NIHRDataInsights/HRCSData huggingface dataset:
Title: Towards an early detection programme for myeloid malignancies
Funder: Cancer Research UK

Abstract: The myeloid malignancies are a range of related neoplasms, including the myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Collectively, they affect 8-10 per 100,000 individuals per year and are lethal to the majority. Advances in cancer genomics have uncovered their genetic basis and the identification of the phenomenon of clonal haematopoiesis (CH) has highlighted their common pre-clinical ancestry. Despite such progress, myeloid cancers remain lethal to the majority of sufferers, therapy has changed little over 25-30 years and prevention or early diagnosis programmes are entirely lacking. We recently demonstrated that individuals at risk of developing AML can be identified years in advance by studying the characteristics of CH clones by whole-blood DNA sequencing. In addition, we observed that non-genetic markers, such as increased variation in red blood cell size, are independently predictive of leukemic progression. Our findings provide proof-of-principle that myeloid cancers can be predicted years in advance, but our predictive power is limited and our models cannot be used in screening programmes. In separate studies, we and others also observed that somatic mutations alone cannot predict clonal behaviour of CH and that non-mutations factors (e.g. ageing, chemotherapy), significantly influence clonal growth. In this proposal, we aim to identify non-mutation factors driving CH progression and develop new scalable approaches that can be used to i) identify those with CH and ii) improve our ability to identify those at risk of leukaemic progression. Our overarching aim is to lay the foundations for the initiation of early detection programmes for myeloid cancers. We will identify a cohort of 120 individuals with CH and 30 controls, by screening 900 volunteers aged over 60 years. We will follow up these individuals for 4 years, study the characteristics of their CH over this period and identify factors that influence clonal behaviour/expansion by examining health/medication/lifestyle factors, routine blood parameters, plasma cytokine levels and functional assays of mutant blood stem cells. In parallel we will performed detailed studies of blood cell parameters and use deep learning approaches to identify morphological features predictive of clonal behaviour from blood smears. We will use the findings of our work to develop more potent predictive models to identify individuals at risk of leukaemic progression and establish a rational approach for clinical management of these individuals. In addition, we will use our findings to derive insights into potential therapeutic approaches that can influence progression of CH.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: CRUK Beatson Institute Drug Discovery Programme
Funder: Cancer Research UK

Abstract: One of the key aims of the Beatson Institute is to translate our basic research for patient benefit and we are working towards this goal in two main areas; drug discovery based on biological pathways under investigation in the basic science programmes and links with clinical trials through our clinical colleagues. Our goal is to establish an integrated, industry-standard drug discovery programme to translate basic biology research from the Beatson and other CRUK centres into medicines for the treatment of cancer. The Drug Discovery Programme (DDP) at the Beatson has established expertise in Fragment-Based Drug Discovery (FBDD) within the Structural Biology group, integrated alongside Chemistry and Biology. State-of-the-art 600MHz NMR with cryo-cooling is used in conjunction with Surface Plasmon Resonance (SPR) as our primary fragment screening technologies, backed up by X-ray crystallography.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/14/026: ENRICH - Randomised, Phase II open label study of Rituximab/Ibritinib vs Rituximab/Chemo in older patients with mantle cell lymphoma
Funder: Cancer Research UK

Abstract: Background Mantle cell lymphoma (MCL) is a relatively rare type of Non-Hodgkin’s Lymphoma with an incidence of 1 per 100,000 of the adult population. For younger patients with this condition the treatment of choice involves intensive chemotherapy combined with the monoclonal antibody rituximab, followed by a stem cell transplant. However the median age at presentation of this disease is in the mid 60’s that precludes this treatment option for the majority. For older patients the current treatment of choice involves less intensive chemotherapy with rituximab followed by a period of maintenance therapy with rituximab alone. The best overall results reported in a multi-centre setting use the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) regimen. Whilst this combination delivers high response rates, all patients relapse and it is associated with universal alopecia, a 17% incidence of Gd III/IV febrile neutropenia, 4% cardiac events and an associated mortality of 2-4%. The oral BTK inhibitor ibrutinib is a new agent that produces unprecedented responses in MCL when used as a single agent in patients with relapsed refractory disease. The overall response rate observed is approximately double that seen with other single agent drugs in this setting with very few in the way of side-effects. The addition of rituximab to ibrutinib may increase response rates compared with ibrutinib alone without significantly increasing toxicity. Aims & Methods This is a randomised controlled trial that compares the standard chemotherapy approach with a novel chemo-free strategy for older patients with newly diagnosed MCL. The chemotherapy arm in this study is permissive between CHOP & Bendamustine. These chemotherapy options will allow the inclusion of older frailer patients. Chemotherapy will be randomised against ibrutinib, which will be given daily until disease progression. Both arms will contain rituximab delivered in the same schedule, which will allow a indirect comparison of chemotherapy versus ibrutinib in this clinical setting. The primary end point of the trial is progression free survival and is powered for superiority. However, if the novel arm of this study is not superior then it may still be considered a better arm if non-inferior but with significantly better toxicity and quality of life profiles. The results may be used to guide future treatment of older patients with newly diagnosed mantle cell lymphoma.


Research activity codes: 6.1 PHARMACEUTICALS;6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Investigating the contribution of gamma-delta T-cells to immunosurveillance of cancer and response to immunotherapy
Funder: Wellcome Trust

Abstract: Gamma-delta T-cells are critical for protecting against carcinogenesis in mice but clinical associations have been equivocal and human trials of gamma-delta T-cell therapy have been disappointing. Previous studies have been limited by unavailable technologies to describe these cells with sufficient granularity whilst clinical trials have largely focussed on the more numerous V-delta-2 subtype. Using contemporary methods such as TCR-sequencing and ex vivo culture systems to extract gamma-delta T-cells from human tissues, we recently demonstrated that only certain subtypes of these cells, namely the V-delta-1 subtype, are associated with survival in triple-negative breast cancers. This proposal aims to extend our previous findings to a pan-cancer setting by mapping, with greater and necessary detail, these cells in melanoma, breast, lung and other cancers with a particular focus on V-delta subtyping, differential effector functions and cell regulatory axes. Importantly, we will also map gamma-delta T-cell interactions with alpha-beta T-cells as these cells have been established as being critical to cancer immunosurveillance. We will stratify our findings to clinical outcomes to build a novel reference human tumour gamma-delta T-cell atlas to guide ongoing translational efforts in adoptive gamma-delta T-cell therapy. Hence, this proposal may lead to rapid translation into clinical benefit.

Lay abstract: Modifying the immune system, particularly T-cells, can now cure some patients with stage-4 cancer. However, most patients do not benefit. T-cells are white blood cells which can be further divided into alpha-beta and gamma-delta T-cells. Most current therapies work on alpha-beta T-cells. Gamma-delta T-cells can control cancers in mice, but remain under-utilised in human therapy as clinical trials involving these cells have been disappointing. Using modern sequencing and cell-growing technologies previously not widely available, we recently demonstrated that only certain gamma-delta T-cells, the V-delta-1 subtype, predict survival in aggressive breast cancers. Here we will extend the characterisation of these cells, in far greater detail, into a pan-cancer setting to include melanoma, lung, breast and other cancers. By defining what makes these V-delta-1 cells protective, we will instruct ongoing and future gamma-delta T-cell therapy trials and thus open up effective immunotherapy to those who do not benefit from alpha-beta T-cell therapies.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRAIN: A phase 1b clinical trial with dose escalation and dose expansion phases of ASTX660 in combination with standard radical radiotherapy in cervical cancer with chemoradiation
Funder: Cancer Research UK

Abstract: Background Inhibitors of Apoptosis Proteins are considered attractive targets for anti-cancer therapy. Antagonists of these proteins have the potential to switch pro-survival signalling pathways such as TNFa signalling, in cancer cells towards cell death, thus promoting apoptosis. ASTX660, developed by Astex Pharmaceuticals, is a novel dual cIAP1/XIAP antagonist currently in clinical trials for treating advanced solid tumours i.e. head and neck squamous cell carcinoma (HNSCC), cervical carcinoma and other tumour types that are characterized by a molecular feature that may confer sensitivity to ASTX660, and various lymphomas. Preclinical studies performed using ASTX660 in combination with cisplatin and radiotherapy (RT) showed an inhibition of tumour growth and enhanced survival in multiple HPV+/- HNSCC models. Additional data using a syngeneic mouse oral cancer (MOC) models also showed ASTX660 in combination induced tumour growth inhibition compared to RT alone and ASTX660 alone. Therefore, there is a good rationale to combine ASTX660 with cisplatin and radiotherapy chemoradiation schedules which are standard of care in cervical cancer. Cervical cancer remains a major cause of death from cancer worldwide and improvement in locoregional control is closely related to survival improvement hence this study has the potential to improve survival in a population of relatively young active women. Aims: 1. To determine the safety and maximum tolerated dose (MTD) of ASTX660 with cisplatin based chemoradiation (CRT) in primary treatment and establish a recommended Phase 2 dose (RP2D). 2. To determine whether the efficacy seen warrants a future phase II/III randomised study of CRT compared with CRT+ASTX660. 3. To incorporate translational studies which test biomarkers which have the potential to identify patients likely to do well or poorly during front line treatment (genomic signature analysis and circulating tumour cells). Methods: This is a phase 1b, randomised, non-comparative, open-label, multicentre study to characterise the safety and clinical activity of ASTX660 when administered in combination with cisplatin based CRT to patients with newly diagnosed cancer of the cervix. How the results of this research will be used: The results from this phase 1b study will be used to justify and inform a phase II/III study.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Real-world risk-stratified early detection and diagnosis using linked electronic health records data (RREDD-EHR)
Funder: Cancer Research UK

Abstract: Most patients with cancer initially present with symptoms to general practitioners. To achieve faster diagnosis, we need to improve our ability to assess the risk of cancer in these patients. The tools currently available to doctors typically focus on the presence or absence of typical cancer symptoms; however, half the patients do not present with such symptoms. The patient’s medical history, such as the previous use of prescriptions and diagnostic tests (and their findings) and whether a patient suffers from chronic conditions, and their underlying susceptibility to cancer, are usually not taken into account. We will aim to enhance our ability to calculate the risk of as-yet-undiagnosed cancer in patients presenting to primary care with symptoms. We will, analyse data on symptoms combined with treatment and diagnostic test history; update risk calculations at different times as information accumulates along the diagnostic process; incorporate information on pre-existing conditions to improve estimates; include information on underlying risk of developing cancer, taking into account genetic and lifestyle exposures; and evaluate the possible use of artificial intelligence/machine learning. We will use Electronic Health Records from primary care data sources, where possible linked to hospital care, diagnostic imaging and cancer registration data. The work will enable doctors in their assessment of cancer risk; and support clinical guidelines development and healthcare policies.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Elucidating the role of the extracellular matrix as a nutrient source to fuel breast cancer cell metabolism
Funder: Cancer Research UK

Abstract: Background. Altered cellular metabolism is one of the hallmarks of cancer. Due to tumour growth rate and limited blood supply, the tumour microenvironment is often hypoxic and deprived of nutrients (including glucose and amino acids). Cancer cells have been shown to use extracellular protein to support nutrient signalling and cell growth; however, the contribution of a complex 3D extracellular matrix (ECM) and its endocytosis to cancer cell growth and metabolism is very unclear. Aims. Here, I will characterise the contribution of the extracellular matrix in fuelling breast cancer cell growth in 3D environments. My preliminary data indicate that the presence of a collagen I, matrigel or laminin/entactin matrix is sufficient to rescue breast cancer cell growth in nutrient deprived conditions, in a way that requires ECM endocytosis. Interestingly, the ECM promotes cell growth/survival in the absence of amino acids or glucose, but not in serum, suggesting that the lack of specific nutrients can be compensated, at least in part, by the ECM. Furthermore, the ECM promotes cell proliferation under glutamine and amino acid starvation, but not serum or glucose, while it significantly reduces apoptosis in glucose-free media. Taken together, these data suggest that the ECM can sustain cell growth/survival through different mechanisms depending on the specific starvation conditions. I therefore hypothesise that, under nutrient-deprived conditions, breast cancer cells use ECM internalisation and breakdown to support their proliferation/survival. To investigate this, I will assess the contribution of complex 3D matrices and ECM receptors to cancer cell growth and elucidate whether ECM trafficking is driven by nutrient starvation. I will define how ECM internalisation impinges on cell metabolism and nutrient signalling and whether ECM-dependent growth is promoted during carcinoma progression. Methods. I will use imaging-based approaches to quantify cell growth, proliferation and survival, as well as nutrient signalling, in the presence of simple matrices (such as collagen, matrigel and laminin) and complex 3D cell-derived matrices generated by fibroblasts. Cell metabolism will be analysed using a metabolomic approach and metabolic labelling of cell-derived matrices. Impact. The outcome of the proposed work will define the role of the ECM and its internalisation in supporting breast cancer cell metabolism in nutrient deprived conditions. This will lead to the identification of potential novel targets for therapeutic intervention, as well as new regulators of breast cancer progression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/15/071: CHALLENGE UK: A UK cohort of the Colon Health And LifeLong Exercise chaNGE trial (supported by Stand Up To Cancer)
Funder: Cancer Research UK

Abstract: Background: There is compelling data from observational studies that physical activity (PA) is strongly associated with colon cancer recurrence, survival, and quality of life. The CHALLENGE trial is an international collaborative randomized controlled trial (n=962) led by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG). CHALLENGE aims to determine whether a supervised PA programme in patients with high risk Stage II/Stage III colon cancer will improve 3-year disease-free survival (DFS) in comparison to standard care. The impact on patient-reported outcomes and quality of life will also be assessed. Given the sample size required to robustly demonstrate the effectiveness of this intervention it is both clinically and economically desirable to conduct the study as a multi-national collaboration. We propose a UK arm (n=160) of the CHALLENGE trial with identical study design but with a number of UK-specific aims. UK-specific aims: 1. To make a significant contribution to the primary endpoint to ensure generalizability of the results to the UK population. 2. To undertake a UK-specific assessment of quality of life. 3. To undertake a within-trial cost-utility analysis to assess cost-effectiveness of the intervention compared with standard care. 4. To determine compliance with the PA programme by means of real-time physical activity monitoring. 5. To assess the feasibility and acceptability to patients and clinicians of delivering a combined behavioural support and PA intervention in the UK setting. 6. To undertake correlative biomarker studies and establish a UK bank of tissue (archival tumour and serum) for future mechanistic and biomarker research. Methods: Patients with high risk Stage II/Stage III colon cancer who have completed adjuvant chemotherapy treatment will be randomised to a structured 36-month combined behavioural support and supervised PA intervention or to standard care (provision of general health education materials). The UK study will benefit from an internal pilot study to confirm both recruitment and adherence assumptions that have contributed to study design. How the results of this research will be used The results of this study could have significant impact in a number of ways: 1. Change in practice: Provision of level one evidence for PA as a treatment strategy for improving outcomes in colon cancer would necessitate changes in current care pathways. 2. Cost-effectiveness: If PA is found to be an effective treatment the cost effectiveness of this approach will inform future UK health care guidance.


Research activity codes: 6.7 PHYSICAL
Health categories: CANCER AND NEOPLASMS
Title: AGCT1531: A Phase 3 Study of Active Surveillance for Low Risk and a Randomized Trial of Carboplatin vs. Cisplatin for Standard Risk Paediatric and Adult Patients with Germ Cell Tumours
Funder: Cancer Research UK

Abstract: Background Germ cell tumours (GCTs) are considered rare in both children and adults, but represent the most common solid cancer diagnosed in teenagers and young adults (TYA). Overall, most patients with a GCT can expect cure. However, TYA GCT patient’s survival outcomes are worse than either children or adults. It remains unclear why. To try and address this discrepancy the Malignant Germ Cell Tumour Consortium (MaGIC), a new international cross -discipline collaboration, has combined trial data sets, re-analysed and published new risk stratifications to frame current trial design (AGCT1531) inclusive of paediatric, TYA and adult patients. We know the current standard of care (cisplatin- based chemotherapy) causes significant organ toxicity for all survivors and including a substantial increased risk of second malignancies and cardiotoxicity: this risk accrues with age. By decreasing exposure to unnecessary chemotherapy or substitution of a less toxic analogue this trial aims to maintain survival and improve quality of survival. An independent health economic analysis has shown that validation of GCT- specific biomarkers (microRNAs) could allow immediate clinical translation for patient benefit. Proving superiority to conventional staging and surveillance tests, will reduce patient exposure to ionising radiation and may allow a reduction in burden of curative therapy. Aims of AGCT1531 1. Remove chemotherapy for low risk patients curable with surgery alone 2. For those who require chemotherapy for cure, investigating substitution of carboplatin (a cisplatin analogue) for cisplatin to maintain EFS 3. To measure the toxicity profile of both carboplatin and cisplatin using standard of care testing alongside novel patient reported outcomes. 4. To validate an established panel of four circulating microRNAs as universal markers of diagnosis, recurrence and response to therapy. Methods AGCT1531 is an international multi-center phase III observational and open-label randomized controlled trial, risk-stratified for children, TYA and adults with GCT. Randomisation stratified according to both age and site. A non-inferiority design used to evaluate risk of change in EFS-events. How the results will be used 1. It will introduce new standards of care for all patients receiving treatment for GCT, irrespective of age, with less burden of toxic therapy and maintenance of overall survival. 2. An independent health economic analysis has shown that validation of GCT biomarker would allow immediate clinical translation for patient benefit and introduce substantial health -care cost savings. 3. Provide a platform for analysing the TYA outcomes discrepancy


Research activity codes: 6.1 PHARMACEUTICALS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS