NIHRDataInsights/HRCSData huggingface dataset:
Title: Understanding the metastatic niche to target cancer recurrence
Funder: Cancer Research UK

Abstract: One of the main challenges that we face in treating cancer is the likelihood that, at the time of diagnosis, malignant cells have already left the primary tumour and spread to other organs. Thus, even following complete removal of the primary tumour, these disseminated cells can reside within ‘primed metastatic niches’ only to reappear later as metastasis. We are, therefore, focussed on understanding how primary tumours are able to prime organs for metastasis, how this priming may be assessed and whether the metastatic niche may be targeted therapeutically. We anticipate that a deeper understanding of the mechanisms underlying metastatic niche priming will enable us to predict patterns of metastasis, the likelihood of disease recurrence and will reveal therapeutic vulnerabilities. Our core-funded programme will be dedicated to furthering our understanding of the way in which primary tumours influence the microenvironment of metastatic target organs by addressing three interlinked research aims: 1. To establish how metabolites released by primary tumours influence invasiveness and the priming of metastatic niches 2. To determine the mechanisms through which mutant p53s generate metastatic niches 3. To investigate how a novel signalling pathway mediating ‘nuclear capture’ of endosomes promotes invasion and metastasis By addressing these aims, we will identify circulating biomarkers that can predict recurrence, and discover how tumour metabolism influences cellular processes (such as cell migration and endosomal trafficking) which drive invasion, metastasis, and awakening of dormant disseminated tumour cells.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: PRIMETIME: Post-operative avoidance of Radiotherapy In Minimal risk womEn: Translational bioMarker ImplemEntation
Funder: Cancer Research UK

Abstract: Background Earlier detection and improvements in patient management have dramatically improved outcomes for women with breast cancer. Following breast conservation surgery (BCS), systemic therapy is standard and currently radiotherapy (RT) is recommended for all women. It is hypothesised that a subgroup of patients can be identified supplementing clinico-pathological factors with immunohistochemical biomarkers where a very low local relapse (LR) rate can be predicted such that RT and its associated risks could be safely avoided. Aims In women aged =60 years (or younger with relevant co-morbidities) with favourable pathological features treated for early breast cancer by BCS and adjuvant endocrine therapy to: • Use immunohistochemical biomarkers (IHC4-C) to direct selective avoidance of RT • Assess ipsilateral LR risk at 5 years (primary endpoint) and 10 years following omission of postoperative whole breast RT • Confirm viability of collecting data relating to cancer outcomes using record linkage with the National Cancer Registration Service. Methods The study design is a prospective cohort with treatment directed by IHC4-C biomarker algorithm recruiting women treated by BSC and prescribed prolonged endocrine therapy for whom the residual risk of LR in the breast is estimated to be much less than 1% per year. The target population is women aged =60 years (or younger with relevant co-morbidities) following complete microscopic resection of pT1/G1-2/ER+/PgR+/HER2-/pN0/M0 invasive breast carcinoma, with =1 mm microscopic margins of normal tissue. IHC4-C algorithm will be used to assess whether or not the patient is classified as VERY LOW risk of recurrence (recommended avoidance of RT) or not (standard RT). To allow the local relapse rate to be estimated with a precision of ˜1%, the study aims to recruit a total of approximately 2200 women (assuming 70% of those screened are classified as VERY LOW risk). The study will establish mechanisms for collecting data (local, distant relapse, death, cause of death) directly from routinely collected health data by setting up record linkage with NCRS datasets and test the accuracy and completeness of such a system to inform the viability of such methods for future studies. How results will be used Results will potentially reduce the treatment burden for patients, confirm the viability of collecting research outcome measures via national databases and save costs by changing UK and international practices.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Full Duration Non-clinical Studentships - Accelerator Award A26813 "HUNTER: Hepatocellular Carcinoma Expediter Network"
Funder: Cancer Research UK

Abstract: HUNTER – Hepatocellular Carcinoma Expediter Network Background Primary liver cancer, predominantly hepatocellular carcinoma (HCC), is the 2nd commonest cause of cancer death globally. While mortality from other cancers is falling, HCC mortality is escalating –because incidence is rising, but also because many HCC are detected at advanced stages when surgical cure is not possible and medical treatments are limited. Recent studies using immune checkpoint inhibitors have elicited remarkable responses in 20% of HCC patients. While not all patients are responders, these trials offer genuine hope that immunology-focused research may hold the key to better treatments for many more patients. The pressing scientific need is to understand how the diseased liver microenvironment and combined molecular cues determine immune cell phenotypes promoting HCC development or progression. Aims 1.To create an HCC-specific network of clinicians and scientists, embedded within the wider community 2.Delivery of a multi-omic integrative analysis of the HCC immunology landscape in archived tissues 3.Creation of a high quality prospective tissue & data collection - standardised, contemporary and fit for purpose, to support HUNTER and research community initiatives 4.Identify and further characterise candidate immunosuppressive mechanisms and biomarkers 5.Develop preclinical models that recreate the tumour and its environment 6.Establish high-dimensional platforms for analysis of HCC immune escape mechanisms 7.Creation of the first HCC focused PhD training scheme for scientists and clinicians Methods The Patients with advanced HCC that are fit to treat presenting to any one Unit are scarce, as are the clinicians and scientists with the required research expertise for the analyses. HUNTER will bring together outstanding investigators from UK, Spain and Italy who will work together to deliver (1) the urgently needed fresh tissues resource, (2) a PhD training programme, (3) the immunogenomic and metabolomic characterisation of the immunosuppressive HCC microenvironment, and (4) the relevant pre-clinical animal and human models required for translation. How the results of this research will be used HUNTER will create the team, knowledge, resources and models that will enable the research community to answer specific research questions centred on the stratification, monitoring and improvement of immunotherapy for HCC. HUNTER will accelerate research addressing the urgent medical needs, namely: 1. To identify biomarkers predicting response to existing immuno-modulators 2. To provide the resource and knowledge that will aid the future identification of novel molecular targets for harnessing immune control of HCC 3. The development of models that recapitulate the tumour microenvironment needed for preclinical testing


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: CRUK/12/041: BALLAD - A global study to evaluate the potential benefit of adjuvant chemotherapy for small bowel adenocarcinoma (International Rare Cancers Initiative study - IRCI 002)
Funder: Cancer Research UK

Abstract: Background Small bowel adenocarcinoma (SBA) is a rare cancer, representing less than 5% of gastrointestinal cancers. SBA carries a poor prognosis at all stages. For SBA patients who undergo potentially curative resection there is a 40-65% 5 year overall survival, whereas patients who have a non-curative resection, this is only 15-30%. To date there is no standard ajuvant regime to treat these patients. Given the lack of good quality, evidence based data, it was agreed that a study considering adjuvant chemotherapy versus no chemotherapy was appropriate for patients in which the benefit of adjuvant chemotherapy was uncertain. For patients who are unwilling to accept randomisation or where the benefit of chemotherapy is certain there would be a randomisation between single agent 5FU or Capecitabine versus 5FU or Capecitabine plus Oxaliplatin. Aims Assessment of the efficacy of observation against 24 weeks of adjuvant post-operative chemotherapy Assessment of the efficacy of 24 weeks of adjuvant post-operative 5FU/Capecitabine monotherapy versus 5FU/Capecitabine plus Oxaliplatin Secondary aims include the assessment of toxicity of chemotherapy, assessment of the cost effectiveness of the treatment alternatives and the establishment of a central data/biospecimen/tissue bank for patients with this rare cancer Methods This will be an open label, randomised controlled, multi centre, global study with disease free survival as the primary end point Patients will be randomised in 2 separate groups Group 1 - Patients where the benefit of chemotherapy is uncertain. These patients will be randomised 1:1 to chemotherapy versus no chemotherapy Group 2 - Patients where the benefit of chemotherapy is clear and those not willing to accept a no treatment arm. These patient will be randomised 1:1 between 5FU/FA or Capecitabine with or without Oxaliplatin. The site will be able to chose between 5FU or Capecitabine prior to randomisation for individual patients Results/Analysis The following approach will be taken for both study quesions. The primary frequentist analysis will be a conventional analysis of DFS using Cox regression tecniques in the ITT population. Assuming this result is statistically significant at 20% one sided level of statistical significance this result is then combined with the clinicians prior to determine a final posterior distribution.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/15/077: EARL - Electrocautery ablation for the prevention of lung cancer (the EARL trial)
Funder: Cancer Research UK

Abstract: Background: The majority of patients with Lung Cancer present with advanced disease, precluding curative treatment. Earlier detection and treatment should improve survival. Squamous cell lung cancer accounts for 43% of cases and develops through a succession of increasingly severe pre-invasive stages, readily identified by autofluorescence bronchoscopy (AFB) and accessible to biopsy. Our internationally unique cohort shows 60% of patients with High Grade Lesions (HGLs) progress to cancer within 3 years. Using conventional treatments of surgery or radiotherapy harms normal lung tissue and hence there is a motivation to eradicate these lesions with a tissue sparing therapy. Photodynamic therapy (PDT) has proven to be an excellent ablative therapy in early lung cancers and pre-invasive disease of the oesophagus and oropharynx. Its tissue specificity, efficacy and repeatability lead us to believe it is the correct therapy to trial for airway HGLs. We will therefore perform the first randomised control trial of treating HGLs. Hypothesis: PDT treatment of HGLs will reduce the rate of lesion progression to invasive cancer compared to standard clinical practice of surveillance bronchoscopy alone. Method: This is a phase III multicenter 2:1 randomised control trial, with an incorporated phase II (pilot) component to examine accrual and response. Patients will be randomised to either (A) PDT and AFB surveillance (intervention arm) or (B) regular AFB surveillance alone (control arm). We will recruit 100 patients (24 in phase II) to detect progression rates of 30% and 60% in the intervention and control arm, respectively (2-sided alpha of 5% & power 80%). Outcomes: (i) Primary outcome: Proportion of patients who have histological evidence of progression to cancer based on histological classification at 3 years. (ii) Secondary outcomes: HGL regression, time to progression, lesion dimension and depth, number of invasive cancers, new HGLs, HRQoL (EQ-5D-5L, LC-13), quality adjusted life years (QALYs), resource utilisation, spirometry and biomarker evaluation. (iii) Translational research: Determine whether changes in cell cycle proteins and genetic architecture can predict lesion progression and treatment response and create the largest tissue biobank of its kind. Conclusion: Early detection and treatment are not only primary goals of the NHS and CRUK, but desperately required by patients. A successful outcome in this trial would give us a therapy that will prevent the development of lung cancer. PDT will be incorporated into international guidelines and will become the standard of care for treating HGLs.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: CANCER AND NEOPLASMS
Title: ASCENT: Analysis of screen-detected lung cancers genomic traits
Funder: Cancer Research UK

Abstract: Background: Low-dose CT scanning (LDCT) for lung cancer has been shown to reduce lung cancer-specific mortality in high-risk populations. In lung cancer screening (LCS), a high proportion of lung cancers are identified at an early, resectable stage. However, several risks to participants exist including over-diagnosis of prognostically insignificant cancers, undergoing invasive procedures for benign disease, or risking disease progression during radiological surveillance. In anticipation that LCS programmes are likely to commence world-wide implementation soon, more information is needed regarding screen-detected nodules/cancers to refine diagnostics and optimise LCS outcomes. In 2019, University College London will launch the LCS trial ‘SUMMIT’, in which 25,000 London participants will undergo LDCT screening. Cancers detected will be prevalent (first screen), incident (found between screens) or nodules that grow quickly or slowly, assessed by volume doubling time. We propose to relate genomic analysis to growth rate in tumours resected from this cohort. This will enable combining further clinical and radiological data and peripheral blood analysis, yielding a significant resource to study potential biomarkers determining nodule/cancer/patient outcomes and hence reducing potential screening harms. Aims: 1. Establish a biobank of resected screen-detected tumours, alongside matched peripheral blood samples, clinical and radiological data and survival trends. 2. Identify markers of clinical significance by performing whole exome sequencing on cancers diagnosed during surveillance/interval LDCT scans and correlating genomic signatures to radiological rates of growth. Methods: Tumour surplus to diagnostic requirements will be collected at the point of resection and frozen. These will be matched to existing SUMMIT data (including clinical information, LDCT datasets, baseline blood tests and survival trends), alongside additional perioperative blood samples collected to enable cell free tumour detected nucleic acid (cftNA) analysis. From this biobank, tumours diagnosed during surveillance/interval LDCT will undergo whole exome sequencing, assessing genomic traits including but not limited to: copy number alterations, presence of recognised mutation signatures or driver mutations, and tumour mutation burden. These trends will be correlated to radiological growth rates to characterise genomic differences between fast-growing versus more indolent screen-detected cancers. How the results of this research will be used: Data from this initial analysis will inform future programmes of work, namely identifying potential biomarkers in peripheral blood or radiomic signatures identifying adverse prognostic features in this cohort through non-invasive means.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Leukaemia Biology Group
Funder: Cancer Research UK

Abstract: Background Acute myeloid leukaemia (AML) is defined by a block to the normal differentiation of myeloid cells resulting in accumulation of blasts in the bone marrow and failure of normal haematopoiesis. Despite the genetic heterogeneity the differentiation block is the cardinal feature of the disease and emerging evidence reveals that mutations cluster in particular categories of gene. Indeed, the great majority of patients with AML have one or more mutations targeting a transcription factor, chromatin modifier or regulator of DNA methylation emphasising the absolute centrality of epigenetic and transcription factor dysfunction to the disease. Investigation of this dysfunction holds rich promise for discovery of new therapeutic targets for development through to the clinic: AML remains a significant cause of morbidity and mortality, with poor survival. Our recent work has uncovered new aspects of this dysfunction as well as therapeutic opportunities. We discovered that two transcription factors, FOXC1 and IRX3, which are neither required for nor expressed in normal haematopoiesis, are frequently expressed in AML conferring a block to differentiation. We also discovered that some leukaemias are dependent upon the transcription factor GFI1 which, unexpectedly, can be inactivated therapeutically by inhibitors of LSD1, a protein hitherto best known for its histone demethylase activity. Indeed, following our identification of LSD1 as an effector of the differentiation block in MLL-translocated AML, we completed a successful first-in-man, first-in-class phase 1 trial of the inhibitor ORY1001 demonstrating drug-induced differentiation of leukaemic blasts in patients. Aims We propose to address the following questions: 1: How are transcription factor genes FOXC1 and IRX3 derepressed in AML? 2: How do derepressed transcription factors FOXC1 and IRX3 confer a differentiation block in acute leukaemia? 3: How can existing and new treatment targets in AML be uncovered and developed towards the clinic for patient benefit? Methods & how the research will be used At the heart of the program will be exceptional access to clinical material from patients undergoing treatment at The Christie and our ability to expand substantially patient cells in vitro in stromal co-culture and in vivo as patient-derived xenografts. Questions will be addressed using state-of-the-art sequencing and mass spectrometry techniques, as well as model systems and genetic strategies, including CRISPR. Through our links with the Institute’s Drug Discovery Unit and pharma, targets, drugs, biomarkers and approaches identified by this programme will be carried forward to clinical trials for evaluation with improved patient outcomes being the goal.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Cellular and molecular origins of cancer
Funder: Cancer Research UK

Abstract: The principal aim of my research is to reduce the morbidity and mortality of patients with cancer through improved understanding of tumour biology. With a particular focus on children’s brain tumours, we are working to understand the cellular and molecular origins of cancers and the pathways that drive them. We hope to achieve this goal by: ?Conducting extensive genomic analyses of brain tumours to identify cancer causing genetic abnormalities. ?Integrating studies of genetic and cell signal alterations in cancers with studies of normal progenitor cells to determine the cellular and molecular origins of tumours. ?Understanding the impact of signaling pathways on normal stem cell biology and tissue development Translating knowledge of tumour biology into effective new cancer cures through pre-clinical and early clinical trials of molecular targeted therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS
Title: Mechanism and selective targeting of ubiquitin ligases
Funder: Cancer Research UK

Abstract: Background The ubiquitin system comprises more than 1000 proteins that coordinate to modulate cellular protein levels and signalling processes. In cancers, components of this system are often deregulated or hijacked to promote oncogenic signalling or escape immune surveillance. Ubiquitin ligases (E3s) perform the final step of ubiquitin conjugation to protein substrates, and in cancers in which E3s are altered, the specificity of the E3-substrate relationship presents an opportunity for therapeutic intervention. CBL and MDM2 E3s are linked to a variety of cancers. Mutations in CBL are found patients with myeloproliferative neoplasms. In mouse models, CBL mutants elicit oncogenic signals that promote development of leukemia. CBL proteins function as key checkpoints in inhibiting the activation of host immune cells to combat cancers, suggesting targeting CBL proteins has potential in immunotherapy. MDM2 plays a critical role in regulation of the tumour suppressor protein p53. While mutations in p53 are identified in many cancers, nearly 50% of cancers retain wild type p53 but have concomitant elevated levels of MDM2 and loss of p53 activation. Several compounds are currently in clinical trials to reactivate p53 by inhibiting the MDM2-p53 axis but on-target toxicities limit the efficacy. Our recent study demonstrates that targeting the ligase activity of MDM2 is an alternative method for reactivating p53 with potential fewer on-target toxicities. Aims The proposed programme aims to develop and characterize molecular probes that modulate select E3 functions of CBL and MDM2 and to use these probes to explore the potential of targeting these E3s for developing cancer therapeutics. We also seek to further elucidate the mechanisms and functions of both E3s. Methods Our approach involves identifying inhibitors of MDM2 and CBL using phage-displayed ubiquitin variant and peptide libraries, validating their binding mechanisms using structural studies and biochemical and cell-based assays, and assessing their effects in cancer cell lines. We will also apply Cryo-EM and mass spectrometry analyses to explore the mechanisms and functions of both E3s. How the results of this research will be used The programme will expand our knowledge of the roles and functions of CBL and MDM2 using structural and cell biology studies and produce molecular probes selective for these two E3s. Some of these probes are small molecules that are suitable starting points for the development of cancer therapeutics.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS