NIHRDataInsights/HRCSData huggingface dataset:
Title: ASTEROID – A Phase I proof of concept study of ASTX660 in combination with PEmbROlizumab: utilizing triple IAP blockade as a strategy to maximize Immunogenic cell Death and the generation of a efficient adaptive immune response
Funder: Cancer Research UK

Abstract: Background The role of the immune system in controlling the growth of cancer has been demonstrated by the efficacy of cancer immunotherapy (CIT) in a variety of tumour types leading to survival benefits in clinical trials. It is estimated that up to half of all cancer patients could be eligible for immune checkpoint blockade using antibodies against programmed cell death protein-1 (PD-1) or its ligand (PD-L1) but only a minority respond (Haslam 2019). Translational analyses of single agent CIT studies have demonstrated that these are less effective in tumours that are devoid of T cells - suggesting that defects in effective T-cell priming may be a major immune escape mechanism in cancer. Dying cancer cells (and the mode of death by which they die) have a critical role in initiating a robust immune response. cIAP1/2 and XIAP are key members of the inhibitor of apoptosis (IAP) protein family that function as important gatekeepers of cell death and pro-survival inflammatory and immunogenic signalling pathways. ASTX660 is a small-molecule antagonist of IAPs which we hypothesise can more efficiently cause immunogenic cell death and stimulate inflammatory signalling required for the priming of an effective adaptive immune response with the potential to synergise with immune checkpoint inhibitor blockage. Aims The primary aim of this study is to define a recommended phase 2 dose for the combination of ASTX660 with Pembrolizumab. The exploratory aims of this study are to look for pharmacodynamic changes induced by ASTX660 in the tumour, tumour microenvironment and the host immune response and to evaluate the preliminary anti-tumour activity of ASTX660 in combination with Pembrolizumab. Methods A multi-centre open label Phase I dose finding and proof-of-concept study of the combination of ASTX660 together with Pembrolizumab will be conducted in patients with advanced solid tumours. Paired blood and tumour will be collected for exploratory pharmacodynamic translational assays. How will the research be used? This phase I trial will yield the recommended phase 2 dose for the combination of ASTX660 with Pembrolizumab, but also critically this study will provide comprehensive translational laboratory data on the effects of IAP blockade on not only the tumour, but also the host immune response. The translational learnings from this study will be of particular relevance to the large numbers of patients whose tumours are devoid of immune cells, likely due to a failure of efficient cross-priming leading to later stage randomised combination studies in multiple tumour types.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Understanding how epithelial driver mutations in colorectal cancer orchestrate tumourigenesis in vivo
Funder: Cancer Research UK

Abstract: Colorectal cancer is the 4th most common cancer in the UK, and the 2nd most common cause of cancer related death. Genomic sequencing has identified mutations in the tumour suppressor gene APC as the most common genetic alteration in colorectal cancer, with other recurrent mutations in cancer-associated genes such as KRAS, TP53 and SMAD4. Mutation of APC results in hyperactivation of the Wnt signalling pathway, and drives the substantially increased proliferation and altered differentiation of intestinal epithelial cells critical for tumour initiation. Given APC mutation increases Wnt signalling in a Wnt-ligand independent manner, it has made it difficult to design inhibitors to this pathway that retain efficacy in cells that have lost APC. Moreover, compounding mutations in oncogenes such as KRAS result in resistance to common, otherwise effective therapeutic strategies – a significant clinical problem. To address this problem, we will use cutting-edge genetically engineered mouse models and advanced organoid culture techniques to study all aspects of colorectal cancer initiation, progression and metastatic spread. We will identify putative therapeutic targets that specifically suppress the growth of APC-deficient cells, while sparing the normal intestinal epithelium, and novel approaches that overcome therapeutic resistance caused by commonly occurring mutations in oncogenes such as KRAS. We will then use alignment of our collection of high clinically relevant, aggressive and metastatic models of late-stage colorectal cancer to defined molecular subtypes of human disease in order to identify relevant patient populations who might respond to therapeutic challenge against putative targets. Our aim is to benefit colorectal cancer patients through improved target identification and validation that we ultimately aim to translate to the clinic.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Early detection of prostate cancer in the general practice setting: The BARCODE1 Study
Funder: Cancer Research UK

Abstract: Background The discovery of the code of the human genome has led to the anticipation that this will be able to transform healthcare. It is hoped that this will enable identification of individuals who have a higher risk of certain diseases which opens up the possibility of risk stratification for early detection. We therefore expect that early detection of cancer can be targeted to such higher risk groups who would have (i) a higher proportion of cancer; (ii) a higher proportion of cancer which needs radical treatment and if detected earlier would be more likely to be cured and (iii) an acceptability of undergoing more intensive screening techniques as such groups have more to gain from targeted more intensive screening methods as their risk of over-diagnosis is lower. Furthermore, such populations in a higher risk stratum provide greater power for the assessment of new early detection strategies as a smaller sample size is needed to identify statistically significant results using new biomarker methodology. These three paradigms are embedded in this proposal which aims to capitalise on our previous success in finding genetic risk profiles which predispose to prostate cancer. Aims -To analyse a 130 SNP polygenic risk score (PRS) in saliva samples from 5000 men aged 55-69 years in General Practice to identify men in the top 10% of the risk distribution to offer earlier prostate cancer detection -To assess the uptake of prostate MP-MRI screening in men in the top 10% of the PRS -To assess the proportion of clinically significant prostate cancer in these men and follow them up to assess outcomes -To assess metabolomic profiling to identify better markers for early detection in prostate cancer in higher risk men. Methods A saliva test will have genotyping for a 130 SNP profile and men at higher risk from this genetic profiling will be offered MRI of the prostate and biopsy. This will be correlated with metabolomic measurements of biological fluids to determine a prostate cancer screening algorithm that targets screening to those at higher risk. How the results of this research will be used. This project will assess if the new genetics can be used to target more intensive prostate analyses (MRI and Biopsy) to find aggressive disease earlier. It will also look for new markers using metabolomics on urine and blood samples. This would alter screening policy in the UK.


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: Development of advanced optical tools for early detection and diagnosis of oesophageal cancer with high mechanical and chemical specificity
Funder: Cancer Research UK

Abstract: Oesophageal cancer affects over 9000 people in the UK each year. It has very poor survival rates: overall only 12% of patients survive oesophageal cancer for ten years or more. Current diagnosis is based on endoscopy associated with biopsy/resection, which samples less than 1-2% of the entire oesophagus. Methods are urgently sought for real time detection and risk stratification of the patient at endoscopy to improve prognosis. This project is aimed at: • Using advanced analysis to establish correlations between chemical and mechanical properties of Barrett’s oesophagus (BO) at a molecular level; • Elucidating the role of cellular/molecular hydration in determining the micromechanical behaviour of epithelial tissue and whether this can provide contrast for early-stage dysplasia; • Understanding the molecular origin of elasticity of epithelial cells and the extracellular matrix in BO and whether this correlates with progression to high-grade dysplasia and invasive malignancy; • Developing a new early detection and diagnosis method based on combined Brillouin-Raman scattering across a wide frequency range through a microscope to achieve simultaneous chemo-mechanical mapping of tissues; • Testing the feasibility of using micro Brillouin-Raman spectroscopy for diagnosis of dysplastic BO, squamous dysplasia and potentially broader applicability on other pre-cancerous conditions. Vibrational spectroscopy techniques based on infrared or visible light are non-destructive, label-free and chemically specific, providing information on the molecular make-up of tissues. Raman spectroscopy through an endoscope has shown high sensitivity and specificity for detecting BO-associated high-grade dysplasia (HGD) and adenocarcinoma, as well as the ability to grade dysplasia in ex vivo tissue. Early detection and endoscopic resection of BO-associated HGD can prevent progression to invasive OC. Brillouin spectroscopy, an emerging technique in mechanobiology and pathophysiology, can provide complementary mechanical information on a subcellular scale and valuable elastic contrast, similar to a nonintrusive palpation test. Preliminary data demonstrated the existence of correlations between elasticity and composition (epithelial cells vs extracellular matrix) in BO, and Brillouin sensitivity to the water content and biomolecular make-up of tissues. Through this multidisciplinary collaboration, we propose to develop a quantitative approach to investigate the diversity in elasticity, architecture and composition of epithelial tissue in early OC and pre-cancerous states based on a combination of light scattering techniques, with high mechanical and chemical specificity. This will enable early detection of OC and potentially lead to novel treatment routes.


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 and improving the delivery of nanoparticles to tumours
Funder: Cancer Research UK

Abstract: Background: The large-scale development of nanomedicines has almost exclusively relied on passive targetting via the EPR effect, in which, here, raised vascular permeability and reduced lymphatic clearence are hypothesised to enable molecules to preferentially access and remain in tumour tissue. However, the validity of the EPR effect in cancer has been the source of considerable controversy, and whilst it has been extensively verified in animal models, it has shown much more variable efficacy in human tumours. Aims: Our aims are to better understand the cause of this variability in the EPR effect in human tumours, and to investigate ways that passive targetting can be applied effectively, such as through the physical modification of the tumour microenvironment. Methods: We will bring together three novel technologies that will be developed and applied within the project: magnetic resonance imaging (MRI), 3D microscopy and computational simulation. These will be used in combination to study the delivery of nanoparticles (liposomes) with known physico-chmeical properties, using human extracoporeal machine-perfused organs (HEMPOs) containing tumours, as models for studying nanoparticle delivery. Both metastases in resected human liver and pancreatic adenocarcinoma will be used to form a mechanistic understanding of the relationship between tumour microstructure, nanopartical physico-chemical properties and nanparticle delivery. Delivery of hyaluronidase to enable delivery of nanoparticles to pancreatic cancer will be evaluated and optimised, using both conventional and computational experiments. How the results will be used: This project will provide insights into the relationship between tumour microenvironment and nanoparticle delivery, which will enable us to form a clearer understanding of why the EPR effect is variable in humans.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Combining plasma redox-proteomics with machine learning for early detection of hepatocellular carcinoma
Funder: Cancer Research UK

Abstract: Background Primary liver cancer is the third leading cause of cancer-related death worldwide. The most common type of liver cancer is hepatocellular carcinoma (HCC), which develops in the background of liver diseases (e.g. cirrhosis). HCC incidence is rising faster than other cancers worldwide. Given the only cure for HCC is surgery, which can only be used in patients with early-stage disease, there is urgent need to develop new methods for early HCC detection to reduce mortality by increasing the number of patients who can access curative interventions. Current HCC surveillance methodologies in routine clinical practice lack sensitivity and are of doubtful cost-effectiveness, posing a substantial problem for healthcare systems. Aims Oxidative stress is common to liver diseases and cancer and there is evidence that the oxidation status of blood proteins can monitor liver diseased status. We have recently developed an innovative mass spectrometry (MS)-based plasma redox-proteomic platform to measure the oxidation status of plasma proteins. Analysis of a pilot cohort of patients with cirrhosis and early stage HCC identified a subset of plasma proteins with oxidation status altered in HCC patients. Here, we aim to create two classifiers composed by a limited number of plasma proteins whose oxidation status i) to identify patients with early-stage HCC; ii) to stratify patients with pre-existing liver disease according to risk. Methods We will analyse plasma samples from independent cohorts of patients at risk of HCC and with early-stage HCC with our plasma redox-proteomic platform coupled to a machine learning platform. We will use internal and external validation approaches to robustly identify the diagnostic accuracy of our biomarker panel in several patient cohorts, including from plasma collected in longitudinal surveillance studies. Using associated clinical data, we will test the performance of our panel in pre-defined patient groups to ensure we develop an applicable test. How the results will be used This work may lead to an ELISA assay or MS-based test for risk stratification and early detection of HCC, using minimally-invasive circulating biomarkers that require tiny amounts of blood. We will undertake further work to assess patient acceptability, where in clinical pathways the developed test can be implemented and to assess the clinical efficacy of our test in improving HCC survival in randomised controlled trials. We have access to cell lines and animal models that can be used to establish biological plausibility and causality for proteins/pathways discovered in this study.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Identification of biomarkers for the detection of pre-cancerous lesions associated with pancreatic ductal adenocarcinoma
Funder: Cancer Research UK

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a cancer of substantial unmet clinical need. It is currently the fifth leading cause of cancer deaths in the UK and this is expected to raise dramatically within the next 10-20 years. Only 5 % of PDAC patients have disease-free survival 5 years after diagnosis and medium survival is just a few months. The main issue with PDAC is that progression of the cancer is largely asymptomatic and presentation/diagnosis usually occurs when the disease is at a very advanced stage. It is therefore imperative to identify biomarkers for the early detection of PDAC. PDAC arises from pre-malignant structures known as PanINs (pancreatic intraepithelial neoplasia), which arise due to ductal metaplasia of pancreatic aciner tissue. Although the incidence of PanINs is low, their presence is a significant indicator of the likelihood of developing PDAC. This makes the detection of PanINS a fundamental step in the early diagnosis of PDAC. Previously we described a mouse model lacking autophagy which exhibits hugely exacerbated PanIN formation (Rosenfeldt et al. Nature 2013), with thousands of PanINs per pancreas. We believe this model provides a unique system in which to search for a biomarker of PanIN formation and we therefore plan to search for biomarkers in blood and urine from these mice that are either protein, microRNA or metabolite. Identified factors will then be validated in mice with lower levels of PanINs, which more so reflects the situation in normal pre-malignancy. Finally, we will examine validated potential biomarkers in samples from human patients as well as healthy individual to determine the full potential of each marker for the detection of pre-malignant lesions associated with PDAC.


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: Using a “Timeline of DCIS progression” to create an improved clinical assay for breast cancer risk
Funder: Cancer Research UK

Abstract: Background With the increased uptake of routine mammography over the past decade, diagnosis of ductal carcinoma in situ (DCIS) has risen sharply. Yet, early detection and treatment has not impacted the number of women diagnosed with invasive disease overall. This creates a substantial problem of overtreatment, since as many as 50% of women diagnosed with DCIS would not progress even without any intervention, and many more could likely be treated less aggressively. Aims We have recently completed a large study which molecularly profiled individual DCIS and co-occurring IDC lesions from 145 women. Additionally, atypia, hyperplasia, and dysplasia (ADH) were profiled, along with apparently normal tissues. Comparisons of DCIS with IDC yielded a signature of 50 maximally significant differentially expressed genes, whose expression could be used to order samples into a pseudo-timeline of progression from normal through ADH and DCIS to invasive carcinoma. The goal of this project is to create a limited panel of markers which can be used to assign individual lesions to a position along the timeline and assess their probability of progressing through it. Using a validation cohort with long term clinical follow-up, we aim to determine the relationship between our signatures and clinical outcome, including later recurrence, therapy response, and survival. Methods We will screen a larger cohort of FFPE samples using Imaging Mass Cytometry (IMC). this allows the use of ~30 markers on a single tissue section. The read out will then be normalised and data inputed to a predictor based on our pseudo-timeline, this will then be paired up with the clinical outcome of that patient to test the validity of our predictions. How the results of this research will be used Taken together, the work proposed here has the potential to develop a truly unique marker set with the potential for a multi-gene assay that will stratify DCIS cases with adequate accuracy. We hope that our work will ultimately help guide treatment choices, preventing overtreatment of those patients at low risk of progression, and promoting rapid and appropriate action for those at higher risk.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Understanding the impact of spatial dose modulations on toxicity and tumour response in lung radiotherapy
Funder: Cancer Research UK

Abstract: Background Benefits of lung-RT as the mainstay of lung cancer treatment are limited by radiation-induced lung injury (RILI). Recent developments like hypo-fractionated RT and immunotherapy have prolonged patient survival, but at the risk of increased late toxicities such as pulmonary fibrosis. Novel RT modalities providing local tumour control with reduced RILT are urgently needed for this patient group. Spatial dose modulations (SDM), as provided by mini- or micro-beams, are predicted to spare normal tissue compared to uniform broad-beam radiation without compromising their ability to achieve tumour control. We aim to test this hypothesis in a pre-clinical setting for lung radiotherapy (RT). Aims Our objectives are to: 1. Develop mini- and micro-beam irradiation technology able to deliver breathing motion-gated dose-patterns for pre-clinical lung radiotherapy. 2. Design image-processing software to automatically verify and correlate modulated dose patterns with 4D-micro-CT-images and spatially resolved pathology. 3. Determine the physical parameters providing the largest therapeutic window by assessing the impact of different spatial dose modulations in preclinical models of tumour response and RILI. 4. Understand the mechanisms of radiation response alterations from SDM by evaluating the impact on microvasculature, immune response and tissue architecture. Methods The project comprises four work-packages integrating EPS research with radiobiology and immuno-oncology. WP1: In our EPS research we will build technology for respiratory-gated dose delivery at the radiation research platform for delivery of mini-beams (0.5 – 2.0 mm) and micro-beams (50-100 microns). WP2: We will establish the dose-response dependence of different spatially-fractionated treatments compared to standard therapy in tumour growth delay studies for different tumour models. WP3: Our preclinical models for RILI will allow sensitive determination of radiation-induced lung fibrosis to determine the therapeutic window of SDM at selected radiation doses. EPS research will develop image analysis pipelines to validate and correlate spatially-modulated dose-patterns with lung pathology. WP4: Based on data from WP1-3, WP4 will focus on mechanisms of attenuation of lung fibrosis. Interference of SDM with mechanisms known in RILI or micro-beam-mediated healthy tissue-sparing will be tested. How results will be used Innovations in radiation delivery technologies enabling accurate spatial modulation of radiation dose demand an assessment of their clinical potential, initially in the preclinical setting. This project will assess the full potential of spatial radiation dose-modulation strategies for lung RT, both in terms of tumour control and toxicity attenuation. We expect our research to provide estimates of standard radiation dose equivalents that can be translated into the clinic.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS