We offer training opportunities for clinical and non-clinical students. Below are all the projects that are or were supported by the Centre with a non-clinical or intercalated studentship or a clinical research fellowship (including studentships from the former Imperial Centre) 


 

 

2023

 

 

 

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

Lung cancer is the deadliest cancer worldwide and non-small cell lung cancer (NSCLC) accounts for 85% of cases. 80% of these are inoperable and 5-year survival rates are ~15%. We need new mechanisms to reduce the burden of this disease. Cell proliferation is driven by Cyclin/cyclindependent kinase (CDK) activity. High expression of CDK inhibitor p21Cip1/Waf1 correlates with a poor NSCLC prognosis. Our work suggests that high p21 expression allows NSCLC cells to enter quiescence - a reversible, non-proliferative state, which allows cancer cells to resist chemotherapy. We hypothesise that by preventing p21 binding to and inhibiting CDKs, we can prevent NSCLC cell quiescence and reduce chemotherapy resistance. We will develop first-inclass stabilised peptides that inhibit p21 binding to CDK (“p21 tides”). Our approach has the dual advantage of increasing fractional killing in the primary tumour and reducing the possibility of tumour relapse by eliminating a source of dormant tumour cells.

 

 

 

 

2022

 

 

 

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:

  1. We will characterise the biochemical and biophysical properties of patient lung metastases to identify how their ECM differs from healthy tissue.
  2. We will develop a novel migration-on-chip microfluidic platform capable of generating 3D ECM consisting components with defined concentration gradients, opposing gradients of multiple components, fiber alignment and defined matrix stiffness gradients. We will rely on the diffusion-dominated laminar flow regime inherent to microscale flows to accomplish this.
  3. We will investigate the influence of tumour matrix composition and biophysics on cell migration directionality and speed by recording the migration of tumour cells through hydrogels using time-lapse live-cell microscopy. These aims will rapidly accelerate our understanding of migration in metastasis and may allow us devise interventions that inhibit this process.

 

 

 

2021

 

 

 

Professor Zoltan Takats (Imperial, Metabolism, Digestion & Reproduction) & Dr Marco Bezzi (ICR, Molecular Pathology).

 

Abstract

We propose a project for the development of a novel barcoding strategy that has the potential to overcome many limitations of current technologies. Our system is based on the combinatorial arrangements of unique, transcribed DNA sequences that can be used to generate an RNA barcoding system. One of the major goals of this project is the generation and optimization of isotope-coupled probes for the detection of the RNA barcode by mass cytometry and imaging mass cytometry. Mass cytometry detection of the probes will allow simultaneous cancer cell tracing and phenotyping through the combination of isotope-coupled antibodies targeting specific subsets of proteins and post translational modifications

 

 

 

 

Dr Paul Huang (ICR, Molecular Pathology) & Dr Jun Ishihara (Imperial, Bioengineering)

 

Abstract

We hypothesise that this tumour-specific form of laminin presents a unique opportunity for targeted delivery of drugs and immunomodulatory cytokine payloads for cancer therapy. By employing matrisomal analysis of >250 soft tissue sarcomas, the Huang laboratory has shown that selected histological subtypes such as leiomyosarcomas display upregulated levels of laminin and laminin receptors. In this project, we will utilise sarcomas as a cancer model to engineer next generation anti-laminin Fab antibodies for targeted delivery of immunomodulatory agents for use in cancer immunotherapy.

 

 

 

Dr Andreas Wetscherek (ICR, Radiotherapy & Imaging) & Professor Wayne Luk (Imperial, Computing).

 

Abstract

This project will develop a novel approach to real-time adaptive MR-guided radiotherapy by accelerating MR imaging developed by the ICR applicant through dataflow computing techniques pioneered at Imperial. Uncertainty in the exact location of tumour and organs- at-risk leads to the requirement of fractionated delivery and treatment margins, which could prevent the delivery of curative radiation doses for example in the case of pancreatic cancer. We will make real-time adaptation in MR-guided radiotherapy possible by characterising motion of both tumour and organs-at-risk with low latency and high throughput. This will enable us to realise the potential of next-generation MR-guided radiotherapy to revolutionise cancer treatment by providing unprecedented certainty needed to deliver precision treatment with reduced margins. This will not only lead to increased treatment efficacy by improving local tumour control without increased toxicity, but also enable hypofractionation, leading to shorter treatments.

 

 

 

 

Professor Jorge Bernardino de la Serna (Imperial, National Heart & Lung Institute) & Professor Andrew Tutt (ICR, Breast Cancer Research)

 

Abstract

This proposal aims to understand how the SAC and EC controls chromosomal segregation and how this is impacted by HORMAD1 and drug exposure in model systems relevant to clinical context. In doing so, we aim to generate information that informs the identification of predictive, patient-stratification, biomarkers for microtubule-targeting chemotherapies and mitotic checkpoint kinase inhibitors (currently under investigation in Phase 2 clinical trials). To do this, we will utilise a convergence approach, combining the use of Patient Derived Organoids (PDO), a focus of the Convergence Centre, alongside the use of novel live cell super-resolved spatiotemporal quantitative imaging methods applied to EC, the SAC and chromosomal segregation in these patient derived models.

 

 

 

 

Dr Ali Yetisen (Imperial, Chemical Engineering) & Professor Louis Chesler (ICR, Clinical Studies)

 

Abstract

The overall goal of our work is to develop point-of-care testing to detect key oncogenic early warning signs of cancer development or relapse in children. No practical diagnostic technology exists at present for use in well-children. Recent pre-clinical advances in oncogene detection demonstrate the capability to assign clinical grade and predict outcome based on detailed knowledge of tumour genomics, but this data has not as yet been transitioned into practical point-of-care for use in a routine or outpatient setting. Hence, the ability to screen in particular for solid tumours (which normally requires invasive tissue-biopsy) within general or follow-up healthcare visits, will allow early-stage identification, enabling early, lower-intensity, and perhaps even curative differentiation approaches to be employed, with the long-term benefit of reducing mortality.

 

 

 

 

 Dr Sylvain Ladame (Imperial, Bioengineering) & Professor Sadaf Ghaem-Maghami (Imperial, Surgery & Cancer)

 

Abstract

We propose to deliver a new way to screen for endometrial cancers with a paper-based point-of-care blood test that improves on diagnostic sensitivity and specificity beyond the CA-125 blood test (CA-125 antigen being only produced by certain less common type of endometrial cancers) whilst being significantly less invasive than endometrial biopsies. There is currently no accurate serum based tumour marker available for the majority of endometrial cancers (endometroid adenocarcinomas).

 

 

 

 

 Dr Anguraj Sadanandam (ICR, Molecular Pathology) & Dr Jun Ishihara (Imperial, Bioengineering)

 

Abstract

In this proposal, our objective is to, in a personalized way, remodel immune “cold” (and prognostically poor) pancreatic tumours, specifically enriched for collagen-rich subtype-A, into immune “hot” tumours using a bioengineered CBD-bound cytokine or standard-of-care chemotherapy such that it specifically makes these tumours respond to CPI. This will be achieved/tested using two different approaches using in vivo, and co-culture (ex vivo using organoids and in vitro using 2D cell cultures) models by: Aim 1a-b: increasing the abundance of cytokines a) IL-12 or b) CCL4 (bound to CBD) intratumourally in these pancreatic tumours, followed by CPI therapy (anti-PDL1 with/without anti-CTLA4); and Aim 2: treating with CBD-conjugated gemcitabine (standard-of-care chemotherapy), followed by combined CPI. These two approaches are expected to enhance CD8+ cytotoxic T cells. As a comparison, we will use subtype C tumours that are intrinsically enriched for T cells (immune hot) and anticipated to respond to CPI. We believe that our proposal may provide a personalized way of selecting a subset of pancreatic tumours that will benefit most from CPI after switching from immune “cold” to “hot” phenotype.

 

 

 

 

Dr Periklis Pantazis and Dr Victoria Salem (Imperial, Bioengineering),  & Mr Christopher Peters (Imperial, Surgery & Cancer)

 

Abstract

In this project we will develop the potential of bioharmonophore-PS conjugates to significantly enhance the specificity and treatment field of PDT for oesophageal cancer. We will create novel bioharmonophore-PS conjugates targeted to oesophageal cancer subtypes, we will show proof of concept in a state-of-the art in vivo imaging platform. We will work with patient-derived tumour lines to further improve the specificity of our novel agent, with the potential for effective and accurate ‘personalised PDT’.

 

 

 

2020

 

 

 

Professor Pantelis Georgiou (Imperial, Electrical and Electronic Engineering) & Professor Chris Bakal (ICR, Cancer Biology)

 

Abstract

Despite recent advances in surgical procedures, improvements in radiotherapy, and the development of new drugs; the recurrence rate for many cancers remain high. For example, of patients with pancreatic ductal adenocarcinoma (PDAC) that are successfully treated, the range of recurrence can be as high as 80%1. As with any cancer, early detection of recurrence is key in an attempt to begin follow-up treatments as soon as possible. But such detection methods must be both cost and time effective, in order to limit post-treatment patient visits. Biosensors are a potential tool that may make real-time monitoring of cancer recurrence both feasible and highly cost-effective. These biosensors could alert both patients and physicians to changes in tissue that are indicative of relapse. We  propose a biosensing microchip(Bio-Chip) can  be  developed to monitor in  real-time  the acidification of the tumour microenvironment (TME) following resection/treatment as means to  detect  recurrence  in  real-time. In  this  PhD  project,  a  student  co-supervised  by  team  leaders Pantelis Georgiou (ICL) and Chris Bakal (ICR), and postdoctoral associate Nicholas Moser (ICL) will develop  and  characterize  these  biosensors.  This  work  will  combine  cutting-edge  electrical engineering and materials science (ICL), with advanced quantitative imaging, and cancer models (ICR). 

 

 

 

 

Professor Mengxing Tang (Imperial, Bioengineering), Dr Navita Somaiah (ICR, Radiotherapy & Imaging).

 

Abstract

Success of targeted radiotherapy (RT) is strongly related to oxygenation levels within tumour tissues. Poor oxygen status (hypoxia) is associated with resistance to RT, and is linked to the chaotic capillary architecture observed within tumours as they grow uncontrollably; such disordered angiogenesis is one of the key hallmarks of cancer. As RT technology has improved, highly conformal radiation delivery has become possible, and may allow increased healthy-tissue sparing and higher therapeutic ratios. However, in order to achieve maximum benefit from these technologies and novel radiosensitisers it is essential that accurate, non-invasive imaging biomarkers be developed that can (i) spatially map the biology of the tumour (including hypoxic status) in order to boost the dose to more aggressive regions, and (ii) quantify tumour response during treatment so that RT plans can be adapted appropriately.  Dynamic contrast-enhanced (DCE-), and diffusion-weighted (DW-) MRI provide non-invasive mapping of the properties of tumour vasculature and cellularity respectively.  Both techniques have shown considerable power as response biomarkers for a wide variety of tumour types and therapeutic interventions, and there is increasing hope that these techniques might provide potent biomarkers of response for RT. Although MRI provides excellent anatomical coverage within a clinically feasible time-frame, it still suffers from (i) a relatively low spatial resolution (order of millimetres), (ii) increasing safety concerns on the use of Gadolinium contrast agents used in DCE studies, and (iii) lack of validation of MR-derived biomarkers, which only act as surrogate measures of the underlying biology that occurs at much smaller length-scales. 

 

 

 

 

Professor Simon Robinson (ICR, Radiotherapy & Imaging) & Professor Molly Stevens (Imperial, Materials).

 

Abstract

"Extracellular Vehicles (EVs), a collective term that includes exosomes and macrovesicles, are small cell-derived vesicles that can be isolated from a wide range of bio fluids, such as plasma and urine (Raposo and Stoorvogel, 2013). Cancer cells typically produce higher number of EVs compared to their healthy counterparts (Azmi et al., 2013). EVs are thought to transfer bioactive molecules from cancer cells to various cells at local and distant sites, altering the microenvironment to enable tumour progression, invasion and metastasis (Raposo and Stoorvogel, 2013, Hood et al., 2011, Rak, 2010). EVs have been shown to contain complex populations of proteins, lipids, and nucleic acids (DNA, mRNA, microRNA), and can interact with cells either by direct receptor/ligand interactions or by transfer of luminal contents into the recipient cell cytosol (Tai et al., 2018). Certain tumour types, such as breast cancer, have a propensity to metastasize to specific sites (lymph nodes, bone, liver, lungs and brain) (Weigelt et al., 2005). It has been found that primary tumour-derived EVs are trophic to these sites specifically and that their presence ante cedes emergence of metastases, suggesting that they may prepare a pre-metastatic niche (Hoshino et al., 2015). 
An improved understanding of the nature and consequences of this tropism would shed light on the significance of this process in metastatic progression and could ultimately provide a new therapeutic strategy. However, the physiological roles of EVs are notoriously challenging to study in vivo. This is in no small part due to difficulties in their tracking and visualisation, particularly in animal models in vivo (Takahashi et al., 2013, Lai et al., 2014). Detection of EVs in tissues is typically accomplished histologically. Here we propose to develop Magnetic Resonance Imaging (MRI)-labelled EVs to enable in vivo tracking of EVs, enabling us to study the tropism of EVs derived from metastatic and non-metastatic models of breast cancer. "

 

 

 

 

Professor Ed Tate (Imperial, Chemistry) & Professor Louis Chesler (ICR, Clinical Studies).

 

Abstract

MYC dysregulation is an important driver of Paediatric Cancer: Aberrant expression, mutation or amplification of the key transcription factor and oncogene MYC, and its neural homologue MYCN, defines 20% of poor-outcome adult and childhood cancers, making MYC an important, but undrugged cancer target. Aberrant MYC activity is a known driver of poor clinical outcome and resistance to chemotherapy in significant subsets of children with brain and solid tumours (glioblastoma, medulloblastoma, rhabdomyosarcoma and neuroblastoma). These tumours remain a treatment challenge and collectively account for a majority of annual deaths from cancer in children. Paediatric cancer is significantly under-resourced and the new CRUK Kids & Teens strategy makes this a highest-priority area for targeted support, with the aim of linking leading paediatric cancer scientists with investigators expert in genome-scale technologies, proteomics, developmental modelling and chemistry.

 

 

 

 

Professor Chris Lord (ICR, Breast Cancer Research) & Professor Alex Porter (Imperial, Materials).

 

Abstract

We aim to develop a novel, fully degradable, low-cost targeted nanoparticle platform that delivers  highly  controlled  doses  of  selected  antiproliferative  drugs  to triple  negative breast cancer (TNBC) cells with significantly higher efficacy than previously possible and is can be imaged at greater penetration depths than previously possible.  This strategy may in future, treat more aggressive breast cancers, reduce dosage and drug resistance, and avoid unwanted systemic side effects. TNBC,  a  type  of  cancer  with  high  expression  levels  of  MPS1(~20%),  accounts  for approximately 15% of breast cancers and, once metastatic, is incurable. We have focused  on  TNBC  as  our  primary  indication  for  the  following  reasons:  a)  current treatment  options  in  TNBC  are  limited  and  ineffective  (through  early  relapse);  b)  TNBC tumours  are  characterised  by  a  high  mitotic  index,  a  hallmark  of  chromosomal  instability (CIN)  and  by an  overexpression of  MPS1  that has  been  associated  with poor prognosis; and c) we identified a clear synergy in cell-based and in vivo animal model studies using diverse MPS1 inhibitors in combination with clinically relevant concentrations of paclitaxel, a  standard-of-care  in  TNBC. We  have selected  a pre-clinical  development  candidate, CCT289346 (currently BOS172722), from the multiple chemical series of MPS1 inhibitors developed  with  high  potency,  selectivity  and  favourable in  vitro profiles.  BOS172722 treatment induces significant sensitisation to death, particularly to high proliferated TNBC cell lines, with compromised spindle assembly checkpoint activity. In preclinical animal models, increased levels of the compound show tumour regression, but poor drug tolerance.   

 

 

 

 

Dr Elizabeth Want and Professor Tim Ebbels (Imperial, Metabolism, Digestion and Reproduction) & Dr Nelofer Syed  (Imperial, Brain Sciences).

 

Abstract

Metabolic disturbances is one of the hallmarks of cancer and has been observed in GBM. However, this is an under-appreciated therapeutic target. Arginine is a conditionally-essential amino acid needed for cell growth, T-cell and immune system function and angiogenesis. The effects of arginine are mediated by metabolites such as nitric oxide, polyamines and other amino acids, which are involved in various biochemical pathways that can subsequently contribute to tumorigenesis. We hypothesise that: a) ADI-PEG20 will alter global metabolism in both immune and ASS+ve GBM cells. b) ADI-PEG20 will shift the tumour microenvironment and immune response to an anti-tumour, immune-active state in ASS+ve tumours. Based on our findings, this is the most likely explanation for the response seen. 

 

 

 

 

Professor Iain McNeish (Imperial, Surgery & Cancer), Professor Paul French (Imperial, Physics) & Professor Chris Dunsby (Imperial, Physics)

 

Abstract

Ovarian high grade serous carcinoma (HGSC), the commonest type of ovarian cancer, is characterised by near-universal TP53 mutation and extreme genomic instability. Mutations in BRCA1/2 are seen in c.20%, but classic driver oncogenic mutations are rare. All women with HGSC receive platinum-based chemotherapy, with high initial response rates. However, nearly all patients relapse and develop fatal platinum resistance. The widespread introduction of PARP inhibitor therapy has improved survival, especially for those with BRCA1/2 mutations. However, cross resistance between platinum chemotherapy and PARP inhibition is striking, and true cure rates in HGSC remain under 20%. Moreover, largescale genomic sequencing efforts have failed to reveal broad mechanistic understanding of acquired platinum and PARP inhibitor resistance. We hypothesise that platinum and PARP inhibitor therapies drive epigenetic change in HGSC, which alters expression of genes that drive critical resistance mechanisms. Super-resolution microscopy can image these chromatin changes across the genome, as well as at specific loci that are crucial for DNA damage responses.

 

 

 

 

Mr Srdjan Sasso (Imperial, Department of Metabolism, Digestion and Reproduction) & Professor Molly Stevens (Imperial, Materials).

 

Abstract

The ultimate intention of this project is to establish an effective and translational collaboration between two highly published research groups, and in doing so develop an effective POC diagnostic tool specific to both epithelial and non-epithelial OC. The primary deliverable of the project will be a rapid, simple, and cheap POC test capable of detecting both primary and recurrent OC in biological samples with a high degree of sensitivity and specificity. In addition to addressing an area of unmet clinical need within the field of OC, we anticipate that the technology developed could be applied to a wide-range of cancers for which fast detection vastly improves patient outcomes. We also anticipate a highly productive collaboration between our teams, thus allowing us to use these preliminary results to apply for more significant funding to further develop the platform.

 

 

 

2019

 

 

 

Dr Gabriela Kramer-Marek (ICR, Radiotherapy & Imaging) & Dr Philip Miller (Imperial, Chemistry) 

 

Abstract

The trifluoromethyl group (-CF3) is a key medicinal chemistry bioisostere used to alter the bioavailability, metabolic stability, affinity and lipophilicity of novel pharmaceuticals. It is found in a number of notable drug molecules, including fluoxetine, celecoxib and efavirenz. More recently, the CF3group has also become a desirable group to radiolabel with fluorine-18 for the development of Positron Emission Tomography (PET) tracers. Whilst there have been several promising reports of PET tracers containing [18F]CF3groups, their radio-synthesis is challenging and suffers limitations of low radiochemical yields (RCY) and low molar activities (MA). The generation of [18F]CF3groups via a -CF2carbene intermediate, is one such route, however, low MA’s as result of 18F/19F exchange limited its suitability for further biological evaluation. Another method based on a manganese catalysed radical fluorination method was limited by its restricted substrate scope. Recently, the reaction of [18F]fluoroform ([18F]CHF3) has been realised as route for the ‘direct’ or ‘indirect’ incorporation of [18F]CF3groups into potential PET tracers with improved molar activities and a much broader substrate scope that is necessary for further biological studies.[4] [18F]Fluoroform, however, is difficult to generate, process and react owing to its volatility (boiling point -82°C), chemical inertness and radioactive nature. Such volatile and inert organic radioactive compounds are therefore challenging to trap and react in a safe, efficient and reproducible way. As a result, current state-of-the-art radiochemistry with [18F]fluoroform has unacceptably low RCY’s (of < 1%) which means it cannot be used for downstream biological evaluation or PET imaging. This proposal  aims  to  develop  the  technology  and  labelling  chemistry to facilitate  the trapping  and  direct  reaction  of  [18F]fluoroform,  and  therefore to enable use  of this important reagent for [18F]CF3PET radiotracer development.

 

 

 

 

Professor Chris Bakal (ICR, Cancer Biology) & Dr Sam Au (Imperial, Bioengineering)

 

Abstract

It is estimated that up to four million cancer cells per gram of tumour tissue enter the bloodstream per day in animal models, yet very few of these eventually establish metastases. We do not understand the factors that select the small minority of these cells to succeed. A number of studies have demonstrated that biomechanical forces exerted on nuclei cause significant nuclear deformation, rupture, DNA damage, and potentially mutagenic events that lead to metastasis. Thus, disseminated tumour cells may gain metastatic competency as their nuclei are deformed during transit through narrow blood vessels. In support of this idea, nuclear deformation caused by chromosome missegregation can drive epithelial-mesenchymal transition (EMT) and metastasis through upregulation of cGAS/STING-NFkB signalling axis. Hypothesis: Forces exerted on non small cell lung cancer (NSCLC) circulating tumour cells (CTCs) during transit through the vasculature rupture nuclei; resulting in the activation of cGAS/STING-NFkB signalling axis which promotes EMT and metastasis . This presents a therapeutic opportunity for suppressing metastasis by blocking the activity of this axis. To explore this hypothesis, a student will combine both cutting-edge bioengineering at ICL and quantitative phenotyping approaches at ICR. 

 

 

 

 

Professor Uwe Oelfke (ICR, Radiotherapy & Imaging) & Professor Wayne Luk (Imperial, Computing)

 

Abstract

Advances in real-time adaptive radiotherapy promise improved patient outcome, by adapting the delivered radiation to the actual patient anatomy during treatment. While Monte Carlo (MC) simulation methods have shown to provide superior accuracy in calculating physical dose distributions for radiotherapy, the clinical application of MC methods is limited by long simulation times required to achieve a level with sufficient statistical precision. Analytical dose calculation methods, although capable of running faster, are liable to introducing physical approximation compromising the accuracy particularly for heterogeneous tissues such as lung tissues. In such cases, Monte Carlo simulations that are known to deliver reliable dose distributions would be particularly warranted. The aim of this project is to develop a real-time Monte Carlo simulation system based on dataflow computing engines, which can support continuous real-time adaptive radiotherapy. The research will pioneer a new generation of radiotherapy systems with the potential of revolutionising cancer treatment by their capability of accurately adapting to patient anatomy and to patient conditions in real time, while allowing them to be exploited by medical professionals who may not be experts in high-performance computing or reconfigurable hardware. 

 

 

 

 

 

Professor Dow-Mu Koh (Royal Marsden Hospital) & Dr Matthew Grech-Sollars (Imperial, Surgery & Cancer)

 

Abstract

Brain tumours are one of the four cancers which are hardest to treat and for which there is a strong need for further research (Cancer Research UK). In particular, clinical imaging of brain tumours is limited by a lack of quantitative imaging techniques which can study the physical properties of the underlying tissue, and hence provide in-vivo biomarkers of changes within the tumour. Magnetic Resonance Fingerprinting (MRF) is a novel rapid imaging technique which aims to assess the physical properties of different tissues using one short MRI sequence (Ma et al., 2013). It provides quantitative measures of T1 and T2 relaxivity values (Coppo et al., 2016). MRF was however developed as a generic tool and limited literature exists of its application to brain tumours (Badve, Yu & Dastmalchian, 2017). There is a need to develop this tool specifically for cancer imaging, taking into consideration the clinical challenges faced by Radiologists. MRF could be tailored to produce quantitative values representing the biology specific to the tumour imaged – such as blood flow and microstructure. Within this PhD we aim to develop new MRI brain tumour fingerprinting (BTF) tools. It is critical that the development of such sequences is carried out using input from both a strong physics team, and a strong clinical radiology team. The student joining our team through this PhD will develop the physics for Brain Tumour Fingerprinting  to  answer  challenging  clinical  questions  faced  by  Neuroradiologists,  in  particular,  the  early  determination  of  tumour  transformation  in  patients  with  lower  grade  tumours and tumour response to treatment.

 

 

 

 

Dr Masahiro Ono (Imperial, Life Sciences) & Professor Alan Melcher (ICR, Radiotherapy & Imaging)

 

Abstract

Recent breakthroughs in immunotherapy development have established that anti-tumour immunity is a major exploitable mechanism to fight cancer. Notably, immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 antibodies abrogate negative regulatory mechanisms in the T cell system and enhance anti-tumour immune response, and have been clinically approved for various cancer patients including melanoma, renal cell carcinoma, ovarian cancer, and Hodgkin’s disease. Our recent investigation using a single cell technology identified PD-1 and regulatory T cells (Treg) as two major suppressive mechanisms in tumour-infiltrating T cells from melanoma patients (malignant skin cancer). PD-1 is a surface protein that has a role in suppressing T cell receptor (TCR) signalling and thereby inhibiting T cell activation. PD-1 is highly expressed in over-activated T cells (often called ‘exhausted T cells’), and inhibits their reactions to antigen. Thus the blocking of PD-1 and its ligand PD-L1/L2 can release the activity of tumour-specific T cells. Treg specifically express the transcription factor Foxp3 and suppress anti-cancer immunity, and are a promising target for cancer immunotherapy. Importantly, the immune check point inhibitor anti-CTLA4 antibody not only blocks costimulatory signalling (precisely, CD28 signalling), but also depletes regulatory T cells (Treg). However,anti-CTLA-4 increases the T cell responsiveness to not only cancer antigens but also self-antigens, inducing autoimmune reactions. The proposed project aims to increase the precision of cancer immunotherapy by improving the understanding of T cell regulation in animal models and clinical samples using a multidisciplinary approach.

 

 

 

 

Professor Jyoti Choudhary (ICR, Cancer Biology) & Dr Tolga Bozkurt (Imperial, Life Sciences)

 

Abstract

High-grade serous carcinoma (HGSC) of ovaries is a high-unmet-need disease in women worldwide. Tumours are characterised by frequent mutations in TP53 and BRCA1/2 and high prevalence of copy number alterations (CNAs). The high degree of genomic instability observed in HGSC, and exploited therapeutically by the recently developed PARP inhibitors, translates into a perturbed and varied proteome, with several groups developing proteome-based signatures to predict the disease outcome. Notwithstanding the link between genomic instability and the global proteome changes, it remains unclear how this highly perturbed proteome is stabilised in HGSC cells. The intimate interplay between the mRNA translation, chaperone-mediated protein folding and protein degradation machineries determines the proteome stability. Two major cellular pathways are responsible for protein degradation: the ubiquitin-proteasome system (UPS) and the lysosome-autophagy pathway (autophagy). Whereas the UPS relies on a multi-subunit barrel-shaped proteolytic machine, which degrades single polypeptide chains, autophagy is a membrane-based system  that  sequesters  and  removes  large  protein  complexes  and  protein  aggregates.  By  manipulating  the  proteasomal  and  the  autophagic  activity  in  HGSC  cells,  we  will  address  the  question: what relative contribution does the UPS vs. autophagy each have in degrading/stabilising the proteome in HGSC? By revealing the nodes/targets in the protein networks and understanding mechanisms of the proteome stabilisation via the UPS/autophagy, we will be able to propose new therapeutic strategies to tackle this deadly disease. 

 

 

 

 

2018

 

 

 

Professor Molly Stevens (Imperial, Materials) & Professor Chris Bakal (ICR, Cancer Biology)

 

Abstract

Only recently have cellular-scale 3D structures been available for high resolution analyses of cell behaviour, particularly in regard to nuclear morphology. Recently, Prof Molly Stevens’ programme co-developed a nanotechnological platform capable of safely and rapidly delivering sensitive biocargoes to cells and tissues. Silicon “nanoneedles” possess dimensions that enable their penetration to the cytosol and nucleus within seconds without perturbing cellular function. Porous Si nanoneedles have several advantages over standard techniques used in molecular biological research and regenerative medicine, such as the gene gun and electroporation. The exemplar demonstrations of this powerful nanotechnology were published in three high impact publications in Nature Materials (featured on the Front Cover of that issue). However, porous nanoneedles are rapidly degraded by cells. Within this ICR CRCE Studentship we will exploit new non-degradable nanoneedles recently developed in the Stevens lab, which show excellent cytocompatibility and allow for longer term studies of cellular interactions with nanoscale structures. Intense research efforts are needed to characterise interactions at the cell-material interface to understand the effects of nano-scale structures on cell and nuclear architecture and gene expression.

 

 

 

 

Professor Ed Tate (Imperial, Chemistry) & Professor Julian Downward (ICR)

 

Abstract

S- acylation  of  cysteine  residues  with  palmitoyl-CoA  is  a  reversible  and  widespread post-translational modification (PTM) regulating   processes   including   trafficking,   protein-protein/membrane   interactions,   membrane  architecture  and  protein domain  stabilisation (Figs.  1-2)1-3.  24  mammalian  PATs have  been  identified  to  date, termed  zDHHCs4,  5  after  four  amino  acids  common  to  the  catalytic  site.  zDHHC  isoform  dysregulation  has  been  linked  to  diseases  including  cancer;  but current  technologies  to  investigate    PAT activity and  substrates  on  a  proteome-wide  scale  in  cancer  models are  limited  in  scope3.   The  Downward  group  discovered  that  zDHHC20 knockdown  impedes  pancreatic  ductal  adenocarcinoma  cell  (PDAC)  metastasis and tumour development even after reaching target sites in the lungs. This new DHHC-dependent phenotype  presents  an  exciting  opportunity  to  understand the  role  of DHHC PAT activity in this very aggressive cancer type,  with the aim  of  validating  zDHHC20 and/or  its  substrates  as  first  in  class  drug targets in PDAC and potentially other KRas-driven cancers. 

 

 

 

 

 

Dr Emma Harris (ICR, Radiotherapy & Imaging) & Dr Peter Huthwaite  (Imperial, Mechanical Engineering).

 

Abstract

This proposal develops and uses powerful numerical modeling tools, originally developed for Non-Destructive Evaluation of advancedindustrial materials, for the development of a clinical ultrasound imaging technique for the determination of early tumour response to radiotherapy. We will develop meshed patient-specific models from CT and MR images to input into Pogo to derive attenuation and diffraction corrections, which can be  applied  to  UBS  data. Initially,  the  current  capabilities  of  Pogo  will  be assessed to evaluate the performance for this application; for example, at present,  Pogo  does  not  accurately  capture  propagation  through  viscous media,  so  strategies  to  address  that  with  the  current  package  will  be developed  along  with  testing  approaches  which  could  be  implemented  in the full package to better suit medical applications. This will benefit from a parallel  PhD  research  project,  soon  to commence  at  IC,  and  funded separately, which will focus on the development of the FE methodology for waves in coupled fluid-solid media. 

 

 

 

 

Professor Gail Ter Haar (ICR, Radiotherapy & Imaging) & Dr James Choi (Imperial, Bioengineering)

 

Abstract

Children diagnosed with diffuse intrinsic pontine gliomas (DIPGs) have an 18-month survival rate of only 10%. Over time, nearly every one of these children will die from their cancer. This devastating prognosis comes from the diffuse spread through healthy tissue, reducing the impact of localised surgery and radiotherapy. In such a diffuse cancer, chemotherapy would normally be the better treatment option; but DIPG spreads behind an intact blood-brain barrier (BBB), thus limiting drug efficacy. We have shown that short pulses of ultrasound can produce controlled, temporary changes to BBB permeability. This project will develop and test the first short-pulse drug delivery method for DIPG. By allowing drugs to cross the BBB, it has the potential to revive previously abandoned therapies that showed great promise for the treatment of DIPG. 

 

 

 

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