Studentship projects
Studentship projects
Dr Olivier Pardo, Dr Kirill Veselkov and Professor Michael Seckl (Imperial, Surgery and Cancer) & Dr Paul Huang (ICR, Molecular Pathology).
Abstract
Non-small cell lung cancer (NSCLC) is the most prevalent lung cancer subtype. Despite the
successful introduction of immunotherapy for treatment of this disease, most patients still
subsequently require chemotherapy and die of metastatic disease. Hence, NSCLC is an area of
urgent therapeutic need. RSKs (p90 ribosomal S6 kinases), of which four isoforms exist in
humans (RSK1 to 4), are serine/threonine-kinases involved in multiple biological processes . We
showed that downregulation of RSK1 and RSK4 had opposite effects on cell invasiveness and
drug response in NSCLC. RSK4 silencing prevented metastasis and sensitised to chemotherapy
while that of RSK1 promoted invasiveness and drug resistance. Overexpression of these
kinases had the converse effects. This is clinically significant as we found RSK4 overexpressed
in ~60% of NSCLC and RSK1 downregulated in NSCLC metastasis. Also, high RSK4
expression correlates with poor prognosis in lung adenocarcinoma patients while that of RSK1
correlates with improved overall survival in lung cancer. So, despite high protein sequence
homology (~85%), RSK1 and 4 show several divergent biological functions in lung cancer and we
demonstrated that targeting RSK4 selectively, using one of our allosteric activation inhibitors, is
of therapeutic benefit in vivo. While the opposite effects of RSK1 and 4 associate with differential
regulation of apoptotic and cell migration processes, selective signalling mediators of the two
kinases explaining these discrepancies are unknown.
Through our proposed multidisciplinary project that combines molecular biology and artificial
intelligence, we intend to identify these mediators as this knowledge would have direct
translational relevance. Indeed, it would reveal new therapeutic opportunities that could substitute
for direct RSK4 inhibition in case of de novo/acquired resistance to our inhibitors for this kinase
or synergise with them by targeting complementary nodes in the same pathway.
Professor Molly Stevens (Imperial, Materials) & Dr Anna Wilkins (ICR, Radiotherapy & Imaging)
Abstract
The biological response to cancer therapy is extremely varied and complex. As a result, designing tools which monitor perturbations of specific proteins or nucleic acids in liquid biopsies can be challenging and often lead to low specificities and/or sensitivities. This means that expensive, low- throughput imaging techniques (e.g., MRI, CT or PET/CT) or invasive biopsies are the preferred way to monitor therapy progress. These scans are limited in resolution and will typically detect macroscopic and not microscopic changes in tumour growth. As a result, it is challenging to understand whether a therapy is effective in a timely, accurate manner. Patients with metastatic urothelial (bladder) cancer have a one-year survival rate of 33%. Recent trials have shown that treatment with Atezolizumab, an anti PD-L1 immunotherapy drug, can improve the survival of patients with this aggressive cancer. However, most patients still experience early progression post-therapy. This has led to research into a combinatorial approach in which radiotherapy is included into the treatment plan. However, for the reasons discussed above, in practice it is very difficult to know how a patient is responding to the therapy in a timely fashion. Therefore, there is an unmet clinical need for a way in which to monitor systemic therapy so that the treatment plans can be changed as soon as possible. The aim of this proposal is to devise a new way in which to monitor a therapy response in a timely and less-invasive manner, from liquid biopsies. This new technology would not be based on the typical specific biomolecule detection (such as PCR, ELISA etc.) but would be a system which would generate a unique ‘fingerprint’ in response to a patient’s sample. An analogy would be the way in which our smell receptors do not recognise molecules specifically but generate a unique signal which we can recognise with excellent accuracy. Our sensor will consist of an array of wells containing novel green-fluorescent polymer nanoparticles (NPs) developed in the Stevens group. In each well, the nanoparticles contained will have a unique surface coating which, when a patient sample is added, will respond differently depending on the biomolecules contained in the biofluid – and as a result generate a unique fluorescent signal. The working principle of the array is that small changes of the distance between the green NP and red dye will lead to drastic changes in the bulk fluorescent signal, due to the Förster resonance energy transfer (FRET) phenomenon. Therefore, when a patient sample is added to the array, the contained biomolecules will form a corona around each NP. This will perturb in the dye-NP distance and result in a unique fluorescent signal from each well depending on the linker used. By combining the fluorescent data from each well, a ‘picture’ of the biomolecular make-up of the patient sample can be generated.
Dr Anna Barnard (Imperial, Chemistry), Dr Alexis Barr (MRC-LMS, Institute of Clinical Sciences) & Dr Claudio Alfieri (ICR, Structural Biology)
Abstract
Professor Louis Chesler (ICR, Clinical Studies), Professor Matt Fuchter (Imperial, Chemistry), Professor Hector Keun & Dr Anke Nijhuis (Imperial, Surgery & Cancer)
Abstract
Neuroblastoma is a paediatric extra-cranial cancer and the leading cause of death from cancer in children. High-risk tumours (40% cases) carry oncogenic drivers such as MYCN, ALK and ATRX but current treatment regimens are not personalized or molecularly targeted. Therefore, there is an urgent unmet need for novel targeted therapeutics to improve cure rates. Aryl-sulphonamides such as indisulam and E7820 are anticancer compounds that act as molecular glues, driving highly selective ubiquitination and degradation of the splicing cofactor RBM39 via interactions with DCAF15-E3 ligase. We (Nijhuis et al. Nature Commun. 2022) have recognised that high-risk neuroblastoma models are exquisitely sensitive to indisulam. This is likely because high MYCN expression, associated with high-risk disease, activates a transcriptional program that relies heavily on timely and correct RNA splicing. We hypothesised that indisulam-mediated aberrant RNA splicing leads to vulnerabilities that can be exploited therapeutically and discovered that the combination of RBM39-depletion and other targeted agents demonstrated a strong synergy in neuroblastoma cells. While these findings suggest that there are therapeutic benefits of combining aryl sulphonamides with other anti-cancer drugs, we propose to generate dual inhibitors that can target two mechanisms simultaneously and reduce the likelihood that clones resistant to treatment arise while avoiding drug-drug interactions. The project will focus initially on synthetic and medicinal chemistry to explore this hypothesis and will also include biological characterisation of the resultant compounds, including: biochemical assessment of dual-target compounds; cellular validation of lead compounds; in vivo validation of lead compounds; investigation of the mechanism of synergy through global proteomics, RNA sequencing and bioinformatics.
Professor Darryl Overby (Imperial, Bioengineering) & Professor Alan Melcher (ICR, Radiotherapy & Imaging)
Abstract
Aims: 1. To develop a platform to investigate immune-cancer cell interactions and their spatiotemporal dynamics within perfused murine tumour explants ex vivo. 2. To optimise radiotherapy parameters (dose, fractionation) to initiate an anti-tumour immune response. 3. To determine the role of tumour-associated fibroblasts on immune suppression.
Hypothesis: Radiotherapy can enhance tumour immunogenicity and promote T-cell recruitment to potentially overcome immunosuppressive effects of tumour associated fibroblasts, but spatiotemporal dynamics play a key role in this process.
Rationale: Although immune checkpoint inhibitors (ICPIs) have achieved great success in melanoma and a number of tumour types, ICPIs only benefit around 12% of patients across the breadth of cancer. One reason is likely because many tumours are immunologically “cold”, containing few cytotoxic CD8+ and conventional/effector CD4+ T-cells, dendritic cells and M1- polarised macrophages and high numbers of immunosuppressive Tregs, tumour associated fibroblasts and M2-polarised macrophages.
Dr Sam Au (Imperial, Bioengineering) & Professor Udai Banerji (ICR, Cancer Therapeutics)
Abstract
Cancer associated fibroblasts (CAFs) secrete proteins that promote drug resistance and the evolution of cancer cells. In some cancers such as pancreatic ductal adenocarcinoma (PDAC), stromal cells greatly outnumber cancer cells within tumours. Current attempts to study clonal evolution and heterogeneity involves growing large populations of cells that are individually genetically barcoded and quantifying barcodes following selection pressure as a measure of heterogeneity. While the Banerji Lab uses these experimental models, such methods do not lend themselves to studies with co- cultured cell types e.g., cancer cells and CAFs. Technologies that help us study how CAFs drive evolution and heterogeneity in PDAC is an unmet need. Commonly used co-culture systems such as mixed cultures in flasks or Transwell membrane systems have a number of limitations that make them poorly suited to evolution and drug resistance studies including: a) variability in the degree of paracrine signalling & physical contact between cell types since growth is often patchy and in the case of membrane systems, independent populations lack physical co-contacts altogether, b) difficulty exploring dynamics since tracking the state of individual cells and their progenitors in macroscale over time is challenging, and c) are not scalable to high throughput screening. Droplet based microfluidics (Fig. 1) can address all of the above issues. This technique involves the controlled formation of nanolitre-femtolitre (10-9 -10-15 L) droplets segregated by immiscible oil. Droplet microfluidics is capable of precise control over co-culture conditions (i.e. 1:1 cancer cell:CAF within in each droplet), allows for the easy tracking of individual cells since each droplet acts as an isolated bioreactor, and is scalable, capable of generating >20,000 droplets per second. No droplet microfluidic platforms however have been developed to study cancer evolution and drug resistance within CAF and tumour co-cultures. We have also previously used pooled whole genome CRISPR screens to find genes relevant to drug resistance. However, this technology has not been applied to finding genes within cancer cells that are key to drug resistance induced by CAF co-cultures. Following droplet microfluidic screens, we will establish a new methodology where following transfection of a pool of lentiviruses, cell cultures of pancreatic cancer cells will be cultured in a perfusion system to allow identification of genes within cancer cells that cause sensitivity or resistance to anticancer drugs upon contact with secreted proteins from CAFs.
Hypothesis: Co-culture of cancer cells and CAFs using novel platforms will enable the study of how cancer associated fibroblasts (CAFs) affect PDAC evolution and drug resistance
Professor Amin Hajitou (Imperial, Brain Sciences) & Professor Rylie Green (Imperial, Bioengineering)
Abstract
The overall survival rate for cancers has doubled over the last 40 years, however many hard-to-treat cancers such as glioblastoma multiforme (GBM) continue to show little or no increase in survival rates. GBM remains hard-to-treat due to the challenge associated with delivering chemotherapeutic drugs to the tumour without causing significant off target toxicity. The current targeted treatments reduce off target toxicity but have potentially severe effects because they fail to address key physical challenges associated with the delivery. Overcoming these challenges will enable high concentrations of chemotherapeutics to be released directly into the tumour microenvironment. One technology that shows potential for this type of delivery is electrophoretic drug delivery. This mode of delivery can enable delivery of chemotherapeutic agents into the highly pressurised tumour microenvironment due to the use of electrophoresis to offload the drugs without the need for a liquid carrier. Immobilising drugs in a polymeric material enables the device itself to act as a functional reservoir and coupling this matrix with conducting polymers (CPs) creates a two-part polymer network of drug loaded polymer and electroactive CPs enabling ionic delivery.
This project aims to evaluate the release of common chemotherapeutic agents’ doxorubicin and cisplatin from the two- part polymer system. Using high sensitivity analytical techniques alongside molecular modelling, a complete picture of the mode of release will be understood. Utilising this information, a model of post- release drug diffusion within the tumour microenvironment will be created. Simultaneously, this model will be validated through the delivery of chemotherapeutic agents to a 3D glioblastoma spheroid model. Creating and validating a model of electrophoretic release within a tumour will aid in the demonstration of device efficacy. This project leverages expertise from laboratories directly involved advancing the treatment of GBM. Overall, the clinical outcomes of this project will be a step forward in the development of a therapeutic option capable of both improving patient quality of life during treatment due to the absence of off-target effects and the overall patient survival rate for GBM.
Professor Pascal Meier (ICR, Breast Cancer Research), Dr Periklis Pantazis & Dr Chris Rowlands (Imperial, Bioengineering)
Abstract
Why do cancer treatments often fail? What mechanisms do cancer cells use to subdue normal cells in their neighbouring tissue and expand at their expense?
In this proposal, you will delineate the mechanism of cell competition between tumour and normal cells in patient-derived tumour organoids. You will develop a winner-loser contact sensor using optogenetics to track cancer cell evolution in tumouroids with high precision. You will follow the competitive behaviour between tumour and normal cells at single-cell resolution in real time across consecutive cancer cell generations using a recently established volumetric microscope system. Whole-genome and RNA sequencing of competing cells will allow you to identify their respective ‘fitness’ fingerprints. To obtain insights into potential novel therapeutic regimes based on cell competition, you will also expose competing cells to standard-of-care drug combinations and evaluate how cell competition might contribute to tumour evolution. Ultimately, the knowledge you will acquire will pave the way to effectively restraining tumour evolution by changing the fitness landscape of cancer cells while strengthening the one of surrounding healthy tissue, thereby suppressing drug resistance and improving therapeutic outcomes.
Dr Sam Au (Imperial, Bioengineering) & Dr Paul Huang (ICR, Molecular Pathology).
Abstract
Tumour cell migration is key behaviour in metastasis as cells disseminate from primary and invade distant organs. The extracellular matrix (ECM) is a complex three-dimensional milieu containing structural proteins, proteoglycans and bound growth factors & enzymes that regulate migration. Tumour cell migration through matrix is further complicated by the fact that individual components can have both migration-inhibiting and migration-promoting functions. For instance, collagen physically obstructs migration until it is degraded by matrix metallinoproteineases but also serves to enhance migration by promoting integrin-mediated cell adhesion. Importantly, the competing role of collagen in this process is dependent upon both its concentration and organisation. While many studies have been conducted on the role of collagen in migration, we still have a poor understanding of the role of other ECM proteins on tumour cell migration.
In this project we three distinct aims:
Professor Zoltan Takats (Imperial, Metabolism, Digestion & Reproduction) & Dr Marco Bezzi (ICR, Molecular Pathology).
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Dr Paul Huang (ICR, Molecular Pathology) & Dr Jun Ishihara (Imperial, Bioengineering)
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Professor Jorge Bernardino de la Serna (Imperial, National Heart & Lung Institute) & Professor Andrew Tutt (ICR, Breast Cancer Research)
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Dr Sylvain Ladame (Imperial, Bioengineering) & Professor Sadaf Ghaem-Maghami (Imperial, Surgery & Cancer)
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Dr Anguraj Sadanandam (ICR, Molecular Pathology) & Dr Jun Ishihara (Imperial, Bioengineering)
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Professor Pantelis Georgiou (Imperial, Electrical and Electronic Engineering) & Professor Chris Bakal (ICR, Cancer Biology)
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Professor Mengxing Tang (Imperial, Bioengineering), Dr Navita Somaiah (ICR, Radiotherapy & Imaging).
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Professor Simon Robinson (ICR, Radiotherapy & Imaging) & Professor Molly Stevens (Imperial, Materials).
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Professor Ed Tate (Imperial, Chemistry) & Professor Louis Chesler (ICR, Clinical Studies).
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Professor Chris Lord (ICR, Breast Cancer Research) & Professor Alex Porter (Imperial, Materials).
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Dr Elizabeth Want and Professor Tim Ebbels (Imperial, Metabolism, Digestion and Reproduction) & Dr Nelofer Syed (Imperial, Brain Sciences).
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Professor Iain McNeish (Imperial, Surgery & Cancer), Professor Paul French (Imperial, Physics) & Professor Chris Dunsby (Imperial, Physics)
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Professor Eric Aboagye (Imperial, Surgery & Cancer) and Dr Richard Lee (Royal Marsden Hospital).
Dr Gabriela Kramer-Marek (ICR, Radiotherapy & Imaging) & Dr Philip Miller (Imperial, Chemistry)
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Professor Chris Bakal (ICR, Cancer Biology) & Dr Sam Au (Imperial, Bioengineering)
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Professor Dow-Mu Koh (Royal Marsden Hospital) & Dr Matthew Grech-Sollars (Imperial, Surgery & Cancer)
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Dr Masahiro Ono (Imperial, Life Sciences) & Professor Alan Melcher (ICR, Radiotherapy & Imaging)
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Professor Jyoti Choudhary (ICR, Cancer Biology) & Dr Tolga Bozkurt (Imperial, Life Sciences)
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Professor Andrea Rockall and Professor Charlotte Bevan (Imperial Surgery & Cancer), Mr Mathias Winkler (Imperial College NHS Trust) & Dr Ben Glocker (Imperial, Computing).
Professor Hector Keun (Imperial, Surgery & Cancer) , Professor Ed Tate & Dr Adrian Benito Mauricio (Imperial, Chemistry).
Dr Masahiro Ono (Imperial, Life Sciences) & Professor Kevin Harrington (ICR, Radiotherapy & Imaging)
Professor Molly Stevens (Imperial, Materials) & Professor Chris Bakal (ICR, Cancer Biology)
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Dr Emma Harris (ICR, Radiotherapy & Imaging) & Dr Peter Huthwaite (Imperial, Mechanical Engineering).
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Professor Gail Ter Haar (ICR, Radiotherapy & Imaging) & Dr James Choi (Imperial, Bioengineering)
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Dr Matthew Williams (Imperial, Surgery & Cancer) and Professor Francesca Toni (Imperial, Computing)
Professor Charlotte Bevan (Imperial Surgery & Cancer), Professor Joshua Edel (Imperial, Chemistry) & Dr Sylvain Ladame (Imperial, Bioengineering).
Professor Hector Keun (Imperial, Surgery & Cancer), Dr Diego Oyarzún & Professor Mauricio Barahona (Imperial, Mathematics)
Dr Doryen Bubeck (Imperial, Life Sciences) & Professor Ed Tate (Imperial, Chemistry)
Mr James Kinross and Professor Ara Darzi (Imperial, Surgery & Cancer) & Professor Zoltan Takats (Imperial, Metabolism, Digestion & Reproduction)
Professor Ed Tate (Imperial, Chemistry), Professor Eric Aboagye (Imperial, Surgery & Cancer) & Professor Charlotte Bevan (Imperial Surgery & Cancer).
Professor Ed Tate (Imperial, Chemistry)
Professor Michael Seckl, Dr Olivier Pardo & Dr Filippo Prischi (Imperial, Surgery and Cancer)