NIHRDataInsights/HRCSData huggingface dataset:
Title: Contribution of autophagy to the maintenance, invasion and metastasis of melanoma stem-like sub populations.
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Mouse models of cancer are a valuable tool for the investigation of tumour growth, progression and response to therapy. However, as these models likely cause pain and distress to the mouse, researchers have an obligation to minimise the use of mice, and if possible replace them with non-animal alternatives. The current proposal aims to develop and optimise two novel models, a 3D in vitro human melanoma skin equivalent (MSE) and an in vivo zebrafish xenograft of human melanoma, to replace the use of mice in research. Malignant melanoma is a growing world health concern, with an incidence that has risen more than any other malignancy in the last 40 years. Although curable by surgical resection at early disease stages, metastatic disease is highly invasive, and evolves with an extensive repertoire of molecular defences against immunological and cytotoxic attack, rendering this type of tumour, as yet, incurable. Targeting melanoma stem-like subpopulations, including those expressing stem cell markers CD271 and ABCB5, which constitute a self-renewing, tumour-maintaining subpopulation, that sustain melanoma growth and drive tumour progression, may represent a novel therapeutic strategy for melanoma. Since pilot data also suggests CD271/ABCB5 expressing melanoma subpopulations use autophagy, a critical recycling mechanism for the maintainence of cellular homeostasis, modulating autophagy may offer a novel therapeutic approach to target these cells. This project will thus use the developed MSE and zebrafish xenograft models of human melanoma to test the hypothesis that autophagy contributes to the maintenance, invasiveness and metastatic potential of CD271/ABCB5 expressing stem-like melanoma subpopulations.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Development of human ex vivo bone-tumour niche for the study of cancer bone disease
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: This proposal will standardise and validate the use of a human ex vivo assay for the study of cancer-bone disease, thereby replacing mice as the first stage model for the study of cancer cell interactions within the skeleton, and providing a new system to assess novel drugs aimed at reducing cancer metastasis to and proliferation within bone, in addition to blocking tumour-induced osteolysis. Uniform slices (0.5cm thick) of human bone from cores (0.5cm diameter, approx. 5 cm length) isolated from femoral heads removed during surgery will be cultured ex vivo. Human tumour cells (breast cancer, myeloma) will be seeded within each bone slice at a known density using either A) direct injection over 30 mins, followed by an overnight colonisation and transfer to experimental well plate; B) implantation as above followed by 1hr gentle agitation prior to overnight colonisation; C) immersion of bone slice in matrigel and implantation of tumour cells within bone/gel environment, followed by culture as in A. All cultures will be maintained for either 3, 7 or 10 days in aMEM (+1%BSA) as used previously and replenished every 3 days. Anti-cancer therapies previously tested within our group (bortezomib, zoledronate) will also be added to culture media in this assay and results compared to previous in vivo studies. As with murine skeletal samples from tumour-bone disease models, bone from this assay will be assessed by microCT scanning and histomorphometric analysis to quantify bone volume and architecture, bone mineral density, tumour and bone cell distribution. In addition, media will be collected to assess the release of bone- (alkaline- and acid phosphatase) and tumour-derived factors (PTHrP, TGF-B, myeloma-specific IgG2bk) and correlated with measurements obtained using stored serum from mice from past experiments. Representative STANDARD slices from throughout the bone core will generate baseline data with SAMPLE slices cultured under experimental conditions.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: Sources and atmospheric processes determining airborne concentrations of polycyclic aromatic hydrocarbons and their degradation products
Funder: Natural Environment Research Council

Abstract: The polycyclic aromatic hydrocarbons are a group of chemical substances present in the atmosphere which are known to be a cause of lung cancer. They are formed when carbon-containing fuels such as coal, oil or gas are burned, as well as being emitted from some industrial processes such as aluminium smelting. Whilst road vehicles and home heating are known to be significant sources, the relative amounts coming from different sources are not well known and this research intends to use measurements of these compounds in the atmosphere to infer which sources are mainly responsible. It is also known that polycyclic aromatic hydrocarbons are changed by chemical reactions in the atmosphere but the rates of these reactions are not well known and these are also to be studied. These reactions cause the formation of other chemicals known as PAH-derivatives for which measurement methods will be developed. The outcome will be a much improved understanding of the sources and processes affecting these compounds in the atmosphere leading ultimately to the possibility of more cost-effective control measures being taken.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS
Title: Living with and beyond Prostate Cancer: Does more investigation result in better health? A study of the impact on men of increased and variable investigation and treatment of prostate cancer in the Island of Ireland.
Funder: Prostate Cancer UK

Abstract: This project will exploit a unique data set from the cancer registries of two geographical areas - Northern Ireland (NI) and the Republic of Ireland (ROI) - where men are investigated and treated differently for prostate cancer. PSA and biopsy rates are higher in the ROI resulting in prostate cancer diagnosis rates that are 34% higher than NI. Men in ROI are more likely to receive radiotherapy or surgery and less likely to receive hormone therapy than men in NI. This study will look at the effect these differences have on the long term outcomes and quality of life of men who are investigated for prostate cancer in these two countries. The researchers will first look at the effect of prostate biopsy on overall wellbeing, both for men who are and men who are not diagnosed with prostate cancer as a result. They will also measure emotional wellbeing and physical side effects in men who were treated for prostate cancer 1, 5 and 10 years ago. This project will provide important information about the wider and long-term consequences of prostate cancer investigation and treatment. It will also highlight men's long term needs for supportive care services and add to the debate about prostate cancer screening.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS
Title: PET Imaging biomarkers of the resistant malignant phenotype
Funder: Department of Health (England)

Abstract: Biomarkers of drug resistance are urgently needed in oncology, so that patients are not exposed for long periods to toxic drugs which are ineffective for long periods. Objectives: The study i) resistance to capecitabine (a 5-FU based prodrug) and ii)angiogenesis in patients with locally advanced and metastatic breast and rectal cancer as angiogenesis inhibitors are commonly given to improve response rates to 5-FU based treatments.Methods: We plan to use novel PET probes of thymidine metabolism and angiogenesis namely [18F]fluorothymidine ([18F]FLT) and [18F]AH-111585, respectively, and determine the relationship between i) radiotracer pharmacokinetics and therapeutic pharmacodynamics, ii) radiotracer pharmacokinetics and other predictors of response to capecitabine i.e. plasma deoxyuridine, thymidylate phosphorylase, thymidylate synthase, CpG methylation iii) clinical response to capecitabine and changes in radiotracer pharmacokinetics, iv) [18F]AH-111585-PET and tissue/imaging methods of angiogenesis (microvessel density, expression of VEGF, expression of HIF-1alpha, microbubble contrast ultrasound/DCE-MRI)1) 30 patients with locally advanced and metastatic breast cancer will be imaged using [18F]FLT at baseline, 1-2hours post 1st dose of capecitabine, and at day 20 of capecitabine monotherapy. 2) 30 patients with locally advanced rectal cancer will be imaged using [18F]FLT at baseline, 1-2 hours post 1st dose of capecitabine. An [18F]AH-111585 scan will be performed at day 2. This will be co-registered with MRI and contrast-enhanced microbubble ultrasound, and correlated with tissue markers of angiogenesis obtained from routine biopsies. 3) 20 patients with metastatic rectal cancer: baseline with [18F]AH-111585 and after 2 weeks of treatment with an anti-angiogenic agent. Clinical response will be measured using RECIST.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Dynamic PET imaging for radiotherapy dose-painting of lung tumours: development and evaluation of movement-correction methodologies.
Funder: Department of Health (England)

Abstract: Conventional radiotherapy achieves poor outcomes for lung cancer, and `dose-painted' techniques which selectively boost radiation doses delivered to tumour regions that respond less well to treatment may be useful. However the success of this approach depends on accurately identifying regions that should receive higher doses. This is potentially achievable using dynamic PET (positron emission tomography) imaging; but dynamic PET data is collected over long time-scales during which lung tumours can move considerably, degrading the image quality. In this project image processing techniques will be developed and implemented which efficiently correct the effects of lung tumour movement in dynamic PET images.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Magnetic Resonance Lymphangiography of Breast Cancer Related Lymphoedema: clinical implementation of a novel quantitative imaging and analysis protocol.
Funder: Department of Health (England)

Abstract: There is much still to discover about the mechanisms leading to breast cancer related lymphoedema, but this understanding is dependent on the ability to produce informative images of the lymphatic vessels. Current techniques require either the repeated use of radiation or dedicated equipment, and are therefore available only in specialized centres. This project aims to create a Magnetic Resonance examination which can produce images of the lymphatic vessels without using radiation, in order to understand better what happens to lymphatic drainage. This type of examination could be available to most NHS hospitals and can be implemented using existing MRI equipment.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;6.4 SURGERY
Health categories: CANCER AND NEOPLASMS
Title: Develop better bowel cancer treatments, via translational research, into new surgical techniques including robotics, biosensors and fluorescence guided surgery.
Funder: Department of Health (England)

Abstract: Prof. Jayne's research focuses on new developments in minimally invasive surgery with the aim of bringing innovation in engineering and the biological sciences from "theory to theatre". In this he hopes to advance current surgical approaches to cancer for the benefit of patients and healthcare providers.


Research activity codes: 5.4 SURGERY
Health categories: CANCER AND NEOPLASMS
Title: Translate findings from basic cell biology science into new treatments for cancer.
Funder: Department of Health (England)

Abstract: Prof. Stebbing's research will help people living with cancer to have a better quality of life, by overcoming resistance to chemotherapy and hormonal therapy. His research aims to integrate laboratory science and clinical work to produce newer targeted therapies by utilising a new approach that focuses on a newly identified genetic tumour signature.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Improving the diagnosis and treatment of childhood cancer through functional imaging
Funder: Department of Health (England)

Abstract: Imaging is essential for diagnosing cancer and planning treatment, but current methods have significant limitations. Professor Peet's group have been developing functional imaging techniques which probe tumour properties, allowing improved diagnostic accuracy and the tailoring of treatment to the individual. Future work will concentrate on translating these advances into routine clincial practice.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Understanding how to improve the lives of men living with prostate cancer
Funder: Prostate Cancer UK

Abstract: There are >250,000 prostate cancer (PCa) survivors in the UK, a figure projected to rise to >800,000 by 2040. The needs of this increasing population remain poorly understood. A 30% higher PCa incidence in Republic of Ireland than Northern Ireland provided an ideal setting to investigate how PCa investigation and treatment impacts men's lives. We have recruited 3,504 PCa survivors, 1-17 years post-diagnosis, to the Prostate Cancer Survivorship Cohort, the largest population-based study worldwide. We seek supplementary funding to maximise the potential of this unique resource for advancing understanding of PCa survivors' needs. Using already-collected data we will investigate: (a) psychological wellbeing (prevalence and predictors of depression, anxiety and distress); (b) utility (health-related quality-of-life and its predictors); (c) functional status (patterns of urinary, bowel, and hormonal-treatment-related symptoms, and sexual functioning); and (d) treatment decision-making processes. We will conduct qualitative analyses of men's calls to freephone facilities and questionnaire freetext to illuminate men's experiences. Analyses will uncover what helps men live better after PCa and identify subgroups who might benefit from additional support. The results will inform development of interventions, support services, and policies which will have the potential to improve the lives of PCa patients/survivors in the UK and internationally.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS
Title: Development of a novel cytotopic immunotherapeutic cocktail for targeted treatment of advanced prostate cancer
Funder: Prostate Cancer UK

Abstract: Patients with advanced prostate cancer currently have two treatment options: palliative radiotherapy and Hormone ablation therapy. These treatments have considerable side effects without stopping cancer progression. Immunotherapeutic modalities have been successfully used in prostate cancer–but only in very late stage disease as they induce considerable systemic toxicity. A targeted surgical delivery of novel tissue-localisable immunotherapeutic drugs to the prostate would eliminate cancer cells in the prostate and around the body by breaking immune tolerance, with minimum toxicity to patients. We will use the novel cytotopic-modification technology, to derivatise anti-cancer proteins with amphiphilic peptide-tails for tumour localization. This technology has previously created APT070(Mirococept), a tailed CR1-fragment (now in phase I/II kidney transplant trials) which tethers to cell-membranes and inhibits complement in-situ more effectively than soluble CR1. The immunotherapeutic proteins IL-15, anti-CTLA4 and anti-PDL1 will be cytotopically-modified. For these proof-of-concept studies, we will determine the optimal doses and combination ratios needed for efficacy of these drugs in-vitro and in-vivo and will confirm whether the agents are retained in the tumour site. We propose that locally administered anti-cancer cytotopic-derivatives will have greater efficacy and retention at much lower drug doses and reduced systemic-toxicity compared to the equivalent non-tailed agents.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Imaging avb3 integrin expression in skeletal metastases from prostate cancer with 99mTc-maraciclatide single photon emission computed tomography (SPECT): staging and therapy monitoring
Funder: Prostate Cancer UK

Abstract: Currents methods for measuring treatment response of bone metastases are relatively insensitive and it can be several months before a response or lack of response can be determined. Many patients will therefore experience side effects from treatment they are not benefiting from. New imaging methods are needed to evaluate response in bone metastases at an earlier time to guide effective treatment in individual patients. v3 integrin is central to the development and progression of bone metastases in prostate and other cancers and is highly expressed on osteoclasts. 99mTc-maraciclatide is a SPECT imaging agent, targeting v3 integrin in tumour angiogenesis. Similar compounds have also shown osteoclast specificity and targeting of bone metastases. We propose a proof of principle pilot study using 99mTc-maraciclatide SPECT imaging in bone predominant prostate cancer to determine the efficacy of this scanning method for detecting and measuring treatment response of bone metastases. 25 patients with bone-predominant, castrate-resistant prostate cancer requiring systemic treatment (Abiraterone) will undergo 99mTc-maraciclatide SPECT imaging (baseline and 12 weeks). Sensitivity, level and variability of targeting will be assessed at baseline. Changes in bone metastasis uptake at 12 weeks will be correlated with clinical response, other biomarkers of osteoclast activity, tumour angiogenesis and tumour load.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Prostate cancer immunotherapy using genetically targeted T-cells, guided by a stromal-specific immunocytokine
Funder: Prostate Cancer UK

Abstract: Genetically delivered chimeric antigen receptors (CAR) can be used to target T-cells against several malignancies. Clinical studies have demonstrated the enormous promise of this technology, but highlight the requirement for sustained T-cell survival in-vivo. Furthermore, toxicity has been problematic, indicating the need to deliver T-cells precisely to tumour deposits. To develop CAR-based immunotherapy for prostate cancer, we have engineered the P28z CAR, directed against prostate specific membrane antigen. P28z is co-expressed with a chimeric cytokine receptor named 4αβ, which allows the selective expansion of the resulting “P4”+ T-cells ex-vivo using IL-4. Here, we wish to test a novel approach to enhance survival and effector function of P4+ T-cells in-vivo. An immunocytokine named FAB4 has been constructed in which IL-4 is coupled to a FAB antibody fragment that binds fibroblast-activating protein – a target that is expressed selectively in prostate cancer stroma. We hypothesize that administration of FAB4 will support P4+ T-cells maximally in prostate tumour deposits, thereby increasing efficacy and minimizing toxicity due to T-cells and cytokine administration. Here, we aim to demonstrate proof of concept for the efficacy of this approach in-vivo. Attainment of this milestone would lead on to optimisation of efficacy and toxicity assessment prior to clinical evaluation.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Role of Receptor Activity Modifying Protein-3 in regulation of lysyl oxidase-2 during tumour metastasis
Funder: Prostate Cancer UK

Abstract: Tumour growth and metastasis are dependent upon signalling between tumour cells and between tumour and host. Lysyl oxidase like-2, is an exciting new cancer drug target involved in metastasis which is responsible for over 90% of prostate cancer deaths. LOXL2 signals through a receptor accessory protein known as RAMP3. Pilot studies show that RAMP3 antibodies block cell tumour proliferation, increase apoptosis and inhibit primary tumour growth in vivo. In addition, syngeneic prostate cells injected into RAMP3 null mice fail to spread rapidly from the primary site where wild-type mice die rapidly with lung and bone metastases, though both groups develop primary tumours. This study is to determine relative contributions of intercellular communication between tumour cells and between tumour and host by injecting tumour cells lacking expression of RAMP3 or LOXL2 into prostates of mice and analysing tumour burden and RAMP3 and LOXL2 expression in tumours and host tissues near tumours. RAMP3 has potential for therapeutic development because it has a low physiological profile but high impact on tumourigenesis and progression. Intellectual property includes one granted patent on specific RAMP3 antibodies while an earlier filing with broader claims is in examination. Inhibitors of LOXL2 are already in clinical trials.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Prostate cancer response assessment and treatment stratification through circulating free tumour DNA detection
Funder: Prostate Cancer UK

Abstract: Advances in prostate cancer (PC) drug development led to the regulatory approval of several new agents for the treatment of advanced disease. The use of four to five lines of drug treatment is now standard clinical practice, hampering the application of overall survival endpoints for the next generation of drug treatment trials. Thus, the identification of innovative response markers is an urgent clinical need to accelerate the development of novel therapeutics for patients with PC. We will apply semiconductor next-generation sequencing technology to quantify tumour specific mutations in circulating free tumour DNA (ctDNA) extracted from blood samples from patients undergoing treatment for PC. Correlation of mutation quantities with existing response assessment technologies such as PSA will reveal whether ctDNA technology is a suitable new tool for response assessment. We will also use ultra-deep ctDNA sequencing technology to assess whether androgen receptor mutations, which are likely to confer resistance to abiraterone, can be detected minimally invasively from blood samples of patients with castration resistant PC. This technology may allow treatment personalization without the need for invasive biopsies. These technologies could have major impacts on the development of novel drug treatments and may foster treatment personalization, improving outcomes for PC patients.


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