Development Fund2019-11-05T15:24:35+00:00

CRUK City of London Centre Development Fund

2019 Cancer Research UK City of London Centre Development Fund Awards

The CoL Centre brings together the discovery science of the Crick and the cross-disciplinary, translational and clinical expertise at UCL, KCL and QMUL and their healthcare partners. The Centre will provide a centre of excellence in cancer biotherapeutics, with an initial research focus on tumor heterogeneity, the microenvironment and immunotherapies, and a major interest in childhood cancer.

The annual CRUK City of London Centre Development Fund provides short-term, pump-priming funding to support innovative research projects and inspirational, proof-of-concept cancer research. The scheme offers funds for up to five £25,000 awards per year.

New Development Fund Call Open for Project Submissions

If you are interested in applying for the Development Fund to support a research project fitting within the Centre’s remit, please read the application information and submit a Development Fund Application Form to cruk.cityoflondoncentre@ucl.ac.uk by Monday 10th February 2020.

For general enquiries regarding the programme please email:
cruk.cityoflondoncentre@ucl.ac.uk

The following projects have been selected for 2019 funding:

 

– Deep Learning of High Dimensional Genetic, Immune and Clinical Parameters to Predict Patient Response to Immune Checkpoint Blockade

Main applicant: Francesca Ciccarelli (Crick/KCL)

Co-applicants: Jo Spencer (KCL), Daniel Hochhauser (UCL), Manuel Rodriguez-Justo (UCL) and Kai-Keen Shiu (UCL)

– Connecting Single-Cell Ligands, Receptors, and Signals in Tumour Microenvironment Organoids

Main applicant: Chris Tape (UCL)

Co-applicants: Vivian Li (Crick)

Tumours are heterogeneous mixtures of different cell-types. In addition to mutated cancer cells themselves, the tumour microenvironment contains multiple stromal and immune cells that each contribute to a patient’s cancer. While we now understand the cellular composition of tumours relatively well, how different cell-types collectively integrate to drive cancer is poorly defined.

Our ignorance of cell-cell communication in the tumour microenvironment largely stems from our inability to simultaneously measure ligands (cues), receptors (transducers), and signals (effectors) across all cells in a tumour. Without such data it is incredibly challenging to ‘connect’ mutations in cancer cells with deregulated phenotypes in stromal and immune cells.

To address this, the UCL Cell Communication Laboratory (www.tape-lab.com) have developed a novel mass-cytometry (CyTOF) technology to measure single-cell post-translational modification (PTM) signalling in organoid models of the colorectal cancer (CRC) tumour microenvironment. While incredibly powerful for understanding PTM signalling, CyTOF data cannot describe the 1,000s of putative cell-type specific ligands or receptors responsible for transducing each signal. As a result, we cannot connect signals between cancer, stromal, and immune cells in the tumour microenvironment.

The aim of this CRUK City of London Development Fund project is to integrate our single-cell PTM technology (CyTOF) with single-cell ligand and receptor transcriptomics (10x Genomics). By simultaneously measuring cell-type specific ligand / receptor expression and PTM signalling in organoid models of the CRC tumour microenvironment (in collaboration with Vivian Li Lab, Francis Crick Institute), this will allow us to ‘connect’ cell-cell signalling across the tumour microenvironment.

– Targeting the Tumour Microenvironment to Enhance Immunotherapy: A Cross-Disciplinary Approach to Assessing Treatment Efficacy

Main applicant: Kairbaan Hodivala-Dilke (Barts)

Co-applicants: Ralph Sinkus (KCL)

Enhancing drug efficacy by manipulating the tumour microenvironment is a primary goal of our laboratory research. We have published that intravenous administration of the integrin-targetting agent, low dose Cilengitide (ldCil), increases tumor angiogenesis and drug delivery whilst reducing hypoxia and desmoplasia in gold standard preclinical models of lung and pancreatic (KrasLSL-G12D/+;p53R172H/+;PDXCre, KPC) cancers. Together this approach reduces tumour growth and metastasis, whilst extending survival (Reynolds et al., Nature Medicine, 2009; Wong et al., Cancer Cell 2015). We have also collaborated with medicinal chemists who have developed a second generation orally available agent, Agent X, currently under patent application. Our new data indicate that combination treatment including Agent X also reduces desmoplasia.

Magnetic resonance elastography (MRE) is an innovative non-invasive imaging technique that not only determines the presence of a tumour but also identifies the desmoplastic pathophysiological status of cancers and can be used to assess the anti-desmoplastic efficacy of cancer therapies. Our partner in this application, Ralph Sinkus’s has developed methods of improved MRE technologies across multiple cancer types has provided the opportunity to utilize MRE as a tool for therapy efficacy (Fovargue et al., NMR Biomed. 2018; Jamin et al., Cancer Res 2015).

Through this City of London Development Fund we now have the opportunity to join forces from Barts and Kings to examine the efficacy our new anti-cancer strategy using state of the art imaging thus bringing added-value to this cross institutional collaboration.

– CAESAR: Comprehensive Analysis of Epigenetic Heterogeneity in SARcoma

Main applicant: Iben Lyskjaer (UCL)

Co-applicants: Adrienne Flanagan (UCL), Stephan Beck (UCL) and Peter Van Loo (Crick)

Despite progress in the histological classification of the different subtypes of sarcoma, the clinical outcome of patients with the majority of these subtypes has not improved over the last 40 years. To change this, there is a need to understand the molecular basis of sarcoma in the context of clinical presentation, outcome and response to therapies.

Deep sequencing of cancer genomes has revealed complex patterns of inter- and intra-tumour heterogeneity, providing insight into a tumour’s evolutionary trajectory and is starting to inform on patient prognosis and therapeutic decisions. The main clinical consequence of tumour heterogeneity and clonal evolution is the emergence of resistance to systemic drug therapy. Epigenetics has been shown to contribute to intra-tumour heterogeneity and evolution, as first reported in haematological malignancies, by measuring DNA methylation at single-nucleotide level using Reduced-Representation Bisulfite Sequencing (RRBS).

This study aims to generate a comprehensive profile at base pair resolution of the DNA methylation heterogeneity in osteosarcoma tumours and for the first time determine if locally disordered methylation exists in osteosarcoma. Building on the samples already collected and submitted to the 100,000 Genomes project, which includes whole genome sequencing of up to 8 samples per osteosarcoma, we will interrogate DNA methylation heterogeneity at a single nucleotide level using enhanced RRBS targeting over 4 million CpG dinucleotides in CpG-rich regions of the genome. Further, we will characterise the epigenetic tumour evolution in osteosarcoma tumours by looking at multiple samples from each tumour lesion, and determine associations between heterogeneity and the presence of particular driver mutations by using WGS data from the 100,000 Genomes Project.

– Intra Tumour Heterogeneity at the Level of Ploidy: A Need to Re-Evaluate Copy Number Inference from Bulk DNA Profiling

Main applicant: Maxime Tarabichi (Crick)

Co-applicants: Nischalan Pillay (UCL), Peter Van Loo (Crick), Kevin Bryson (UCL), Andrew Feber (UCL) and Marnix Jansen (UCL)

Most cancer evolution studies, because they rely on bulk DNA sequencing data, are inevitably compromised by ambiguous estimates of tumour ploidy.

Aberrations in ploidy and in particular whole genome doubling are macro-evolutionary events that are associated with increased fitness of cancer cells and poor prognosis. The largest pan-cancer bulk DNA sequencing studies to date have relied on ploidy estimates derived in silico, which are ambiguous and often incorrect. The problem arises from the fact that, in theory, multiples of 2 times the ploidy are mathematically equivalent solutions to fit the data, and although hints in the data can help select between the various potential solutions, this exercise remains hand-wavy. In addition, tumours can show heterogeneity at the level of ploidy, containing multiple populations with very different ploidy values, which is not modelled by current copy number inference methods.

Hence, our current pan-cancer picture of heterogeneity at the level of copy number and ploidy is challenged, and, although previous and recent results strongly support the use of systematic experimental ploidy validation to inform sequencing-based copy number callers, this still has to become good practice in the field. This is especially relevant and timely for large whole genome sequencing programs such as the 100,000 genomes project, but also for all DNA-profiling-based studies of cancer evolution and intra tumour heterogeneity.

This is why we aim to develop standards for the field by benchmarking ploidy estimated from bulk sequencing against experimental ploidy using FACS, single cell sequencing and digital imaging; and study the extent and spatial mapping of intra-tumour heterogeneity at the level of ploidy. This will be done across multiple cancer types, with a particular focus on undifferentiated sarcomas, which were recently shown to display high amounts of inter- and intra-tumour heterogeneity at the level of ploidy.

– A Novel Approach for Identifying Neoantigens from Cancer Cell-lines and Organoids

Main applicant: Faraz Mardakheh (Barts)

Co-applicants: Chris Tape (UCL)

– Exploring How Rho Regulated Kinases Modulate the Immune Landscape in Colorectal Tumours

Main applicant: Angus Cameron (Barts)

Co-applicants: Shahram Kordasti (KCL)

– Exploring Order in Chaotic Cancer Genomes

Main applicant: Nicholas McGranahan (UCL)

Co-applicants: Sarah McClelland (Barts)

– Non-invasive Imaging of Immune-mediated Tumour Ferroptosis

Main applicant: Timothy Witney (KCL)

Co-applicants: Crispin Hiley (UCL)

– Identification of Novel Mechanisms of Cancer Immunoevasion

Main applicant: Paola Scaffidi (Crick)

Co-applicants: Francesca Ciccarelli (KCL), Gabriella Ficz (Barts), Julian Downward (Crick)