NIHRDataInsights/HRCSData huggingface dataset:
Title: Transcriptional regulation of redox pathways
Funder: Medical Research Council

Abstract: Radiotherapy is effective in treating many types of cancers and generates oxidative stress to induce DNA damage. Ferroptosis has recently been described as a non-apoptotic form of cell death dependent on iron and lipid peroxides that can contribute to radiation-induced cell death. However, before targeting ferroptosis to radiosensitise cells, it is critical that we determine which key pathways are involved in the regulation of ferroptosis in response to radiation. Recently, we found that MAFF plays a significant role in ferroptosis by modulating ROS production and subsequent DNA damage, which will provide a new approach to enhance radiation or FLASH-induced cell killing. MAFF is a bZIP transcription factor that lacks a transactivation domain. Transactivation or repression of MAFF target genes that are involved in cellular antioxidant responses are determined by MAFF heterodimerizing with partners NRF2 and BACH1 or by forming homodimers with itself. Since ferroptosis depends on the production of reactive oxygen species (ROS) from lipid peroxidation and MAFF plays a significant role in redox pathways, we investigated ROS levels in tumour cells after inducing ferroptosis. Our data showed that ferroptosis significantly increased ROS production in control cells, while MAFF knockdown cells did not show any significant change after treatment, indicating that MAFF plays a role in ferroptosis-mediated redox pathways. In addition, lipid profiling using Mass Spectrometry revealed that loss of MAFF lead to significant changes in specific phospholipids essential for cell membranes. To investigate the role of MAFF in ferroptosis and radiation responses, 1) we will determine how MAFF regulate to induce ferroptosis. Then 2) we will examine how MAFF transcriptionally activate or repress target genes in response to radiation. Lastly, 3) we will investigate whether MAFF-mediated redox changes can be beneficial to FLASH radiotherapy. While determining MAFF target genes responsible for ferroptosis, we will also investigate how MAFF transcriptionally regulates its target genes by focusing on its chromatin complex, dimerization, and post translational modifications. To deliver our findings to translational studies, we will specifically compare the effect of conventional and FLASH radiation on ferroptosis. FLASH is a novel approach to radiotherapy, which uses ultra-high dose rates to enhance the therapeutic window. By focusing on the redox mechanisms of MAFF after radiation, we will examine whether FLASH effect can be enhanced by regulating MAFF and its target genes. Therefore, this study will provide a new approach to increase radiation or FLASH-induced cell killing through the MAFF regulation of redox pathways.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS
Title: Physics and Biology of FLASH Radiation
Funder: Medical Research Council

Abstract: FLASH radiotherapy involves cancer treatment with radiation delivered at ultra-high dose rates, i.e. with the radiation dose delivered more than a thousand times quicker than in conventional radiotherapy. This novel radiotherapy technique shows great potential in improving cancer treatment, as it appears to be less toxic to normal tissues compared to conventional radiotherapy but as effective at treating tumours. However, very little is known about the biological mechanisms behind this highly beneficial FLASH effect. We aim to identify these mechanisms, explain the effect, and to find the optimal way of implementing the technique in clinical practice. One of the main hypotheses to explain why FLASH radiotherapy is less toxic to normal tissues is oxygen consumption during the intense irradiation, leading to transient hypoxia in the treated volume. By measuring the oxygen concentration with an appropriately designed oxygen probe inserted in cell media or in mice, we aim to measure the drop in oxygen concentration during the brief irradiation. Thereby proving or (disproving) the hypothesis. We also aim to elucidate when the dose rate is high enough for the beneficial FLASH effect to occur and if it is the delivery time or the pulsed time-dose structure of the irradiation that is the important characteristic for the FLASH effect to occur. We will use whole abdominal irradiation of mice to investigate this for a variety of pulse structure profiles, evaluating toxicity sparing of normal intestinal epithelium using the Swiss-roll technique. We also aim to look at the impact of fractionated treatment for FLASH radiotherapy when treating tumours. For this, we will use subcutaneous, orthotopic, and transgenic mice models of pancreatic and bladder tumours. Treatment efficacy will be monitored and evaluated for single and hypo-fractionated treatment schemes using calliper measurements and bioluminescence and/or MR imaging. In collaboration with Lund University (Lund, Sweden), we will assist in the delivery of the treatment as well as analyse tissue samples from canine patients suffering from spontaneous tumours, for which they will be receiving treatment in Lund with FLASH radiotherapy. We will evaluate treatment efficacy as well as treatment toxicity. This is an important step towards clinical human trials with FLASH radiotherapy. In all our studies, we will be using electrons for FLASH radiotherapy, primarily with our own dedicated linear accelerator. Our collaborators at Penn University (Philadelphia, USA) will be performing similar studies as described above with protons. By combining our data, we will be able to elucidate if there is any difference in the FLASH sparing effect between the two radiation modalities.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Statistical Modelling for biomarker discovery and patient stratification in cancer
Funder: Medical Research Council

Abstract: I am interested in the development of statistical models for the analysis of large genomic and transcriptomic datasets. Specifically, my goal is to integrate large breast cancer datasets in order to identify biomarkers that can be used to stratify patients and to identify potential drug candidates for specific subtypes. The combination of clinical samples and preclinical models can accelerate the clinical implementation of new drugs, however there are multiple statistical challenges that need to be solved in order to bridge the gap between what we observe in vitro, in animal models and in the patient. Finally, these biomarkers must also be estimated through a robust and affordable genomic test.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: NCRI Clinical Studies Group Secretariat
Funder: Medical Research Council

Abstract: The Clinical Studies Groups established by the National Cancer Research Institute (NCRI) have a remit to develop portfolios of trials for specific cancer types or treatment approaches. This includes overseeing the portfolio of existing studies, considering new research questions, developing proposals and securing funding from NCRI members. The study groups are funded by the major cancer charities and by the MRC and are UK wide in their remit. The Groups are multi-disciplinary, with surgery, medical oncology, clinical oncology, radiology, pathology, epidemiology, statistics and other professions involved in clinical trials represented on each Group as appropriate. A list of the Groups is given on at http://www.ncrn.org.uk/Csg/index.htm Each Group meets at least two times per year and a number of the Groups have Sub-Groups and/or Working Parties that meet in the intervals between the main Group meetings. Some of the Groups host National Clinical Trials meetings of between 100 and 450 delegates. Each Group Chairman is responsible to the NCRN Operational Steering Group (OSG) for:The portfolio of trials developed or adopted by the Group - Contributing to studies developed or adopted by the Group - Monitoring the progress of the Group - Receiving input from the NCRN Co-ordinating Centre - Liason with other National and International trials organisations - Proposing membership of the Group in consultation with the NCRN Steering Group - Reporting to the NCRN Steering Group annually and through the triennial peer review mechanism - Providing advice to the NCRN Steering Group or NCRI, attending meetings as needed - Promoting good clinical research practice. A key aim of the NCRI partners was to double the numbers of patients being entered into cancer clinical trials in England within a three year period, this has already been achieved. The Government has provided the infrastructure to underpin phase III clinical trials through a National Cancer Research Network (NCRN). The Secretariat of the NCRI Clinical Studies Group is responsible for the overall day-to-day management and support of the Study Groups and is led by Dr Eileen Loucaides.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT)
Health categories: CANCER AND NEOPLASMS
Title: Novel plasma Human Papillomavirus DNA assay as a predictor of residual disease after chemo-radiotherapy for locally advanced head and neck cancer
Funder: Medical Research Council

Abstract: Following curative chemo-radiation (CRT), approx. 20-30% patients with locally advanced human papillomavirus related (positive) oropharyngeal cancer (HPV+OPC) undergo unnecessary neck dissection (ND) or biopsies based on results of post-CRT 18F-FDG PET-CT (PET-CT): the positive predictive value of which is sub-optimal. Therefore a more reliable marker of 'true' residual disease is required as a means of guiding management decisions. Our newly developed ultrasensitive and specific assay 'HPV-detect' can non-invasively measure the post-CRT plasma HPV DNA levels, and guide management decisions avoiding unnecessary surgical procedures. In a single centre prospective pilot study comprising test and blinded validation cohorts, we have demonstrated that HPV-detect has a sensitivity and specificity in excess of 90% in detecting HPV DNA in pre-CRT plasma, when correlated to tumour biopsy HPV status and that plasma HPV DNA levels at 3-months post-CRT correlate with pathological response. The current proposal is designed to validate the clinical utility of HPV-detect in a large prospective multi-centre study, in order to establish its potential to predict absence of residual disease. To prove specificity of 85% or above compared with PET-CT will require accrual of 143 HPV+OPC patients undergoing CRT; 48 HPV- patients will be recruited as negative controls. Plasma HPV DNA levels will be measured using HPV-detect and at 12 weeks post-CRT will be correlated with the PET-CT. Following the validation study, if HPV-detect demonstrates a specificity of 85% or above we will design a phase III randomised study comparing PET-CT versus an HPV-detect guided treatment algorithm. In parallel, in collaboration with NIHR-Diagnostic Evidence Cooperative, we will study stakeholder perceptions, barriers to adoption of the test and formulate mitigation strategies. In addition we will undertake an economic analysis to study the benefits of implementing the test in the UK healthcare system.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: DO ORIENTED DIVISIONS DICTATE FATE DECISIONS IN MAMMARY STEM CELLS?
Funder: Medical Research Council

Abstract: Adult mammary stem cells drive postnatal gland organogenesis and remodelling, and their self-renewal and fate have direct implications for breast cancer. Their true differentiation potential, however, remains unclear. We recently identified a developmental window during pregnancy where basal cells execute asymmetric cell divisions (ACDs) to achieve unequal partitioning of basal and luminal fate determinants, suggesting that ACDs allow a subset of basal stem cells to manifest bipotency. This project will test this hypothesis by assessing the dynamic relationship between spindle orientation and cell fate decisions in dividing basal cells, and how this translates into alveologenesis. Building on our recent findings establishing KIF5/kinesin-1 as the first plus-end microtubule processive motor controlling spindle orientation and apical polarity, we will determine the consequences of its knockdown in basal cells during pregnancy on the execution of ACDs, and how this impacts on epithelial differentiation and architecture. To this end, we developed a genetic lineage tracing strategy to indelibly mark and follow the fate and dynamics of single mitotic basal cells and their progeny at distinct stages of pregnancy, combined with whole-mount 3D confocal imaging. By this approach, clones arising from a mitotic basal cell can be visualized in their entirety. We will use mathematical modelling to compare the clonal data with predictions from stochastic models for cell fate dynamics, and test the potential causal relationship between mitotic spindle dynamic orientation and cell fate outcomes via Bayesian inference. This unique framework is expected to resolve bipotency in a subset of basal stem cells by establishing oriented divisions as a critical mechanism that rules their fate decisions. Our findings will be important for elucidating the mechanisms controlling the dynamic shifts within the mammary epithelial cell hierarchy, and for understanding how breast cancer arises.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The generation and maintenance of hybrid epithelial-mesenchymal (E-M) cell phenotypes.
Funder: Medical Research Council

Abstract: Cancer cells undergo a partial EMT to generate multipotent progenitors with hybrid E-M phenotypes e.g. CTCs and CSCs, which are critical for metastasis, therapy resistance and relapse. The molecular regulators that retain cells in hybrid E-M states remain uncharacterised; but their transient expression should be necessary and sufficient to maintain cells in hybrid E-M states long enough to generate progenitor cells. We hypothesise WT1 to be such a molecular regulator. This is because WT1 regulates cells undergoing EMT/MET in the embryo and maintains few adult cell-types in hybrid E-M phenotypes. And it is strongly expressed in many solid cancers including CTCs from PDAC patients. WT1 is also ranked the top oncofoetal antigen with clinical trials in many cancers showing promising results, including in PDAC. Also, we recently found that WT1 is a) sufficient to bestow potency and derive cells with hybrid E-M states , b) necessary for the E-M balance in primary PDAC in vivo, and c) a molecular switch governing EMT/MET reversibility. Therefore, we aim to define: 1. The role of WT1 in generating and maintaining the stemness window in normal and neoplastic pancreatic cells. 2. The molecular mechanisms that underlie the role of WT1 in the hybrid E-M phenotypes. Thus, we are repurposing a human pancreatic cell model known to recapitulate the multistage progression of PDAC in vitro, via organoid culture ex vivo and upon xenograft implantation in vivo. In our model, the expression of two of the commonest drivers of PDAC evolution, K-RasG12D and p53R175H, is inducible. We use xenografts as they explore late tumour stages that remain largely elusive in patients such as minimal residual disease following therapy and homing metastatic cells. This work will provide direct insights into the molecular mechanisms underlying the functional roles of WT1 and similarly mis-expressed embryonic factors deployed at the nexus of metastasis, therapy resistance and relapse.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Enhanced phenotyping of melanoma whole slide images with artificial intelligence
Funder: Medical Research Council

Abstract: Background The pathology of melanocytic lesions is one of the most difficult diagnostic areas, resulting in high levels of diagnostic discordance. This project involves the use of convolutional neural networks and random-forest algorithms to afford a reproducible, objective and quantitative assessment of the melanoma phenotype. Aim In this proposed research, we aim to: (1) develop and configure algorithms for the extraction of morphological features at a cellular level to assist the histopathologist in their assessment by providing an automated, reproducible and objective second opinion and (2) explore the use of these morphological features to generate new prognostic biomarkers and better understand melanoma growth patterns. Objectives and Methodology We will employ machine learning methods to generate quantitative cellular data by using a large dataset of whole slide images including atypical melanocytic tumours and melanomas. 3D reconstruction will be performed on a subset of cases to enable improved visualisation and analysis of morphological data as well as comparison to computer-generated models of tumour growth. Data will be correlated with survival and somatic mutation status. Opportunities This novel research will enable the derivation of previously uncaptured phenotypic metrics, which may improve the existing subjective histopathological assessment byproviding an automated second "opinion". It is hoped that this approach will increase diagnostic accuracy in this notoriously difficult area to ensure patients are treated appropriately. These new data may also enable the discovery of new prognostic biomarkers through improved tumour subtyping and through comparing this morphological data to the genomic parameters, we may be able to detect subtle morphological distinctions that indicate the underlying mutation, resulting in improved understanding of the interaction between genotype and phenotype.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Mechanisms underlying inhibition of melanoma brain metastases upon immune checkpoint targeting
Funder: Medical Research Council

Abstract: Technical summary Despite the great promise of anti-PD-1 and anti-CTLA-4 therapies in melanoma, only 11.5% of the patients show a complete response after anti-PD-1/anti-CTLA-4 combination. Thus, a better understanding of the underlying mechanisms is required in order to enable the improvement of therapy. This should include improvement of the efficacy in the brain, as brain metastases (BrM) develop in up to 60% of metastatic melanoma patients and are associated with very poor prognosis. Recent clinical trials provided initial evidence for the efficacy of anti-PD-1 and anti-CTLA-4 in melanoma BrM. Due to the distinct characteristics of the tumour microenvironment in the brain and the blood-brain barrier that limits access of drugs, the molecular mechanisms need to be addressed in the specific context of BrM. We have established a tumour transplantation model of melanoma BrM in which clinically observed intracranial efficacy of anti-PD-1/anti-CTLA-4 combination could be faithfully recapitulated. CD8+ T cells and anti-PD-1/anti-CTLA-4-induced enhancement of their chemokine receptor-dependent trafficking to BrM were critical for the intracranial therapeutic efficacy. The latter also required NK cells and correlated with a significant intra-tumoural increase in microglia and macrophages. Building upon these findings, our goals are to further elucidate molecular mechanisms underlying T cell trafficking to BrM, identify critical NK and T cell effector functions, and determine whether myeloid cells, including microglia and macrophages, are functionally implicated in intracranial efficacy of combined PD-1/CTLA-4 blockade. While primarily based in a tumour transplantation model, our studies will be further validated in a spontaneous BrM model and on human tissue. This is expected to reveal potential strategies for the enhancement of anti-PD-1/anti-CTLA-4 efficacy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Defining the microenvironmental contexture of the biopsy-naive, MRI-characterized prostate.
Funder: Medical Research Council

Abstract: Aims: 1. Define the microenvironmental contexture of non-cancerous tissue within the naïve prostate. 2. Establish the scientific prerequisites for the deconvolution of positive MRIs in biopsy-naïve men without clinically significant tumours. Objectives: 1. Define the constitution of non-cancerous biopsy tissue derived from PSA-screened, biopsy-naïve prostates of PROMIS participants with and without clinically significant tumours. 2. Decompose the microenvironmental contexture of the same tissue by specifically identifying immune cell subsets, cytokines, stromal components and cancer precursors. 3. Extract quantitative features from PROMIS MRIs that effectively discriminate non-cancer from cancer. 4. Create stromal immunohistochemical and transcriptional maps that can be aligned to MRI regions of interest and investigate their relationship with MRI visibility. Methodology: I will annotate inflammation, stroma and cancer precursors on digital H&E images of PROMIS biopsy cores. I will also perform immunohistochemistry and in situ hybridization in the same tissue to identify specific immune cell subsets (including T and B lymphocytes, NK cells and macrophages), Th1/Th2 cytokines, stromal proteins and HGPIN or ASAP. Stromal transcriptomic signatures will be obtained through tissue dissection, RNA extraction and sequencing and, finally, quantitative feature analysis of MRI areas and their alignment with tissue findings will be performed using specialized software in collaboration with imaging experts. Scientific and medical opportunities: The ability to identify pro-tumourigenic microenvironments in patients with and without significant cancer will reform existing diagnostic pathways and expedite novel research on early disease prevention or modulation. The extraction of MRI features that discriminate inflammation from cancer will also spare some men from unwarranted biopsies.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS