Developing research at the convergence of the life, clinical, engineering and physical sciences is the key focus of the CRUK Convergence Science Centre. The Centre supports emerging ideas with its own seed funding scheme: the Development Fund. Below are listed all projects that are or were supported by the Centre (including by the former Imperial Centre).


 

 

2023

 

 

 

Professor Luca Magnani (Imperial, Surgery & Cancer) & Dr Marco Di Antonio (Imperial, Chemistry)


Abstract

It is now widely accepted that cancer evolution and adaptation emerge via parallel Darwinian genetic and transcriptional plasticity. Cancer dormancy and drug-persistor cells represent two examples of the impact of plasticity on treatment outcome. Transcriptional plasticity involves both time and spatial dimensions: for example, dormancy is heritably but transiently acquired by breast cancer cells either spontaneously, in response to therapy or possibly via interaction with normal cells (niche). Current transcriptional tools are inadequate to explore plasticity and its contribution to cancer, as they lack single cell resolution, spatio-temporal control, or heritable transmission. Our aim is to develop innovative technologies by combining photochemistry and spatio-temporal epigenetic changes. We will generate photo-inducible modifiers (OPTO-SNAP) to drive heritable transcriptional changes at individual genes via epigenetic manipulation of gene promoters. By exploiting validated gene libraries, OPTO-SNAP will also be upgraded toward genome wide epigenetic screens. 

 

 

 

 

Dr Ben O'Leary  and Dr Antonio Rullan (ICR & Royal Marsden Hospital, Breast Cancer Research and Radiotherapy & Imaging), & Professor Zoltan Takats, Dr Stefania Maneta-Stavrakaki  and Mr James Higginson (Imperial, Metabolism, Digestion & Reproduction).

 

Abstract

Using a convergence science approach and leveraging an actively recruiting clinical study (ORIGINS), we will develop new patient derived organoid co-culture models and use a novel mass spectrometric technologies to discover candidate biomarkers to select patients for personalised cancer treatment of solid tumours, initially using head and neck squamous cell carcinoma (HNSCC).

 

Unmet clinical need; the prognosis and survival rates for patients with recurrent or metastatic HNSCC are poor, with 5 year survival around 10%. Chemotherapy, including cisplatin or carboplatin, taxanes and 5-Fluorouracil, constitutes the backbone for the treatment of advanced HNSCC, either alone or in combination with radiotherapy or immunotherapy. Drug resistance, both intrinsic and acquired, is a common occurrence in patients with HNSCC, and constitutes one of the most significant challenges in this setting. Despite the wide use of these drugs, no validated biomarkers exist to predict response to treatment. 

Patient-derived organoids represent an excellent platform to study drug resistance, especially if they include elements of the tumour microenvironment (TME) such as CAFs, which influence patients’ response to treatment. The Targeted Therapy Team at ICR is currently generating and characterising organoids from patients, for whom prospective clinical data will be available (ORIGINS CCR5396, CI Ben O’Leary).

Metabolomics and mass spectrometry in cancer research; Metabolomics, especially using mass spectrometry, is an emerging tool for the investigation of underlying mechanisms in cancer. Prof. Takats’ group’s main research focus is the development of novel mass spectrometric techniques, such as Laser Desorption Rapid Evaporative Ionisation Mass Spectrometry (LD-REIMS), which allows high-throughput, real-time analysis of the dynamic cellular metabolism of living cells and organoids. Additionally, mass  spectrometry imaging (MSI) using the same platform can be used to visualise – on a single cell level – the distribution of metabolites in the different cell types and components of the tumour and the TME and reveal intercellular interactions.

 

 

 

 

Dr Burak Temelkuran (Imperial, Metabolism, Digestion & Reproduction), Dr Anguraj Sadanandam (ICR, Molecular Pathology), Dr Salzitsa Anastasova (Imperial, Hamlyn Centre) & Mr Mikael H Sodergren (Imperial, Surgery & Cancer).

 

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a poor prognosis. The Sadanandam lab has significant expertise in defining heterogeneity (including metabolism) in PDA using human samples and preclinical mouse models. PDA cells surviving nutrient and oxygen deficiencies exhibit metabolic adaptations that increase their scavenging and catabolic capabilities. Using a novel Phenotype Microarray experiment (Biolog), we found that exogenous uridine supports PDA energy metabolic homeostasis and growth during glucose deprivation (Sadanandam et al., Nature, in revision). This study further shows that uridine catabolism depends on KRAS/MEK signalling, which is the primary mechanism in 90% of PDAs. Nevertheless, chemotherapy is the current standard-of-care in PDA that potentially alters this energy metabolism. Hence, uridine-based monitoring of therapeutic responses may improve the clinical success of treating PDA. In this proposal, we will develop and apply a miniaturised fibre-based micro-probe using our patented technology to monitor response to gemicitine or KRAS inhibitor ex vivo (organoids/tumouroids) and in vivo (in clinical trial from Mirati Therapeutics; in collaboration with them). For the first time, we will sense uridine and glucose simultaneously in this technology. We will also monitor the oxygenation and acidic levels to investigate their potential be monitor the immunotherapy response. This work directly aligns with the CSCs interventional science strategic priority area. A convergent science approach, leveraging the broad expertise of functional fibres, chemistry, cancer biology and medicine, is essential for this work to be carried out.

 

 

 

2021

 

 

 

Dr Sam Au (Imperial, Bioengineering), Dr Paul Huang (ICR, Molecular Pathology), Dr Benjamin Schuman (Imperial, Chemistry), Dr Amanda Swain (ICR, Cancer Biology) & Dr Marco Gerlinger (Royal Marsden Hospital).

 

Abstract

Cancer organoids are a model of choice to evaluate basic tumour biology and in applications such as drug screening and development. However, their adoption and utility has been limited by a) poor derivation rates for many tumour types and b) added complexity to maintain and study organoid cultures. This project aims to capitalise on the unique strengths and resources of the Convergence Science Centre to address both roadblocks through the establishment of two distinct microfluidic platforms for optimising both the derivation and culture of organoids.

 

 

 

 

Dr Paula Cunnea (Imperial, Surgery & Cancer), Professor Manuel Salto-Tellez (ICR, Molecular Pathology), Professor Christina Fotopoulou (Imperial, Surgery & Cancer), Dr Mark Friddin (Imperial, DSDE), Dr Ali Mohammed (Imperial, DSDE), & Dr Connor Myant (Imperial, DSDE).

 

Abstract

The primary aim of this 1-year proof-of-concept study is to optimise propagation and improve derivation rates of patient derived organoids (PDOs) by developing a system that is capable of 3D printing ovarian cancer-specific extracellular matrices (ECM). We plan to leverage this technology to develop a clinically applicable drug screening platform and pipeline for high grade serous ovarian cancer (HGSOC) PDO treatment to test standard-of-care chemotherapy and targeted therapies. Key tumour matrix proteins will be identified to design a HGSOC-specific ECM, for subsequent assembly using microfluidic chips and printing in 3D. This rapid and versatile biomanufacturing technique will be optimised to ensure high cell viability and facile integration of the multicomponent system for this study. A series of hydrogels will be customised and rigorously tested to ensure full compatibility with the ECM and HGSOC-PDOs. A further step will be the development of tumour-site specific ECMs for culturing of disseminated HGSOC organoids, 2-3 tumour sites (ovary, diaphragm and spleen) will be initially assessed in the first year.

 

 

 

Professor Nicola Valeri (ICR, Molecular Pathology), Professor Luca Magnani (Imperial, Surgery & Cancer), Professor Molly Stevens (Imperial, Materials), Professor George Hanna (Imperial, Surgery & Cancer), Dr Farah Rehman (Imperial, ICHT).

 

Abstract

Current organoids protocols and media have been optimized for colorectal cancer organoids where exogenous Noggin, B27 and EGF support the growth and the proliferation of the culture and warrant a success rate of approximately 70% in both primary and metastatic cancers (Hedayat & Valeri; Vlachogiannis et al).  Similar protocols have been adapted to other diseases and conditions with minor modifications; however, the success rate in other cancer settings such as hormone-dependent breast cancer and esophageal cancers remains very low with a take up rate below 30-40% (Schutgens & Clevers).  Cancer-associated fibroblasts (CAFs) play a critical role in the evolution of esophageal premalignant conditions, cancer initiation, progression, metastasis and response to neo-adjuvant chemotherapy (Lin et al.).  Similarly, CAF contributes to several aspects of hormone dependent breast cancer biology, where activated CAF support estrogen receptor positive cancer cells growth and contribute to therapy resistance (Chen & Song).  Additionally, cellular crosstalk is an essential component in mammary physiology considering the complex interplay among epithelial sub-populations occurring mainly via endocrine and paracrine signaling (Chen & Song).  Taken together these observations support the notion that CAFs might play an important role in promoting the cancer niche ecosystem ex vivo, supporting stimulatory growth factors in light of a crosstalk among cancer cells, CAFs and other components of the tumor microenvironment.  Given the pivotal contribution of the stroma in breast and gastro-esophageal development, neoplastic transformation and response to treatment, we aim to improve the success rate of difficult-to-grow hormone dependent breast and esophageal organoids incorporating and characterizing tissue microenvironment in organoid co-culture conditions. 

 

 

 

 

Professor Nicola Valeri (ICR, Molecular Pathology) & Dr Sam Au (Imperial, Bioengineering),

 

Abstract

Here we aim to study the molecular dynamics and the biology behind tumours’ ability to shed mutant DNA fragments in the circulation using microfluidic models of vascularised tumour organoids. We will integrate molecular data gathered on colon cancer metastases from ctDNA positive and ctDNA negative cases with results on ctDNA fragmentation obtained from patients and pre-clinical models to characterise origins and kinetic of ctDNA. We envision that our project will generate a framework to understand and model ctDNA shedding in colon cancer. Given the relatively short duration of the project, as a proof of principle, we will build our platform using liver metastatic deposits and matched PDOs from patients whose ctDNA status is known (Khan et al. Gut 2017; Khan et al Cancer Discovery 2018). These preliminary data will be used to develop a multidisciplinary application aiming to study the mechanisms of DNA shedding in primary colon cancer patients with minimal residual disease (MRD). We are confident that our project will result in improved detection and treatment of early(er) cancers. 

 

 

 

 

Professor Paul French (Imperial, Physics), Professor Iain McNeish (Imperial, Surgery & Cancer) & Dr Marco Di Antonio (Imperial, Chemistry)

 

Abstract

To develop a cost-effective open-source instrument for simultaneous multiplexed immunofluorescence readouts from standard clinical histological sections. This will entail developing a low-cost open-source hyperspectral immunofluorescence microscope and a workflow utilising only clinically approved murine antibodies to label multiple (up to 6) target proteins in tissue sections with different fluorophores using tyramide signal amplification (TSA). • To modify the TSA workflow by combining it with click chemistry to enable the use of arbitrary selection of fluorescent dyes, reducing the cost of reagents and increasing sensitivity. • To explore clinical application to the histopathology of ovarian high-grade serous carcinoma (HGSC) biopsies, as required to guide neoadjuvant (primary) chemotherapy, to reduce the time and the amount of tissue required for diagnosis. • To clinical explore application to rapidly readout minimal panels of specific antibodies to enable diagnosis of B-cell lymphoma, within context of a collaboration with Kikkeri Naresh and IIT Guwahati in India.

 

 

 

 

Dr Florence Raynaud and Professor Udai Banerji (ICR, Cancer Therapeutics) & Professor Ed Tate (Imperial, Chemistry)

 

Abstract

We propose a unique opportunity to develop the first chemical biology probes targeting the oncogenic Hedgehog (Hh) pathway in vivo by inhibiting hedgehog acyltransferase (HHAT) (Figure 1A). Our team will deliver the first essential steps towards a first-in-class in vivo active HHAT inhibitor, for the first time opening the door to proof-of-concept studies in animal models of cancer, and new tools to investigate Hh signalling. This aim will be delivered through the following objectives, supported by teams at Imperial and the ICR: O1: undertake initial in vitro PK analysis and metabolite identification for each hit series to identify optimisations necessary for in vivo studies (ICR) and confirm hit cellular activity against HHAT (Imperial). O2: Complete synthesis of novel leads to de-risk any metabolic liabilities (Imperial), and complete initial in vivo PK analysis of at lead probes (ICR). O3: Confirm in vitro and in vivo PK properties for improved probes (ICR).

 

 

 

 

Professor Alan Melcher (ICR, Radiotherapy & Imaging), Dr Jun Ishihara (Imperial, Bioengineering) & Professor Iain McNeish (Imperial, Surgery & Cancer)

 

Abstract

We will use unique molecular engineering approaches for an oncolytic adenovirus type-5 (Ad5) bearing the collagen binding domain (CBD) for tumour targeting. CBD binds to the tumour tissue vasculature, enabling tumour-specific delivery of drugs after intravenous injection. We aim to recruit immune cells into the tumour microenvironment (TME) to overcome unresponsiveness to checkpoint inhibitor therapy and increase the potency of the oncolytic virus (OV) therapy. We will make two types of OVs: (i) OVs expressing the CBD on their surfaces, which leads to efficient accumulation of the OVs in the TME via intravenous injection. (ii) OVs expressing CBD-IL-12 to achieve tumour-localised IL-12 delivery.  These novel therapeutics will synergize with checkpoint inhibitors thus improving the therapeutic outcomes of difficult-to-cure cancer patients.

 

 

 

 

Dr Burak Temelkuran and Mr James Higginson (Imperial, Metabolism, Digestion & Reproduction), Dr Robbie Murray (Imperial, Physics)

 

Abstract

In this work, we will demonstrate an ultra-precise, dual wavelength (colour), fibre-delivered surgical laser for simultaneous tumour resection and haemostasis. Currently, tumour removal tools either lack precision (e.g. diathermic/harmonic scalpels), or present poor haemostasis (CO2 lasers). Clinically, both issues can be very problematic - a lack of precision may result in functional tissue removal or damage to critical structures, and excessive bleeding increases the operative time and the risk of complications. This is an exciting new collaboration between two new lecturers (Temelkuran/Murray) and a clinical doctoral fellow (Higginson), fusing expertise spanning physics, fibre robotics and head and neck (H&N) surgery, to prototype an ultra-precise surgical tool for concurrent tissue removal and haemostasis. Our objectives are: O1 - Development of a compact ultrafast picosecond mid-infrared surgical laser.O2 - Multi-material polymeric delivery fibre manufacture for precision light delivery.O3 - Precision tissue removal and haemostasis studies with biological tissue.

 

 

 

 

Dr Rachael Barry (Imperial, Metabolism, Digestion and Reproduction) & Professor Ed Tate (Imperial, Chemistry)

 

Abstract

Over 16,000 people in the UK died of colon cancer in 2017 (CRUK), and prevalence is rising. Early  diagnosis and treatment are key to reducing these numbers. There is an urgent need to identify  disease drivers. Proteins that compromise colon barrier integrity are ideal candidates as drug  targets and early markers of disease. The colon is a monolayer of epithelial cells coated with mucus, which is a physical barrier between  immune cells and the microbiota in the lumen. Disruption of this barrier results in hyperactive  inflammatory response to the microbiota. If not repaired, the cycle of tissue damage and  inflammation supports carcinogenesis. Little is known about what compromises barrier integrity. Hydrolytic enzymes (hydrolases) cleave target substrates and are required for intestinal  homeostasis. Preliminary data demonstrates that faecal samples from mice or humans with colitis  have an increase in hydrolase activities and induce barrier dysfunction (Figure 1). We hypothesise  that these hydrolases cause barrier dysfunction and contribute to colon carcinogenesis. To test this hypothesis in a human-relevant model with a mucosal and epithelial barrier our team is  taking a convergence approach by combining medicine (colon cancer-derived organoids; Marco Gerlinger/MG (ICR collaborator) and Rachael Barry/RB), with bioengineering (Emulate), cell biology  (barrier function; RB) and chemistry (inhibitors; Ed Tate/ET). We will interrogate patient samples (faeces and tissue) to understand the role of hydrolases on  colonic barrier integrity during carcinogenesis. This will uncover potential drivers of disease which  can be explored as biomarkers or inhibited to exploit colon cancer’s vulnerability to an intact barrier.

 

 

 

2020

 

 

 

Professor Rosalind Eeles and Dr Zsofia Kote-Jarai (ICR, Genetics & Epidemiology), Dr John Goertz & Professor Molly Stevens (Imperial, Materials).

 

Abstract

We aim to detect mutant DNA in plasma for early detection of prostate cancer in higher risk mento target whom to image using MRI and biopsy in the futureObjectives to achieve the aim:We will undertake panel somatic gene sequencing of prostate biopsies from men at high genetic risk of prostate cancer who have taken part in a targeted screening study (The PROFILE study) at The Institute of Cancer Research and Royal Marsden (in the prostate risk clinic) to identify somatic mutations in the prostate tissue.(ICR component of the grant)We will then developanovel molecular assayto identify these mutations in ctDNA from plasma collected from these men. To maximize the translational potential of this test, it will be designedto minimize sample consumption while remaining compatible with seamless integration into existing clinical laboratory pipelines and infrastructure.(Imperial component of the grant)

 

 

 

 

Professor George Poulogiannis (ICR, Cancer Biology) & Professor Zoltan Takats (Imperial, Metabolism, Digestion & Reproduction)

 

Abstract

The aim of this project is to unify expertise from the fields of cancer biology, optics, analytical chemistry, computing and fibre-robotics for the characterisation, identification and elimination of positive surgical margins in oncological surgery. Margin of PIK3CA mutant and wild type primary breast tumours will be used for this study. We will develop understanding of the changes in molecular interaction network structures at the invading tumour edge and use this information to create a prototype device capable of the chemical and morphological tissue mapping using Laser Desorption Ionization Mass Spectrometry (LDI-MS) and high-speed Line-Scan Confocal Laser Endomicroscopy (LS-CLE). These capabilities will be delivered at the tip of a multi-material polymeric fibre equipped with novel actuation mechanisms allowing precise motion-control, while maintaining flexibility to allow deployment in challenging surgical sites. The clinical motivation is to achieve complete resection of tumours without the need for time-consuming histology.

 

 

 

 

Dr Navita Somaiah (ICR, Radiotherapy & Imaging), Dr Sylvain Ladame and Dr Robert Channon (Imperial, Bioengineering), Professor Joshua Edel & Dr Aleksandar Ivanov (Imperial, Chemistry).

 

Abstract

There is growing evidence for cfDNA being able to stratify breast cancer patients with respect to disease progression and treatment response, however not much is known with regards to cfDNA in response to radiotherapy.  The team from ICR/RM has recently completed a phase 1 clinical trial (NCT02757651) testing a novel radiosensitiser (intra-tumoural hydrogen peroxide) in locally advanced breast cancers (n=12). Patients have donated blood samples before, during and after radiotherapy with serial monitoring of tumour response clinically and by ultrasound ongoing for 24 months. This study has highlighted the pitfalls of monitoring response post-radiotherapy using standard clinical imaging tools that are not able to accurately detect tumour response/relapse.  Therefore there is a clear need for a low-cost, minimally invasive sensing technology with highly specific tumour biomarkers in order to identify early radioresistance. Teams from ICL have recently developed hydrogel-filled nanopores (HFNs) for capturing and size-profiling of circulating cfDNA in blood with single-molecule resolution (Sulaiman et al 2018). This technology uses DNA fragment size to distinguish cfDNA originating from tumour cells to that (slightly longer) originating from healthy cells.  Hypothesis: Size-profiling of cfDNA in blood can provide useful clinical information to monitor therapy response in breast cancer patients undergoing radiotherapy.

 

 

 

2019

 

 

 

Professor Raj Chopra (ICR, Cancer Therapeutics) & Professor Ed Tate (Imperial, Chemistry)

 

Abstract

Patient-derived co-cultures of tumour and stroma cells have recently emerged as robust preclinical models for challenging solid tumours such as pancreatic ductal adenocarcinoma (PDAC). These biologically relevant settings for inhibitor development accelerate progression towards the clinic. However, complex co-culture models present the challenge that inhibitor effects cannot be directly assigned to a proposed target in a specific cell-type using conventional approaches. This project will address this challenge by converging 3D spheroid co-culture models of PDAC (Chopra) with two physical science innovations (Tate): 1.Novel photochemical probes to directly identify inhibitor target proteins by chemical proteomics.2.Biorthogonal incorporation of proteome-wide labels to differentiate individual cell-types.In this way biological effects will be directly linked to target and mechanism in a complex model through a convergent approach, providing a new paradigm to enhance phenotypic drug discovery pipelines for PDAC, and other cancers. 

 

 

 

 

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

 

Abstract

Treatment response of primary breast cancer to radiotherapy (RT) is strongly associated with blood delivery and oxygenation status within the tumour. Non-invasive imaging biomarkers of vascular function are highly sought after to stratify the patient pathway and improve RT therapeutic ratios. MRI offers markers of vessel dynamics, but due to low spatial resolution these methods only provide surrogate measures. Our aim of is to develop a prototype pipeline for augmenting breast MRI exams with non-invasive contrast-enhanced/super-resolution ultrasound (CEUS/SRUS), which offer a 100-fold increase in spatial resolution for visualisation/characterization of individual capillaries. Our objectives are to: 1. Evaluate a clinically feasible 3D CEUS/SRUS platform for response monitoring in breast tumours undergoing RT. 2. Correlate dynamic MRI measures with CEUS and SRUS for functional readouts in breast tumours undergoing RT. 3. Validate SRUS-derived biomarkers of tumour response to RT using histopathology. 4. Evaluate the feasibility of SRUS for early detection of RT resistance.

 

 

 

 

Dr Gabriela Kramer-Marek and Professor Jeff Bamber (ICR, Radiotherapy & Imaging) & Professor Molly Stevens (Imperial, Materials).

 

Abstract

The photoimmunotherapy (PIT) conjugates currently evaluated in clinical trials are monoclonal antibodies (mAbs) linked to dyes (e.g. IR700DX), which generate reactive oxygen species (ROS) under near infrared (NIR) light irradiation. We will investigate semiconducting polymer nanoparticles (SPNs) as they absorb more light and are more photostable than dyes, providing tissue penetration that should be advantageous for head and neck cancer (HNC) imaging and therapy monitoring. Aim 1. To acquire high resolution 3D photoacoustic images with a pulsed, non-therapeutic NIR light dose to analyse the distribution of targeted SPNs in the tumour and determine the optimum time for PIT. Aim 2. To measure tumour size, vascular density, and vascular function post-PIT using dynamic contrastenhanced (DCE) and blood-oxygenation photoacoustic imaging (PAI). This provides an exciting opportunity to plan, treat with PIT and monitor response with the same NP and, eventually with a single optical-ultrasound instrument.

 

 

 

 

Professor Chris Phillips (Imperial, Physics) & Professor Chris Bakal (ICR, Cancer Biology)

 

Abstract

CCP’s group has recently demonstrated a probe-based technology, (MICHNI) that images ultrastructure in FFPE cell sections at a world record ~2nm spatial resolution. It works with mid-IR light, and this also allows it to map out chemical moieties, (e.g. the B-C group in the anti-cancer drug Bortezomib) if they have a sufficiently distinctive IR absorption characteristic. Here we bid to extend the approach with bespoke antibody tags, analogous to those used in con-focal (CF) fluorescence microscopy, but incorporating either IR distinctive chemical moieties, or metal nano-particles (NP). The resulting technique will combine high biochemical specificity with a spatial resolution that is some at least 10x better than even the best of the Nobel prize winning “super-resolution” (SR) fluorescence microscopy techniques (STORM, PALM etc. ). It promises widespread impact across the whole of cancer biology and drug discovery, but in the first instance we will apply it to a local speciality, the CD7 kinase system in Breast Cancer cell lines.

 

 

 

 

Professor Chris Bakal (ICR, Cancer Biology), Professor Paul French & Professor Chris Dunsby (Imperial, Physics)

 

Abstract

We aim to develop a novel high-content analysis (HCA) platform providing high throughput, super-resolved microscopy (SRM). We will use this platform to image Focal Adhesion Kinase (FAK1) dynamics across bioengineered substrates of varying elasticities and molecular composition that mimic conditions found in immunosuppressive tumour microenvironments (TMEs) that characterise Pancreatic Adenocarcinoma (PDAC). We will simultaneously measure the activity of key transcription factors, STAT1 and NF-kB, whose localization serve as readouts for suppression/activation of the immune response. Finally, we will implement this technology in the context of a small chemical screen. Because FAK1 activity acts to translate the stiffness and composition of the TME into immunosuppressive responses in cancer cells, gaining insight into how FAK1 dynamics during this response will open up therapeutic avenues aiming to manipulate FAK1 activity, and sensitize PDAC cells to immunotherapy. Moreover, this work will set the stage for larger chemical-based screens at super resolution.

 

 

 

 

 

Dr Gabriela Kramer-Marek (ICR, Radiotherapy & Imaging) & Professor Marina Kuimova (Imperial, Chemistry)

 

Abstract

Glioblastoma (GBM) cells have  been  shown  to  employ  a  variety  of  mechanisms  to  suppress  the tumour immune microenvironment. Therefore,  a therapeutic approach  aiming  to abolish  immunosuppressive  cells and activate anti-GBM immunity would provide a powerful treatment strategy against GBM in the clinic. Photoimmunotherapy (PIT) can stimulate anti-tumour immunity by utilising the targeting ability of a specific moiety (e.g., affibody molecule; ZEGFR:03115),conjugated to a cytotoxic photosensitiser (e.g.,IRDye700DX). We  postulate that PIT  targeting of EGFR-positive GBM  cells can alter  the  complex  behaviour  of residual  tumour  cells and trigger  immunogenic  cell  death (ICD),whilst attracting  immune  cell populations to re-establish the cancer-immunity cycle. Our hypotheses will be tested through the following research aims: 1. To  investigate  whether a  light-activated  immunoconjugate will  induce a  release  of  damage-associated molecular patterns (DAMPs) leading to the activation of an immune response. 2. To  assess  whether changes  in intracellular viscosity  correlate  with  the  mechanism  of  DAMPsecretion.3. To  evaluate  the mechanisms  of immune response  to  PIT in  vivo using a murine  orthotopic  GBM model (GL261).

 

 

 

 

.

Dr Andreas Wetscherek and Professor Uwe Oelfke (ICR, Radiotherapy & Imaging) & Professor Wayne Luk (Imperial, Computing)

 

Abstract

This project explores how the latest dataflow computing techniques can be used to accelerate 4D MRI data processing and adaptive radiotherapy, as pioneered by the Magnetic Resonance in Radiotherapy and Radiotherapy Physics Modelling teams at the ICR. The aim is to realise the potential of next generation MR-guided radiotherapy systems to revolutionise cancer treatment, by characterising patient anatomy in real-time and adapting to the physiological motion to optimise treatment efficacy while minimising dose to organs-at-risk. There are two main objectives. First, to improve the performance of 4D MRI data processing to support adaptive radiotherapy, by developing optimised dataflow implementations of such processing based on field-programmable gate array (FPGA) technology, which has shown promise in accelerating many demanding computations including Monte-Carlo based dose calculation, as demonstrated by the Custom Computing Research Group at Imperial. Second, to study how such optimised dataflow implementations can maximise the clinical benefits of an MR-guided radiotherapy system by providing anatomical information in real-time, and enabling on-line dose calculation based on 4D MRI. The project will involve three stages. The first stage covers the development of initial FPGA-based dataflow designs of 4D MRI data processing. Such initial designs would meet accuracy requirements, but may not have high performance. An optimised software implementation will be developed, which will both help derive the dataflow designs and also provide an additional reference for performance comparison. The second stage covers various optimisations to the designs in the first stage to improve their performance. An example optimisation is the adoption of mixed precision representations, which should increase the parallelism for the FPGA to improve performance. The third stage covers a study of how optimised dataflow implementations can realise the full potential of an MR-guided radiotherapy system. Prototypes will be developed and connected to the Elekta Unity system to explore possibilities for providing anatomical imaging in real-time and for enabling continuous on-line dose monitoring based on accelerated 4D MRI data processing.

 

 

 

 

 

Dr Helen McNair (ICR & Royal Marsden Hospital, Radiotherapy & Imaging) & Professor Alison McGregor (Imperial, Surgery & Cancer)

 

Abstract

With over 50% of cancer patients potentially benefitting from radiotherapy it is important that any additional stress during the treatment plan is minimised.  Anxiety and psychological stress of cancer patients and their families during cancer treatment occurs in up to 49% of the patient population.  This can be attributed to a sense of isolation experienced by the patient in the treatment or imaging rooms, separated from their carers and families. Existing interventions are either remotely administered, e.g. verbal communication or music which do not overcome the lack of physical presence and support or include the use of costly invasive sedation methods. Tactile intervention is a non-invasive and drug-free approach, which has the ability to address this treatment isolation. Simulated affective touch has potential to relieve psychological distress . We propose to explore a wearable solution using soft robotics to simulate affective touch with the aim to provide both psychological and physical comfort simultaneously. This has the potential to have a significant role in promoting comfort, facilitating communication between care recipients and caregivers.
Using the existing prototypes developed by Caroline Yan Zheng with the support of MedTech Super Connector – a medtech acceleration programme funded by Research England, this project will use a human-centred design approach and mixed methods to identify the best use case, adapt a proof-of-concept prototype adapted to the radiotherapy and imaging session, and evaluate the feasibility of this intervention.

 

 

 

 

Professor Andrea Sottoriva (ICR, Molecular Pathology), Professor Luca Magnani (Imperial, Surgery & Cancer), Professor Joshua Edel & Dr Aleksandar Ivanov (Imperial, Chemistry).

 

Abstract

The current approach to single-cell genomics and transcriptomic studies involve the isolation of single cells, the extraction of the nucleic acid substrate and the generation of next-generation sequencing libraries. Presently, single-cell RNAseq can either capture 8–9K genes in a few hundred cells or 2–3K genes in up to 10K cells. However, in both cases, the actual measurement involves the destruction of the sample. A central question in cancer is to understand how cancer cells evolve during early oncogenesis and in response to clinical treatments such as chemotherapy, immunotherapy or more targeted therapies. Several groups, including ours, have investigated this problem at the level of cancer cell populations. Tracking genomic changes is possible, as they are irreversible and permanently documented by the genome. On the other hand, tracking dynamic transcriptional changes is currently unachievable, as each time point requires the exhaustion of the sample.  As a result, we are missing critical biological insight as we cannot measure how cancer cells adapt to stimuli by adapting their transcriptome. However, studies have now begun to uncover evidence on how cancer cells might use quick transcriptional transitions to evade treatment, or how transcriptionally defined cells might play a central role during tumour evolution. To bridge this large technological gap, as part of this proposal we aim to develop a step-changing technology, which unites physical sciences, engineering and cancer research in a collaborative project across leading groups to develop the next generation of high-throughput, minimally invasive nanotweezers for RNA sampling and sequencing whilst keeping the cell alive.  The nanotweezers consist of two closely spaced electrodes with gaps as small as 10–20 nm, which can be used for the dielectrophoretic (DEP) targeted trapping of nucleic acids, proteins and even single organelles. DEP can be generated by applying an AC signal (> 1 MHz, < 20 V) to the nanoelectrodes. We have shown that high electric field gradients (∇|E|2 ≈ 1028 V2 m−3) can be generated; enabling the trapping of single-molecules within physiological ionic strengths. Crucially, no cytoplasmic fluid is aspirated. Additionally, we will build mathematical/statistical models to better leverage this novel data. If successful, the proposed convergent approach has tremendous potential to change our current view of cancer.

 

 

 

 

 

Professor Paul Freemont (Imperial, Infectious Disease), Dr Richard Kelwick (Imperial, Infectious Disease), Dr Marko Storch (Imperial, Life Sciences)

 

 

Abstract

This proposal is looking to further develop the next generation of Advanced proteoLytic detector PolyHydroxyAlkanoates (AL-PHA) beads – a set of low-cost, biodegradable, bioplastic-based protease biosensors – in order to detect exosome-associated metalloproteinases as a biomarker for lung cancer.

 

 

 

 

Dr Marco Di Antonio (Imperial, Chemistry), Professor Robert Brown (Imperial, Surgery & Cancer)

 

Abstract

This application is proposing to develop a novel chemical platform that enables the installation or removal of DNA-methylation, in a spatially and temporally controlled fashion, allowing the dynamics and heterogeneity of epigenetic mechanisms to be examined for the first time.

 

 

 

 

Dr Sylvain Ladame (Imperial, Bioengineering), Professor Simak Ali (Imperial, Surgery & Cancer), Professor Laki Buluwela (Imperial, Surgery & Cancer)

 

Abstract

This proposal aims to carry out a proof-of-principle study to demonstrate the use of novel Peptide Nucleic Acid (PNA)-based probes for the in-situ detection of specific DNA mutations in pathological sections of breast cancer.

 

 

 

,

Professor Ed Tate (Imperial, Chemistry), Professor Holger Auner (Imperial, Immunology and Inflammation), Dr Milon Mondal (Imperial, Chemistry)

 

Abstract

USP30 overexpression is strongly associated with drug resistant lymphoma, leukaemia and multiple myeloma, in which apoptotic pathways are dysregulated through altered expression of BCL-2. USP30 depletion sensitizes cancer cells to BH3-mimetics, making it a potential target for cancer therapy, however, its endogenous substrates and regulation remain poorly understood. This project will look to develop activity-based probes to better understand USP30 biology and potential as a therapeutic target

 

 

 

2018

 

 

 

Professor Amanda Cross (Imperial, Surgery & Cancer), Dr Kevin Monahan (Imperial, Medicine)

 

Abstract

Lynch Syndrome (LS) is the most common hereditary ColoRectal Cancer (CRC) syndrome and arises as a result of germline mutations in mismatch repair genes. The lifetime CRC risk associated with LS is as high as 80% without surveillance, however, LS is ‘under-recognised, under-diagnosed and under-managed’. This project will aim to create a national database of people with Lynch Syndrome (LS) to ensure that these patients receive appropriate colonoscopy surveillance consistent with national guidelines by providing an efficient call/recall system for hospitals.

 

 

 

 

Professor Ed Tate (Imperial, Chemistry), Professor Iain McNeish (Imperial, Surgery and Cancer), Dr Scott Lovell (Imperial, Chemistry)

 

Abstract

Epithelial ovarian cancer (EOC) represents a growing women’s issue worldwide. Several studies have revealed that kallikrein-related peptidases (KLKs), a family of serine proteases, are aberrantly expressed in EOC patient specimens and may play a role in cancer progression. This project will use a recently prototyped technology platform using activity-based probes to determine the activity of KLKs in EOC and their potential actionable activities for driving disease progression and drug resistance.

 

 

 

 

Professor Alex Porter (Imperial, Materials), Dr Nelofer Syed (Imperial, Brain Sciences), Professor Theoni Georgiou (Imperial, Materials)

 

Abstract

Treatment option for glioblastoma (GBM), are severely limited and survival remains very poor with existing treatments. This project will aim to generate proof-of-concept that polymersomes bearing chemotherapeutic drugs conjugated to the FDA approved BBB targeting molecule L-DOPA can target, cross the BBB and significantly shrink the size of glioblastoma (GBM) tumours in vivo.

 

 

 

 

Professor Hugh Brady (Imperial, Life Sciences), Professor Matt Fuchter (Imperial, Chemistry), Professor Iain McNeish (Imperial, Surgery & Cancer).

 

Abstract

This project will seek to optimise a novel NK cell-based immunotherapy approach to treat ovarian cancer. This includes the development of compounds and engineering approaches to enhance the ability of NK cells to kill cancer cells.

 

 

 

 

Dr Iros Barozzi (Imperial, Surgery & Cancer), Dr Sung Pil Hong (Imperial, Surgery & Cancer)

 

Abstract

This project is aimed at investigating how a single cell from a heterogeneous tumour adapts to chemotherapeutic drugs and becomes resistant using Single-cell-RNA-sequencing (sc-RNA-seq). It will provide new biomarkers for monitoring and targeting the emergence of resistant clones, while offering insights into the common and unique phenotypic changes induced by different chemotherapeutic agents.

 

 

 

 

Dr Matthew Grech-Sollars (Imperial, Surgery & Cancer), Dr Rebecca Quest (Imperial College Healthcare NHS Trust), Dr Kyriakos Lobotesis (Imperial College Healthcare NHS Trust), Dr Neal Bangerter (Imperial, Bioengineering)

 

Abstract

The overall aim of the project is to implement novel cutting-edge quantitative MRI techniques (MR Fingerprinting) at Imperial College to advance clinical imaging research techniques including radiomics and the use of more accurate machine learning tools. We will be exploring the use of MR Fingerprinting (MRF) in brain tumours, which are known to be heterogeneous and therefore ideal for studying the ability of MRF to discriminate between regions of tumour which are more aggressive and aid clinical diagnosis.

 

 

 

 

Professor Hector Keun (Imperial, Surgery & Cancer), Dr Peter DiMaggio (Imperial, Chemical Engineering)

 

Abstract

This project aims to provide proof-of-concept for a novel convergence science platform to gain new insights into the biological function and regulation of Poly-ADP-ribose polymerases (PARPs) in cancer cells. In addition, it will aim to identify novel determinants of PARP inhibitor response in cancer cells and how these can be exploited therapeutically.

 

 

 

2017

 

 

 

Dr Vessela Vassileva (Imperial, Surgery & Cancer), Professor Eric Aboagye (Imperial, Surgery & Cancer), Dr Kathrin Heinzmann (Imperial, Surgery & Cancer), Dr Ali Ashek (Imperial, Medicine) & Dr Yean Chooi (Imperial, Bioengineering)

 

Abstract

Hypoxia has been identified as a major adverse feature of pancreatic cancer, and is associated with resistance to therapy and poor prognosis. This project will evaluate whether targeting hypoxia in pancreatic tumours can improve the delivery of targeted radionuclide therapy using an antibody directed against carcinoembryonic antigen (A5B7), which is expressed in the majority of pancreatic cancers (85-90%), but not normal cells. The hypoxia pro-drug, TH-302, will be used to selectively kill hypoxic tumour cells, in combination with A5B7, to evaluate whether this can achieve improved tumour perfusion and vascular flow, and radiosensitisation to targeted radionuclide therapy in pre-clinical models of pancreatic cancer. 

 

 

 

 

Dr Constandina Pospori (Imperial, Life Sciences), Professor Cristina Lo Celso (Imperial, Life Sciences), Professor Mauricio Barahona (Imperial, Mathematics)

 

Abstract

This project will explore the hypothesis that tumour heterogeneity may be, rather than a by-product of malignant clone competition, in fact essential for tumour development. By combining intravital imaging, flow cytometry, RNAseq data and mathematical modelling this project will investigate the lineage hierarchy between PDL1-low and –high leukaemic blast subsets and understand if the PDL1‐high blasts function as an accessory but essential subset, creating an immunoprivileged microenvironment.

 

 

 

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