The Convergence Science Intercalated PhD Pathway
For students
This iPhD will train clinical academics to work on multidisciplinary projects that bring together cancer research and the engineering and physical sciences. It is intended for outstanding undergraduate students on the MBBS/BSc degree course and offers the opportunity to include an intercalated PhD as part the course. The PhD consists of 3 years research to be undertaken after the successful completion of the intercalated BSc (iBSc) in year 4 of the MBBS degree. Trainees will re-enter undergraduate medical education at year 5 after the completion of the PhD training.
The iPhD is fully funded, inclusive of a generous tax-free fixed stipend, tuition fees for UK students and the cost for undertaking research. Overseas students are also eligible; however, they should discuss other options to support the difference in international fees with prospective supervisors. The offer doesn’t end there, Cancer Research UK is also committed to underwriting the undergraduate tuition fees for years 1-4 of UK students who successfully apply to this programme. The NHS will cover tuition fees for years 5 and 6.
If you are a year 4 medical student registered at Imperial this opportunity is for you. We welcome interest from students applying to any of the iBSc pathways. However, the opportunity to complete the research component of the iBSc year in cancer research will exist for those applying for the Cancer Frontiers pathway and in convergence science through the Biomedical Engineering pathway. You may also be able to be able to undertake a cancer-related project in some of the other iBSc pathways; however, all will give you a strong understanding of life in a research environment.
You will be trained by world leading experts in cancer biology, engineering and physical sciences at Imperial and the ICR. This will enable you to acquire a broad skill set and learn the language of multiple disciplines.
With a range of outputs spanning research publications, presentations at relevant conferences and translation of your research for patient benefit, the iPhD will provide the grounding for your future success as a clinical academic.
You will receive tailored mentorship from clinically qualified cancer researchers who will provide guidance on successfully navigating the PhD years, becoming a clinical academic and establishing a successful career in oncology.
We asked a selection of our supervisors their thoughts on convergence science, their philosophy to mentoring, what attributes they are looking for in a convergence science student, and what key factors prospective students should consider when choosing a PhD. We also asked a selection of our current students what attracted them to this field, their experience of the programme so far, and what their aspirations are for the future. Click here to read perspectives from our current supervisors and students.
Supervisors:
Project summary
Pancreatic ductal adenocarcinoma (PDAC) accounts for nearly the 80% of all the pancreatic tumours. Its dismal outcome (survival rate below 5% at 10 years) goes along with the constantly increasing incidence rate and lack of effective treatments especially for late stages. This scenario is further worsened by recent findings that identified three to four different subtypes of human PDAC. Although these subtypes have distinct characteristics, there are no biomarkers that can robustly stratify PDAC tumours into these subtypes. Therefore, it is evident that novel approaches to (early) detect PDAC is highly needed. For this project we are proposing to identify specific proteases, unique for each PDAC subtype, by using transcriptomic and proteomic profiles of primary patient PDAs, human PDAC cell lines and 13+ mouse GEM tumours already existing at the Sadanandam lab. Those significant proteases from transcriptome and proteome will be further explored for prognostication and other clinical outcomes such as grade and stage using the receiver operating characteristics curve analysis. Finally, these candidates will be validated using prospectively collected PDAC samples by immunohistochemistry.
A small library of different cleavable peptides will be developed for each selected protease. At this stage both the protease activity and the peptide sequence need to be validated in order to develop active bioresponsive nanosensors. FRET peptide substrate-cleavage assay screen will be used to identify the best candidates by selecting substrates specific to the candidate proteases. Bioresponsive nanosensors will be then synthetised by associating ultrasmall gold nanoclusters to the selected peptides previously biotinylated. Such gold nanoclusters will be further coupled to neutravidin. The neutravidin complexes will also be tested with size exclusion filters to prove that such complexes will be active and exclude steric impediment between the peptide and the catalytic ultrasmall gold nanoclusters (AuNCs). The nanoclusters will be finally tested in vitro using subtype specific PDAC cell lines from human and mouse, and fluorescence assay. The nanocluster library for subtype-specific proteases will be further tested in vivo using xenogeneic and/or syngeneic models that represent different subtypes of PDAC. The bioresponsive nanoclusters will be injected intravenously and they will disassemble only when exposed to the activity of the relevant dysregulated proteases at the site of disease. After protease cleavage, the liberate AuNCs will be filtered through the kidneys and into urine, where they could be detected by an easy colourimetric assay.
The supervisors and work environment
You will work in the laboratories of Professor Molly Stevens who is an expert in regenerative medicine and biomedical materials and Dr Anguraj Sadanandam who is a leader in testing and identifying new cancer therapeutics. Further, you will be exposed to the world class research infrastructure across Imperial and the Institute of Cancer Research.
Supervisors:
Proposal summary
Background:
Prof. Phillips group has developed a new way of imaging cells and tissues. It uses infrared light to deliver images with a resolution of <3nm. This technology (MICHNI: MID-INFRARED CHEMICAL NANO-IMAGING) is ~100 times sharper than confocal light microscopes and is considerably sharper than most implementations of electron microscopy, or the recent Nobel-prizewinning “super resolution” microscopes. Importantly, it is also 100x cheaper and faster than electron microscopy. Supervised by Dr Gerlinger (Medical Oncologist and Clinician Scientist, ICR) and Prof Phillips (Physics Department, Imperial), the project will apply MICHNI microscopy for the first time to answer critical questions in biomedicine.
Questions that will be answered:
1. How does chemotherapy drug resistance develop in bowel cancer?
2. Which immune checkpoint are engaged in highly immunogenic MMRd bowel cancers and prevent killing of cancer cells by the immune system?
Research plan:
We will leverage MICHNI’s ultra-high resolution and the unique ability to draw chemical maps to answer key questions in bowel cancer research. We are investigating mechanisms of resistance to bowel cancer chemotherapy drugs (5FU, oxaliplatin and irinotecan) in a living biobank of cancer organoids from patients with resistant and sensitive tumours. MICHNI will be used to measure how intracellular drug concentration, sequestration into intracellular organelles or complexes and target-engagement regulate chemotherapy resistance. We are furthermore interrogating mechanisms of immunotherapy resistance in highly immunogenic MMR-deficient bowel cancers. The inhibitory immune checkpoint receptors PD1, TIM3, LAG3 and TIGIT are expressed by activated CD8 T-cells and binding to their ligand’s triggers T-cell dysfunction. Which of these are activated by MMRd bowel cancers is unknown. This is a critical knowledge gap for the rational design of immunotherapy combinations with PD1, TIM3, TIGIT and LAG3 inhibitors. We will label anti-PD1, -TIM3, -TIGIT and -LAG3 antibodies with nanoparticles and use these to stain MMRd tumour tissues. Imaging of T-cells that interact with cancer cells will reveal which of the immune checkpoints cluster together at the point where T-cells sample the surface of cancer cells. This will provide information about the immune checkpoints that are activated in individual MMRd cancers. It will subsequently inform the development of immunotherapy combinations that inactivate all relevant checkpoints.
Project impact:
The project will provide key insights into chemotherapy and immunotherapy resistance which we anticipate the inform the development of better chemotherapies and clinical trials of immunotherapy combinations. It will furthermore demonstrate the potential of MICHNI for biomedical research and biomarker identification.
The supervisors and work environment
The team includes the medical oncology (Dr Gerlinger) and experimental physics (Prof Phillips) expertise of two world leading researchers. The student will have access to the cutting-edge research environment at the ICR and Imperial College.
Supervisors:
Proposal summary
Multiple myeloma is an incurable malignancy of the bone marrow, and the second most common blood cancer. New treatment approaches, including mAb and CAR-based immunotherapies, are being developed, creating a need for model systems to evaluate their effectiveness and mechanisms of treatment resistance. A key candidate technology is organoids: model tissues and tumours that are grown in vitro from patient tissue. This interdisciplinary iPhD project will develop a composite bioengineered 3D-organoid model for multiple myeloma. The system will comprise 3 connected bioengineered niches, modelling not only the primary tumour growth in the bone marrow, but also the invasion/destruction of nearby osseous bone, and the metastatic invasion of distant soft tissue sites. This will enable the evaluation of new therapies in terms of their impact on all these key aspects of multiple myeloma pathology. Technologically, the concept is founded on developing new hydrogel biomaterials that mimic the distinct biophysical and biochemical properties of these 3 niches. The developed system will be applicable to both conventional chemotherapy drugs and also to new cellular immunotherapies such as CAR-T approaches.
The supervisors and work environment
The project is a collaboration between Prof. Karadimitris, Professor of Haematology and Director of Imperial’s Langmuir Centre for Myeloma Research, and Dr Iain Dunlop, Reader in Biomaterials and Cell Engineering in Imperial’s Faculty of Engineering (Dept. Materials). The student will have access to cutting-edge research across the Faculties of Engineering and Medicine at Imperial College London.
Supervisors:
Proposal summary
Tumour dormancy is a huge clinical problem. In estrogen-receptor positive (ER+) breast cancer, tumour relapse can occur up to 20-years after surgical removal of the primary tumour and kills 10-30% of patients. We are currently unable to predict who will relapse and when relapse will occur. Therefore, we desperately need a better understanding of the mechanisms underpinning tumour cell dormancy. Cellular quiescence is a state of reversible cell cycle arrest, regulated by cell intrinsic and extrinsic factors. The molecular mechanisms that control cellular quiescence are involved in regulating entry into, maintenance of, and exit from, tumour cell dormancy. By understanding the mechanisms regulating tumour cell quiescence, we can start to design strategies to better detect, track and eradicate dormant tumour cells and improve patient outcomes. Secreted proteins play key roles in regulating tumour dormancy, yet we have a very limited understanding of the roles of most of the ~2500 predicted secreted proteins. By performing a high-throughput, image-based screen of purified secreted proteins, the Barr lab have identified secreted proteins that can modulate tumour dormancy in ER+ breast cancer. These proteins have not previously been implicated in dormancy.
Now, through a multidisciplinary collaboration between the Barr (Imperial) and Turner (ICR) labs, we will combine our expertise in quantitative cell and molecular biology with the clinical expertise and deep understanding of breast cancer pathology in the Turner lab, to understand the role of these secreted proteins in ER+ breast cancer. Specifically, the student will: (i) determine the molecular mechanisms through which the secreted proteins act – through a combination of quantitative fixed and live cell imaging, CRISPR/Cas9 screening and -omics approaches (transcriptomics, proteomics and phospho-proteomics); (ii) identify mechanisms of resistance or sensitivity to dormancy- regulating secreted factors, to be able to ascertain which patients will be responsive to these secreted factors; and (iii) develop an assay to detect and quantify secreted proteins from patient samples, to be able to track the course of dormant disease and potential relapse. Together, this will lead a well-rounded student training experience in cell and molecular biology, fixed and live-cell imaging, transcriptomics, proteomics, handling patient material, immunohistochemistry and targeted mass spectrometry. Through this multidisciplinary discovery research, the student will simultaneously investigate molecular details and begin to develop a novel clinical assay to ensure that their work can be rapidly translated for patient benefit.
The supervisors and work environment
The team includes the medical oncology (Prof Turner) and cell biology (Dr Barr) expertise of two world leading researchers. The student will have access to the cutting-edge research environments at the ICR and Imperial College.
Supervisors:
Proposal summary
Gynaecological sarcomas account for 3-4% of all gynaecological cancers but have a disproportionately worse outcome. For examples, the 5-year relative survival of uterine sarcoma has been estimated to be 30%, compared to 77% for women with any type of uterine carcinoma. There is therefore an urgent need to develop new therapies and biomarkers to enable individualised clinical management of these patients. There is some evidence from clinical trials that targeted therapies such as PARP inhibitors have some efficacy in gynaecological cancers such as uterine leiomyosarcomas. However, the biological basis of these therapy responses are poorly understood and only a subset of patients derive benefit from these drugs. Given the rarity of these diseases (<300 patients in the UK per year), there are very few preclinical models to study biological mechanisms of cancer development as well as to generate preclinical evidence for novel treatment options that enable clinical translation of new precision medicines.
The Overby lab developed an organ-in-chip device to preserve the viability of tissue explants over several days. The explant is placed within a microchannel designed to achieve self-sealing between the explant and channel wall. When a pressure drop is applied across the explant, flow is driven through (not around) the explant to supply internal cells with oxygen and nutrients, and thereby maintain viability. The Huang lab, working in close partnership with the Sarcoma Unit at the Royal Marsden, have developed a unique panel of uterine leiomyosarcoma models (xenografts, organoids and low passage cell lines) derived from advanced/metastatic sarcoma patients. These models, though useful for many applications, neglect the tumour microenvironment (TME), which includes tissue structure and stromal and immune cells resident within a patient’s tumour that influence how cancer cells grow, metastasise and respond to drugs.
This project seeks to address this unmet need by building an organ-on-chip platform for gynaecological sarcomas for the purposes of mechanistic cancer biology studies (e.g. understanding metastasis and tumour-immune cell interactions) and drug development. In this project, the student will adapt the current organ-in-chip design to accommodate explants from gynaecological sarcomas, using PDXs from mice before incorporating primary human tumour explants.
The aims are to:
1) Re-engineer the organ-in-chip platform for gynaecological sarcoma explants
2) Determine how perfusion preserves explant viability and function
3) Demonstrate a chemotherapeutic response within the explant during perfusion and compare
this response against patient-derived spheroid/organoids and precision-cut tumour slices.
The supervisors and work environment
The team includes the mechanical engineering (Prof Overby) and molecular pathology (Dr Huang) expertise of two world leading researchers. The student will have access to the cutting-edge research environments at the ICR and Imperial College.
Supervisors:
Proposal summary
Hepatocellular carcinoma (HCC) is a major health problem, being the third cause of cancer-related deaths worldwide. When diagnosed in an early phase, it can undergo a radical resection; however, even after a successful surgery, almost 70% patients relapse in the following 2 year. In order to improve this outcome, we have launched an ambitious clinical trial, called PRIME-HCC, aiming to show the feasibility and the safety of delivering a short course of immunotherapy with a double combination of immune checkpoint inhibitors (ICI) prior to the surgery. The use of immunotherapy in the neoadjuvant setting allows the comparison of pre- and post-treatment biological samples, including tumour tissue, with the aim of identifying possible predictor of response to the therapy.
The overarching aim of this proposal is to aid identification of mechanisms of action of immunotherapy taking advantage of a unique biorepository of clinical samples collected as part of the neoadjuvant clinical trial PRIME-HCC. As part of this proposal, we will test the hypothesis that tumour-induced dysfunction of the effector CD8+ T-cell response underscores sensitivity to ICI in HCC. We will evaluate 3 cardinal mechanism of T-cell dysfunction: 1) T-cell exhaustion by comprehensive phenotypic evaluation of tumour-infiltrating and peripheral lymphocytes over time; 2) Longitudinal assessment of T-cell clonality in the same samples and 3) Profiling of gut microbiome as a mechanism of induction of T-cell dysfunction. The research plan is articulated around the following research objectives:
The supervisors and work environment
The candidate will acquire an advanced translational experience, while interacting with professionals from different background, from medical oncologists to basic researchers to pathologists. The research can potentially have an immediate positive impact in clinical practice, since an optimised use of immunotherapy in the clinic can facilitate the identification of patients who are more likely to respond to treatment and spare non-responders from unnecessary and potentially life-threatening toxicity.
Supervisors:
Proposal summary
Targeted drug delivery is a goal of cancer medicine, but it remains challenging to deliver drugs to specific locations. Physical barriers, such as the permeability of the endothelium and extracellular matrix (ECM), limit the quantity of drug reaching a tumour. Ultrasound (US) mediated drug delivery holds significant promise for overcoming physical barriers in the tumour microenvironment. One such method for US mediated drug delivery is Acoustic Cluster Therapy (ACT). In ACT, microbubbles and microdroplets are co-administered as clusters. Using diagnostic US, the microbubbles become activated and enlarge, occluding capillaries or small arterioles and halting blood flow through select regions of the microvasculature. Further application of US induces biomechanical effects that permeabilise the vasculature to locally enhance extravasation of intravenous drugs. ACT has progressed to Phase I/II trials (PI: Banerji), and a Phase I trial of US-mediated delivery of gemcitabine in ten patients with pancreatic cancer established safety and provided preliminary evidence of efficacy in terms of overall survival.
Our goal is to understand the mechanism by which ACT permeabilises the vascular endothelium so to optimise and improve drug delivery within a tumour. More specifically, we aim to determine how insonation parameters (peak-negative pressure, mechanical index, etc), treatment regimen (time course, repetition rate, etc), microbubble/microdroplet size and concentration ratio effect drug extravasation and uptake. We expect these parameters to depend on the fine structure and composition of the vascular wall and surrounding microenvironment, which will vary between cancer types, as well as the degree of vascularity and anatomical location that will limit microbubble/US access.
Because of the dependent on microenvironmental factors, we propose to use a novel organ- in-chip device that preserves the viability and function of tumour explants by perfusion. Explants will be obtained from murine pancreatic cancer xenografts that capture and preserve the native tumour microenvironment. Ultimately, this understanding will translate into patient benefit by identifying which cancer types are best suited to ACT and which parameter settings are optimal for effective drug delivery.
The Specific Aims of this project are:
1. To design an US-compatible apparatus to administer microbubbles and microdroplets by perfusion into an explant or tissue slice and perform ACT.
2. To investigate the relationship between ACT parameters and permeabilization of the vessel wall.
3. To demonstrate an enhanced drug response in explants treated with ACT vs without.
The supervisors and work environment
The team includes the mechanical engineering (Prof Overby), ultrasound imaging (Prof. Bamber) and radiation oncology (Dr Harris) expertise of three world leading researchers. The student will have access to the cutting-edge research environments at the ICR and Imperial College.
Supervisors:
Proposal summary
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.
The supervisors and work environment
The team includes the bioengineering (Prof Green) and targeted therapeutics (Prof Hajitou) expertise of two world leading researchers. The student will have access to the cutting-edge research environments across the Faculties of Medicine and Engineering at Imperial College.
Supervisors:
Proposal summary
Endometrial cancer is the 4th most common cancer in women and the most common gynaecological cancer. Women affected by the more common, type 1 endometrial cancers have low grade disease, good response to treatment and relatively good prognosis. Women affected by type 2 endometrial cancers have aggressive, high grade tumours of more uncommon histological subtypes and have worse prognosis. In recent years, studies have demonstrated a link between dysregulation in cellular lipid metabolism and endometrial cancer, especially high grade and more aggressive tumours. By further elucidating the nature of lipid metabolism dysregulation in endometrial cancer, especially in type 2 tumours, there is potential to discover new targeted treatments that could increase survival amongst patients in this group.
We propose a project using Raman spectroscopy to study patient-derived endometrial cancer organoids and organoids of cancer associated endometrial diseases. Raman spectroscopy provides a non-destructive, label-free method for imaging and studying the biochemical composition of biological samples, including complex, 3D, in vitro cell cultures such as organoids. It enables the analysis of biochemical profiles at a subcellular level and is unparalleled in its ability to scrutinise luminal secretions within individual hollow-structured organoids. Because of its non- destructive nature, Raman spectroscopy has the unique advantage of being able to study live organoids, allowing for the potential to monitor organoid responses to drug treatment with shorter experiment time and without sacrificing precious samples.
This project will, in particular, will focus on analysing the Raman lipid profiles of different grades and histological subtypes of endometrial cancer organoids, endometrial hyperplasia organoids and healthy endometrial organoids. We will also study changes in the Raman lipid profile of endometrial cancer organoids in response to treatment with a lipid-targeting small molecule. The overall aim is to improve the fundamental understanding of the disease and fill an essential knowledge gap in the field. In particular, to explore in vitro 3D disease modelling, and screen for novel anti-tumour treatments that target lipid metabolism in endometrial cancer.
The supervisors and work environment
A preliminary study has already been conducted to demonstrate proof of concept, with some very promising results. The candidate will be expected to build upon the preliminary results and design a more complex study. They will join a world-renowned, multidisciplinary research group and be supervised by bioengineers, Raman spectroscopy experts and gynaecological oncologists.
Supervisors:
Proposal summary
Although blocking checkpoint molecules such as programmed death-1 receptor (PD-1) in cancer patients has restored immune-cell reactivity in the tumour microenvironment, the efficacy is limited in the so-called ‘immunologically cold’ tumours; that is tumours with a low density of tumour-infiltrating immune cells. One of the biggest challenge is in recruiting immune cells into the tumour microenvironment. mRNA vaccines demonstrate remarkable efficacy against COVID-19 and extraordinary safety and customisability as a platform technology. There are several ongoing clinical trials testing mRNA to deliver immune drugs into the tumour. mRNA is injected locally (intra- tumourally) to allow the cancer cells and/or adjacent cells to produce immune activators (e.g. IL-12) that stimulate immune cells to attack the tumour. However, mRNA-encoded immunotherapeutics are diffusive and cause systemic side effects in healthy organs. Our method involves fusing extracellular matrix-binding domains to mRNA-encoded IL-12 to create a tumour-tissue retention system for reducing side events and increasing anti-tumour effects. We will test the newly synthesised nanoparticle’s anti-tumour efficacy and immune-related adverse events using both cold and hot head and neck cancer murine models. The student will be able to learn chemical synthesis, molecular biology techniques, cell culture assays, murine cancer models, and immunological analyses. Desired students should understand basic chemistry, immunology and preclinical cancer models.
The supervisors and work environment
The team includes the gene therapy (Dr Patel), molecular imaging (Dr Kramer-Marek) and bioengineering (Dr Ishihara) expertise of three world leading researchers. The student will have access to the cutting-edge research environments at the ICR and Imperial College.
Supervisors:
Proposal summary
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.
The supervisors and work environment
This project offers an ambitious iPhD candidate several competitive advantages and key skills as a future clinician scientist:
Supervisors:
Proposal summary
CDK4/6 inhibitors have emerged as a powerful class of agents with clinical activity in a number of malignancies. In combination with endocrine therapy, they are a standard first-line treatment option. Despite their success, the majority of patients eventually acquire resistance to these treatments and the inhibition of CDK7 is being developed as one strategy to overcome resistance to CDK4/6 inhibitors. CDK7 inhibitors have shown substantial anti-tumour effects, particularly in estrogen receptor (ER)-a positive breast cancer. CDK7 inhibitors are currently undergoing clinical trials aimed at patients with advanced or metastatic cancer (e.g., Ali lab, ICEC0942, aka CT7001/Samuraciclib, phase II). Despite available knowledge of the CDK4/6 pathway, attempts to identify molecular biomarkers that predict response or resistance to CDK4/6 inhibitors in human breast cancers have proved challenging. There is a urgent and unmet need to non-invasively monitor the progression of the disease in these patients.
Circulating tumour cells (CTCs) are present at low numbers in the peripheral blood of patients with solid tumours. Their isolation and characterisation has been proposed as a non-invasive proxy to determining the changing patterns of drug susceptibility as tumours acquire new mutations. Treatments are continually adjusted in response to mutations so if viable CTCs could be functionally characterised over the course of a patient’s therapy, there is an opportunity to non-invasively identify the most effective treatments. However, a major bottleneck is the inability to isolate CTCs non- destructively thus precluding functional drug assays.
In this project, we propose to use single cell microfluidic techniques to determine the drug susceptibility of CTCs and metastatic tumours compared with the primary solid tumour to CDK inhibitors in an in vivo xenograft metastatic breast cancer model. The candidate will work in a highly multidisciplinary environment spanning engineering, biomedical and clinical laboratories, bringing to bear novel microfluidic technology and single cell sequencing to understand heterogeneity to drug treatment at the single cell level, an area of unmet need. This project will deliver unprecedented molecular insight into the response to drugs in the major components of metastatic disease with the aim to guide clinical decisions and complementary research into drug design. It opens the door to uncovering biomarkers of resistance to CDK4/6 inhibitors and offers a strong platform for future progression to human patient studies.
The supervisors and work environment
The team includes the physical sciences (Dr Salehi-Reyhani), molecular biology (Prof Ali) and medical oncology (Prof Coombes) expertise of three world leading researchers. The student will have access to the cutting-edge research environments across Imperial College.
Supervisors:
Proposal summary
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:
The supervisors and work environment
The Huang Lab (ICR) specialises in soft tissue sarcomas and lung cancers and has ready access to patient samples and expertise in ECM characterization. The Au Lab (Imperial) is a bioengineering group that specialises in the development of organ-on-chip and tumour-on-chip microfluidic devices for studying cancer metastasis. These platforms hold numerous advantages over traditional in vitro methods for this project including:
Supervisors:
Proposal summary
Brain tumours are one of the most challenging cancers to diagnose and treat. Amongst these challenges are the fact that any surgical intervention (or even just a biopsy) carries significant risk of permanent cognitative damage, that surgical margins must be as small as possible to preserve brain tissue, that chemotherapy has limited effect due to the blood-brain barrier, and that radiotherapy carries significant risk of neurological trauma. Any technique which can recover more information from a biopsy, minimize surgical margins or diagnose tissue in situ would therefore be worth developing, particularly if it allows improved treatment outcomes without requiring poorly- tolerated therapeutic interventions.
Raman microspectroscopy is just such a technology. It is based on the inelastic scattering of light, i.e. light scattering in which the light changes colour. It turns out this colour change tells you about the molecules that the light scattered from, which in turn helps you infer the status of the sample. Unfortunately, biomedical Raman microscopy is not easy to interpret, requiring advanced algorithms to recover the relevant diagnostic information. In addition, it can be slow. Part of the student’s work may include developing new algorithms to better recover relevant information from the sample, guided by Dr Rowlands who has expertise in optical instrumentation, software engineering, algorithm development and hardware automation.
Of course, there must be a use for the gathered Raman spectra, and in this case the goal is to help classify the tumour so as to determine its sensitivity to metabolic restriction. This technique exploits the fact that tumours can rely on very different metabolic pathways to normal; it should therefore be possible to deny them critical metabolites while minimising the effect on normal cells.
The Syed lab is a pioneer of this kind of therapy, developing tumour xenografts from which to determine which forms of metabolic restriction the tumour might be sensitive to.
The supervisors and work environment
The iPhD student on this project will be able to tackle a range of different tasks, according to their interests and aptitude. This might include the development of new xenograft models, automation and refinement of the Raman spectrometer, AI techniques to provide virtual histopathological staining, or even to perform a (non-clinical) diagnosis themselves. As this encompasses a wide range of skills, the supervisory team will help train the student in the necessary methods and techniques.
Supervisors:
Proposal summary
Primary brain tumours remain amongst the most difficult to diagnose and treat due to their highly heterogeneous nature. Previous approaches have studied cell models, biofluids or tissues to elucidate molecular changes due to tumours or their treatments, but these lack spatial information. Current approaches to tackle this include imaging mass spectrometry, which is yielding promising information. However, a more detailed view of the tumour microenvironment would aid our understanding of how treatments are affecting the tumour cells themselves, and in some cases may reveal why patients do not respond to treatments.
The Phillips lab have developed an entirely new way of imaging cell sections. It works across the mid-Infra-Red spectral region and uses spectral “fingerprinting” to deliver label-free chemical maps with a spatial resolution of <3nm, i.e. beating diffraction by ~3000x. This is ~100 times sharper than a standard confocal microscope, and also considerably sharper than most implementations of either electron microscopy (EM), or any of the recent family of Nobel-prizewinning fluorescence based “super resolution” methods. Now we can see the intracellular organelles (i.e. the so-called “ultrastructure”) that were previously only accessible with electron microscopy (EM) at about 100x the complexity, time and cost. This is the first time these structures have been imaged optically and the images contain astonishing detail. There is even a possibility of finding entirely new intracellular structures, ones that don’t stain in EM.
This technology would allow for an unprecedented level of information on structural changes that occur as a result of therapeutic intervention using readily available tissue sections from both mouse models and patient samples. Moreover, it has the potential to provide diagnostically relevant information in much the same way that frozen sections are used during patient surgery but with greater detail.
The supervisors and work environment
The team includes the experimental physics (Prof Phillips), brain sciences (Dr Syed) and spectroscopy (Dr Want) expertise of three world leading researchers. The student will have access to the cutting-edge research environments across the Faculties of Natural Sciences and Medicine at Imperial College.
Imperial and ICR academics submit research project summaries; the purpose of the submission is to showcase the research opportunities that are available for prospective students. A list of project summaries can be found on this page in October of each year.
Students commencing the iBSc year review the project summaries and identify 3 projects that they would like to undertake if interested to do a PhD. After review, your top 3 preferences should be submitted to the Programme Manager. The project supervisors will be informed of the students wish to undertake their projects and will arrange meetings with you to discuss the opportunity with them.
After meeting with the supervisors, students will rank their preferred project in order of 1 to 3 and submit rankings. Your preferred choice for supervisor will be informed, and should they agree, you will work with them as a partner between January and April to develop a comprehensive PhD project proposal. The proposal will be reviewed by a panel of experts who will make judgements on scientific quality and suitability for a PhD.
Finally, an interview will be arranged for shortlisted students, which will include the student and supervisory team, to explore a) the quality, suitability and feasibility of the project for a PhD, b) the support provided by the supervisory team and c) the motivations of the student to undertake a PhD.
If you are unsuccessful in gaining your top choice of project, your second choice will also be made available to you
Flexibility underpins the iPhD Programme; we are cognisant that not all students will immediately decide to do research. Therefore, the opportunity also extends to students who may become enthusiastic about scientific research during their 15-week iBSc research project which usually starts in January. At this stage students could either submit a proposal with your iBSc project supervisor providing it is in an area of cancer research (this project could be an extension of the iBSc research) or ask to review a list of available projects. Students would then follow the ranking process as outlined in stage 3 and work with the supervisors to build a full PhD proposal for submission in April.
For more information on this opportunity send an email to Dr Garrick Wilson (garrick.wilson@imperial.ac.uk).
generation of
convergence scientists
