NIHRDataInsights/HRCSData huggingface dataset:
Title: Development of T-cell costimulatory antibodies for skin cancer immunotherapy
Funder: Medical Research Council

Abstract: Checkpoint inhibitors are not effective for many patients with cancer. Immunostimulatory antibodies (ISAs) targeting T-cell costimulatory receptors (e.g. 4-1BB, CD27 and DR3) enhance anti-tumour immunity but research is needed to improve their effectiveness in human cancers. Some ISAs depend on Fc gamma receptor (FcgR)-mediated crosslinking for optimal activity, but this can result in off-tumour toxicity and depletion of activated T-cells. Bispecific ISAs (bs-ISAs) can target ISAs to tumours without requiring FcgR-mediated crosslinking. However, the optimal costimulatory receptor targets and ISA/bs-ISA formats for many human tumours have not been resolved. I will examine the effects of ISAs/bs-ISAs on tumoral immune responses in human melanoma and cutaneous squamous cell carcinoma (cSCC), building on our experience of using these cancers as models for studying tumour immunity and immunotherapeutic antibodies. The effects of different ISAs (anti-4-1BB, anti-CD27 and anti-DR3) and isotypes of these ISAs (IgG1, IgG2 and IgG4) on tumoral immunity will be examined using ex vivo melanoma and cSCC tissue slice cultures. Flow cytometry will analyse T-cells from tumour tissue slices (for activation markers, cytotoxicity, proliferation, cytokine production), confocal microscopy will quantify tumour cell death and transcriptomic profiling will be conducted with targeted RNAseq. I will characterise FcgR expression in melanoma and cSCC and ascertain FcgR requirement for ISAs for enhancing tumoral T-cell function. Functional experiments and tumour tissue slice cultures will examine whether bs-ISAs targeting T-cell costimulatory receptors and PD-L1 provide superior co-stimulatory receptor activation and enhancement of tumoral T-cell responses compared to combination treatment with parental monospecific IgG1 antibodies and anti-PD-L1. The results of this study will evaluate whether ISAs/bs-ISAs can form a therapeutic approach for skin cancer and be informative for other cancers.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Small molecule treatments for EGFR inhibitor resistant lung cancer
Funder: Medical Research Council

Abstract: Epidermal growth factor receptor (EGFR) signalling is a key oncogenic driver. A significant proportion of non-small cell lung cancer (NSCLC), in particular, is driven by sensitising mutations in EGFR (L858R and Exon 19del). EGFR kinase inhibitors (e.g. erlotininib, gefitinib) are effective treatments but ultimately resistance develops, commonly through further mutations in the kinase domain involving T790M. More recent therapies, most notably osimertinib, are efficacious in treating T790M resistant disease and osimertinib is also becoming an established first line and adjuvant therapy. Osimertinib is a covalent inhibitor that targets C797 in EGFR, and resistance to treatment often arises through further mutations that affect this covalent mechanism, most commonly C797S. There is currently no available treatment for C797S mutated lung cancer. We have identified compounds that are capable of inhibiting growith of EGFR mutant tumour cell lines including those that carry C797S osimertinib resistance mutations. The compounds posess the properties of drug-like small molecules and their technical profiles and SAR give confidence that they are optimisable leads. A robust test casade involving enzyme assays, mechanistic and phenotypic cell assays and structural biology is in place to enable optimisation. In this project, we will opsimise the compounds to deliver an in vivo active compound for in vivo target validation.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: MICA - Developing novel single-cell multiplexing methods to identify drug targets for the treatment of multiple myeloma
Funder: Medical Research Council

Abstract: My goal is to develop novel multiplexed single-cell technologies to identify the mechanisms that contribute to Multiple Myeloma (MM) disease pathology. MM is a cancer of plasma cells in the bone marrow, that due to its rapid proliferative function, can quickly develop resistance to first line proteasome therapy. Currently, the mechanisms that contribute to MM development or drug resistance are poorly understood. A better understanding of the complexity and diversity of the MM bone marrow tumour microenvironment (TME) is required to identify novel treatment targets. Given the cellular heterogeneity within the TME, the TME needs to be studied at the single-cell level. However, current single-cell methods are costly, specialised and most are restricted to measuring only one analyte at a time, typically RNA. In collaboration with colleagues at a UK biotechnology firm, we have established cost-effective multiplexed single-cell technology that is capable of capturing both RNA and DNA on the same oligonucleotide. This technology therefore enables the measurement of both the transcriptome as well as the accessibility of the chromatin, within the same cell - an important advance in the area of single-cell technology. To realise the full potential of our technology, I will expand its utility to include the multiplexing of transcriptomics with epigenomics and genomics (mutational profiling). These improvements will be used to profile bone marrow samples isolated from pre-malignant patients, patients with MM, and MM patients with drug resistance. To facilitate biological interpretation of the data, I will develop single-cell computational tools and systems biology methodologies. These will allow me to map the interactions between the different biological components of the TME and inform how MM develops and drug resistance occurs. Ultimately, I will generate a list of priority drug targets that will be followed up by the Oxford Centre for MM Research, University of Oxford.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Developing Existing Healthcare Technologies to Deliver More Affordable and Effective Cancer Care
Funder: Medical Research Council

Abstract: Our aim is to improve cancer survival and decrease cancer morbidity by designing and implementing innovative late phase studies that have a major impact on clinical practice. We focus on adaptive trials that test more than one primary research hypothesis to increase efficiency including multi-arm multi-stage platforms, umbrella, and basket trial designs, primarily in the phase III setting. Cancer incidence is increasing rapidly, and disproportionately so in low and middle income countries (LMICs) where it is estimated that 70% of cancers and 80% of cancer deaths will occur in 2020. This programme focusses on the need for affordable and less toxic therapies that can be implemented across a range of economic settings. We evaluate existing healthcare technologies (e.g. drug repurposing or rescheduling, established imaging techniques, surgery and radiotherapy) to optimise clinical efficacy and/or broaden the patient group that can benefit. We address clinical questions others are unlikely to tackle, either due to a challenging clinical scenario, geographical setting, and/or lack of interest or support from the pharmaceutical industry. Consequently, and particularly in the future, we will focus on: a) cancers with a high incidence and mortality in LMICs; b) rarer and less common cancers; and c) prevention and early diagnosis as an affordable approach to improve outcomes. Integrated working with methodology colleagues enhances trial design, conduct and analysis, and facilitates the implementation of results. Examples of drug repurposing projects include the evaluation of aspirin as an adjuvant therapy in common solid tumours and metformin as a potential anti-cancer therapy. Immuno-oncology projects are focussed on shorter and more affordable regimens and are underpinned by novel trial designs developed at the MRC CTU. Primary prevention cancer trials are long term projects; our aim is to conduct them efficiently, making optimal use of electronic health records. We are developing an increasing network of investigators in LMICs - integral to this work is our capacity building activities in terms of education and mentorship in clinical research methodology, particularly in India. Impact is recognised by change in clinical practice and incorporation of the new clinical approach into international guidelines. Maximising the potential between discovery science and applied research is key to our strategy with biological samples from trial participants analysed by cutting edge scientists and, where appropriate, results fed back into clinical practice and future trial designs. We are also building upon our trial work particularly in prostate cancer and our aspirin-related studies to establish repositories of trial data to facilitate meta-analyses.


Research activity codes: 6.1 PHARMACEUTICALS;6.4 SURGERY;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS
Title: Improvement of NK cell-infusion therapy for metastatic breast cancer by targeting tumour-associated macrophages
Funder: Medical Research Council

Abstract: This study aims to understand and overcome the NK cell inactivation induced by tumour-associated macrophages (TAMs) in the metastatic breast cancer (MBC). Aim-1) Define the mechanisms by which TAMs suppress NK cells: By flowcytometry, Q-PCR, and our in vitro/in vivo imaging techniques, I will investigate dynamics, activation status, and effector molecule expression of NK cells in our MBC mouse models with or without TAMs. I will also identify secreted/surface factors expressed by TAM and its mimetic NK-suppressive bone marrow derived macrophage (BMM), and test whether the ablation of these factors blocks the BMM-mediated NK cell suppression by our in vitro cytotoxicity assay. Aim-2) Identify therapeutic targets that can potentiate human NK cell efficacy: I will search suppressive molecules expressed in THP1 human macrophages cultured with tumor-conditioned medium (NK suppressive) by omics analyses. I will then knockdown the candidate molecules (as well as candidates found in aim-1) in THP1 macrophages, and assess their suppressive effects on cytotoxicity of NK92 human NK cells against MDA231 human breast cancer cells. Aim-3) Develop clinically relevant models to validate candidates: Using our established protocol, I will prepare macrophages and NK cells from human induced pluripotent stem cell (iPSC), and utilize them to develop our in vitro NK cytotoxicity assay into a more clinically relevant model. I will also establish and validate an in vivo model for evaluation of NK infusion/TAM intervention therapy, i.e., I will define the effects of NK92 cell infusion with or without pharmacological TAM depletion on the metastatic tumor growth of MDA231 cancer cells injected into mammary fat pad of mice. Using these models, I will validate the identified therapeutic targets. I envisage that this research will generate novel data that impact therapeutic strategies to suppress lethal metastatic tumour formation in breast cancer patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Immuno-chemotherapeutic Metal Complexes for Cancer Stem Cell-Directed Therapy
Funder: Medical Research Council

Abstract: Cancer is one of the leading global healthcare challenges and has a high impact on society. Despite significant advancements in cancer care, fatal incidences of tumour recurrence are still common. Cancer relapse is strongly linked to the existence of cancer stem cells (CSCs), a sub-population of cancer cells that can evade current therapeutic regimens and activate tumour regrowth and metastasis. Currently there are no drugs (single or combinations) that can remove CSCs of any tissue type. The identification of chemical agents with therapeutic potential, including for cancer treatment, is of high importance for research in chemical biology and medicinal chemistry. Traditionally organic molecules have dominated research in this area, and thus relatively little is known about the therapeutic properties of metal-containing compounds. Even less information is known about the immunotherapeutic potential of inorganic compounds. The chemical diversity offered by metal complexes provides a platform to explore areas of biologically relevant chemical space that cannot be achieved by purely organic compounds. The versatility of metal complexes, which arises from the choice of metal, oxidation state, redox state, number and type of ligands, coordination geometry, magnetic and optical properties, can be harnessed to develop new agents to overcome immediate challenges in diseases including cancer. This proposal will combine fundamental inorganic chemistry and immunotherapy to develop all-in-one immuno-chemotherapeutic metal complexes to safely and selectively remove tumour cells through cytotoxic effects, and reactivate dormant immune response against residual CSCs. Specifically, we will develop copper(II) complexes that can induce immunogenic cell death (ICD) of CSCs by reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, hence acting as an anti-CSC vaccine. The outcomes of the project could ultimately lead to new strategies to achieve extended tumour remission. This is a highly multidisciplinary project that will forge new directions in medicinal inorganic chemistry, and will address key limitations in current CSC-directed therapeutic approaches.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: BioProton: Biologically relevant dose for Proton Therapy Planning
Funder: Medical Research Council

Abstract: Oxygen plays an important role in life on earth. The air that we breathe provides cells with the oxygen required for energy production. This need for oxygen increases for cells that rapidly multiply such as those associated with cancer; however, the supply is limited. As a tumour increases in size not all parts will be located near to vessels carrying oxygen rich blood. This results in a reduction in the oxygen levels in cells located furthest away from the blood vessel. It has been shown that these cells with low levels of oxygen (termed hypoxic) are more resistant to damage from radiation than those that are well oxygenated. This is also known to be the case for irradiation with protons. In proton therapy, a beam of protons is fired at the tumour in order to destroy the DNA in the cancerous cells, thus killing the tumour. The amount of energy and number of protons required to achieve this is determined by the tumour volume. Currently in proton therapy the tumour is irradiated such that the whole tumour volume receives the same dose (energy deposited per unit mass). If, however, parts of the irradiated tumour are more resistant to the radiation than others this technique of delivering a uniform dose across the tumour volume is not optimal. The research planned in this project aims to address this through the use of computer modelling and imaging to produce a method of increasing the dose to those low-oxygen radiation-resistant parts of the tumour whilst delivering an appropriately lower dose to the well oxygenated regions. This advancement will improve proton beam therapy and benefit any patient undergoing this form of cancer treatment. The benefits will include increased chance of survival and fewer side effects associated with the treatment


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Biophysics of cancer: modelling and assessing physical resistance to therapy
Funder: Medical Research Council

Abstract: This proposal will use organ-on-chip technology and Atomic Force Microscopy (AFM) to investigate the mechanical properties of in vitro cultured microtumours of pancreatic cancer as they develop under physiologically relevant flow conditions and how the mechanical stiffness of these tumours relates to drug resistance. Solid tumours develop in the body to form areas of dense, rigid tissue, similar to that of scar tissue. Within tumours, there is a complex microenvironment of biophysical conditions that determine the progression of the disease and provide physical barriers to drug delivery. Pancreatic cancer is hallmarked by a dense, fibrous tumour mass in which solid stress and hydraulic pressure cause the collapse of blood vessels, the main route for drug delivery. In addition, the high internal pressures act against the movement of drugs into the tumour mass. Yet despite these critically important physical factors, most in vitro testing of drugs is done against cell culture models that neglect these biophysical parameters entirely. This proposal we will create microtumours of pancreatic cancer by using microfluidic droplet generators to seed pancreatic tumour cell lines into microgels of defined size (500 um) and culture them under continuous flow conditions similar to what the cells would experience in the body, giving them a more natural environment in which to develop. We will use AFM to assess the mechanical rigidity of these tumours as cells proliferate and deposit matrix stiffening components into their microenvironment and compare them to the same tumours grown in static wells in order to determine the role and importance of hydraulic cues in microenvironment development. We will then use the platform to investigate the crucial relationship between the mechanical properties of these microtumours and their resistance to the penetration of drugs into their structure. We expect that the stiffer the microtumour, the less drug uptake will be observed. This will then be correlated to microtumour viability for a complete picture of tumour development and resistance to drug delivery. Lastly, using our innovative approach, we will investigate new routes to facilitate drug uptake in solid tumours by exposing microtumours to agents that actively break down the stiff matrix and potentially increase drug penetration. Pancreatic cancer remains one of the deadliest modern-day cancers, with 93% of those being diagnosed dying within 5 years. Current drug treatments for pancreatic cancer are largely ineffective. Only by improving our in vitro models of disease, in which we accurately model the mode of drug resistance, can we improve treatments and patient outcomes. This proposal focussing on pancreatic cancer but will be applicable to all solid tumours.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Defining colorectal cancer development through colonic crypt dynamics, somatic mutations and their spatial distribution in normal colorectal mucosa
Funder: Medical Research Council

Abstract: Around half of somatic mutations present in colorectal cancers (CRC) have arisen previously in normal colorectal epithelium. To become fixed, mutations must occur in colonic stem cells that succeed in populating one of the proliferative niches that define the crypt. The mutation then repopulates the crypt by clonal expansion to form a fixed mutant clone. This project will enable the frequency, spatial distribution and fixation rate of mutated clones within the mucosa of the human large intestine to be quantified and compared to the primary tumour site using multiple clonal crypt markers. Are mutant clones random and due to errors of DNA repair? Do they cluster due to toxins released from bacterial blooms or secondary mutational events occurring in prior expansions of somatically altered epithelium? As well as the distribution of mutant clones, the colonic crypt fusion/fission rate will also be assessed, the incidence of driver mutations and if there is any association between these. The longer-term objective is to understand the factors that dictate the age-related burden and distribution of somatic mutations and to establish the analytical approaches to define and quantify their impact. Mutation rate and rates of clone fixation and expansion within the background normal colorectal epithelium between patients with and without colorectal cancer will be compared. How the distribution of these events change with patient demographics and cancer type will be assessed as well as comparing patients from different global locations. For patients with cancer, the spatial distribution of mutations and relation to tumour proximity will also be assessed. By quantifying these, the differences in background mutation and clone fixation/expansion rate in these groups will be determined.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Sub-clonal RNASH2B/RB1 loss, luminal-to-basal transformation, and novel therapeutic vulnerabilities in metastatic prostate cancer
Funder: Medical Research Council

Abstract: Background: Clinical outcomes remain sub-optimal in mCRPC, which is invariably lethal. There is an urgent need for novel therapeutic strategies and predictive biomarkers. 20-30% PC patients harbour DNA repair defects. PARP inhibition is synthetic lethal with defective DNA repair impacting homologous recombination. Our lab recently reported that RNASEH2B loss (gene locus: 13q14.3, adjacent to RB1 on 13q14.2 and BRCA2), which results in the accumulation of misincorporated ribonucleotides into DNA, is synthetic lethal with PARPi. Hypothesis: Sub-clonal co-deletion of RNASH2B and RB1 is a key mCRPC vulnerability related to luminal to basal transition, sensitizing to PARPi, ATRi, and immunotherapy by generating a high neo-antigen burden. Targeting this emerging vulnerability to eradicate aggressive disease sub-clones could improve outcome from mCRPC, detectable through circulating biomarker assays. Aims: I will A) Define clinical emergence of sub-clonal PC RNASEH2B/RB1 loss with endocrine resistance and following exposure to Olaparib. I will correlate this with markers of basal/neuroendocrine differentiation and replication stress (IHC; RNAish; FISH; CTC/cf DNA sequencing); B) Evaluate the impact of RNASEH2B +/- RB1 knockdown on replication stress and response to PARPi/ATRi (CRISPR; PDX-O; Conditional transgenics); C) Determine if RNASEH2B loss associates with an immunogenic phenotype (high neoantigen burden, tumour infiltrating lymphocytes and PD-L1 expression) and immunotherapy sensitivity (Multi-colour immunofluorescence; IHC; Exome/RNAseq). D) If the above hypotheses are proven, I will establish a biomarker-driven phase II trial of PARPi+/-ATRi and immunotherapy in mCRPC with RNASEH2B/RB1 loss. Implications: I envision that this research will improve molecular stratification, targeted treatment, and clinical outcomes of mCRPC, identifying an emerging therapeutic vulnerability for aggressive, resistant basal, 'neuroendocrine', disease sub-clones.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS