclides
The Ma lab develops molecular radiotracers by incorporating radioactive metals into peptides or proteins that target tumour cell-surface receptors. This enables quantitative whole-body molecular imaging of cancer using PET or SPECT cameras. This type of molecular imaging can aid in (i) development of antibody-based therapies, (ii) understanding tumour or tumour microenvironment heterogeneity, and (iii) diagnostic imaging of cancer. We also develop targeted radionuclide therapies that incorporate therapeutic radiometals into the same molecular architectures to deliver therapeutic radiation.
Research areas: Mechanisms of chromosomal change in cancer
Normal cells carry two perfect copies of 23 pairs of chromosomes. Cancer cells in contrast exhibit multiple changes in chromosome number and structure. Moreover, cancer cells continually edit their genomes via defects in genome replication and division. This process – chromosomal instability– predicts worse cancer prognosis, and represents an important target for new cancer therapies. The McClelland lab uses cell biology, imaging, and genomics to tackle multiple questions relating to the mechanisms and vulnerabilities of cancer chromosomal instability.
Research Areas: Exosome based omics and clinical imaging
The central mission of the Ng group is to deliver a coherent & translationally oriented Imaging-OMIC combination approach for clinical studies. Tissue and circulating exosome based omics have been combined successfully with the use of clinical imaging to individualise cancer treatment, especially in the context of human epidermal growth factor receptor (HER) targeted treatments. Our team has recently shown in a Phase II head and neck anti-HER cancer therapy trial, that exosomal HER receptor measurements, which present a new way of following this receptor rewiring mechanism, can contribute significantly to the prediction of a favourable treatment response as measured by CT (RECIST) (ASCO, Journal of Clinical Oncology 36: Suppl 6043). In addition, our lab specialises in Tumour Immunology imaging e.g. we lead the exosome and immune cell CyTOF analysis within the deep immune profiling theme of the EU Innovative Medicine Initiative (IMI) 2 consortium: Human Tumour Microenvironment Immunoprofiling (IMMUcan).
Research area: Structural biology
The Pfuhl group has been involved in work on Aurora-A kinase for some time now. Having mainly focused on Aurora-A associated proteins we now want to look at Aurora-A for the first time by NMR spectroscopy. Structural studies by NMR spectroscopy can provide new insights into dynamics and interactions that could not be provided by crystallography. NMR is especially strong for the mapping of binding sites of inhibitors in proteins. Aurora-A is the target of numerous drugs but for quite a few there is actually no structure information about their binding site and how the change the conformation of the kinase. This could be resolved by NMR so that the mode of action of such drugs could be improved in the long term.
Another unresolved question is structure and function of the N-terminal domain. Because this portion needs to be removed to allow crystallisation of the catalytic domain there is no information about its structure and how it could be involved in the regulation of kinase activity. This question has been overlooked somewhat despite the fact that e.g. phosophorylation of the N-terminal domain can activate the kinase in the absence of the canonical phosphorylation of the activation loop.
The PhD student would learn protein expression & purification and the basics of modern protein NMR. The student will study the structure of this important drug target and how its conformation can be modulated by partner proteins, posttranslational modifications and interaction with inhibitors. This will provide the student with a deeper understanding of how drugs work and how a precise understanding of molecular mechanisms is essential to develop more effective cancer treatments.
Research areas: Molecular mechanisms regulating tissue growth, invasion, metastasis and tumour heterogeneity using the fruit fly Drosophila melanogaster as a genetically tractable model organism
The Ribeiro research group uses the fruit fly Drosophila to uncover the mechanisms regulating tissue growth, metastasis and tumour heterogeneity. This particular project aims to define the functional role of glioblastoma EGFR variants in the context of tumour heterogeneity. For this, we will use our newly generated genetic system for studying tumour heterogeneity and combine it with in vivo and in vitro models of glioblastoma, including the fruit fly Drosophila and mammalian organoid cultures.
Research areas: Mechanisms controlling epithelial homeostasis and extrusion
Epithelial cells work together to provide barriers, yet turn over rapidly by cell death and division. The Rosenblatt lab discovered that a process termed cell extrusion promotes cell death in response to physical crowding links these two processes to maintain constant numbers essential to their function. We use zebrafish to study how extrusion is hijacked to drive tumour invasion, mice to study how extrusion overactivation causes inflammation in asthma, and cell culture to identify the signalling controlling extrusion.
Research area: Genome stability
Inhibition of the immune checkpoint molecules, PD-1, CTLA-4 and PDL-1 have recently shown great clinical promise in many cancers. However, definitive biomarkers for response to immune checkpoint inhibitors are lacking. A recent Phase II clinical trial in patients with deficiency in the DNA mismatch repair (MMR) pathway indicated that MMR status predicted clinical benefit with the PD-1 inhibitor, pembrolizumab. These findings have led to the first tissue-agnostic approval for anti PD-1 therapy for unresectable or metastatic solid tumours with MMR deficiency. However, it is becoming increasingly clear that many MMR deficient tumours fail to respond to anti-PD-1 therapy with approximately 50% refractory to treatment. Furthermore, in the proportion of those MMR-deficient patients that do respond, there is a wide diversity of clinical benefit. MMR-deficient tumours are clinically characterized by levels of microsatellite instability (MSI) and a recent study has revealed the degree of MSI is in part responsible for diverse response of MMR-deficient tumours to anti-PD-1 therapy. However why this is the case and how this can be clinically translated remains largely unknown.
The Martin lab’s research has focused largely on the use of synthetic lethal approaches to target loss of MMR in tumour cells (Martin et al., EMBO Mol Med 2009; Mendes-Pereira et al., EMBO Mol Med 2009; Martin et al., Cancer Cell 2010; Martin et al., Cancer Res 2011; Hewish et al., Br. J Cancer 2013; Locke et al., Cell Reports 2016; Guillotin et al., Clin Cancer Res 2017; Rashid et al., Cell Death & Disease 2019). Due to our significant experience in MMR biology, we are now interested in understanding the role of MMR loss in the cellular response to immune checkpoint inhibition. Our exciting preliminary data suggest that loss of specific MMR genes results in a differential increased expression of the immune checkpoint molecule, PD-L1. Therefore, we have evidence that loss of specific MMR genes can trigger differential expression of PD-L1 and we hypothesize that it is this differential expression that may in part determine sensitivity to anti-PD-1 therapy. In this PhD proposal, we will use both CRISPR-Cas9 generated MMR deficient cancer cell lines and in vivo models to elucidate the precise genetic determinants upon MMR loss that may predict response to immune checkpoint blockade.
Research areas: Tumour suppressor in cancer biology, hypoxia biology, microRNA biology and novel mechanisms in Immuno-Oncology.
The Sharp lab focuses on the role of the tumour suppressor protein LIMD1 and its family members Ajuba and WTIP and how their deregulation in normal tissue contributes to the development of lung, renal and breast cancer.
More recently we have demonstrated the key role LIMD1 has as a scaffold protein in regulating the hypoxic response (how cells sense and respond to low levels of oxygen), through our seminal discovery of LIMD1 binding the PHD2, VHL and HIF proteins (Nature Cell Biology 2012). Furthermore, we have demonstrated that disruption of this complex and its regulation contribute to the development of lung cancer with very poor prognosis (EMBO MM 2018).
The full molecular characterization of this novel tumour suppressor is therefore the main focus of my group’s continued research. By understanding the function(s) of LIMD1 and indeed its family member proteins (Ajuba and WTIP); we can begin to understand how loss of this important tumour suppressor(s) contributes to disease pathogenesis and specifically tumorigenesis. We have also initiated new studies into targeting LIMD1 negative cancers and also the interplay of LIMD1 and LIM-domain protein with Immune-Oncology. This latter area is very novel and would be where we would like the MBPhD student to join us in deciphering this new biology in lung cancer models. We are particularly focused on lung cancer as areas of high unmet clinical need, working closely with colleagues in oncology at Barts Cancer Centre to translate discoveries into patient benefit.
Research area: Cell-Cell Communication in The Tumour Microenvironment
The Cell Communication Lab at UCL Cancer Institute studies how cancer cells interact with stromal and immune cells in the colorectal cancer (CRC) tumour microenvironment (TME). We have recently developed a novel single-cell technology to measure cell-type specific signalling in CRC TME organoids (Qin et al., Nature Methods, 2020). The MBPhD student will use this technology to mechanistically study how novel biotherapeutics kill CRC patient-derived organoids and can be deregulated by the CRC TME.
Our work focuses on the understanding of how the principle forces of cancer evolution-mutations and selection shape cancer development and progression and result in cancer relapse and treatment resistance. We make our observations through a series of unique translational studies in patients, which allow us to evaluate cancer dynamics in both space and time and under the selective pressure of therapy. We test the repeatability of these observations through functional experiments. The Turajlic lab is focused on two main cancers: kidney cancer (both sporadic and in the context of VHL disease) and melanoma. Lastly, we are working on methods to capture critical information about cancer evolution in a clinically tractable way.
Research areas: Cancer epidemiology; translational research with a specific interest in immunotherapy; urological cancers; pancreatic cancer
As a cancer epidemiologist working with national registers and hospital-based (biobank) data, Dr Van Hemelrijck has expertise in clinical data, statistics, clinical practice and patient care in the area of uro-oncology. She works on clinical projects linking lab-based work with clinical outcomes (with a specific interest in immunotherapy). Thus, given her expertise in both quantitative and qualitative research in the field of uro-oncology, Dr Van Hemelrijck can provide projects in a translational research setting.