NIHRDataInsights/HRCSData huggingface dataset:
Title: Improving the QUALity and value of care for people with Poor Prognosis Cancers (I-qual-PPC)
Funder: The Health Foundation

Abstract: Around a third of people diagnosed with cancer each year in Scotland survive less than one year. Although there are agreed care standards and national comparative audits for better prognosis cancers, there is a lack of evidence on the benefits and harms of current care pathways for people with poor prognosis cancers (PPC). This important evidence gap leads to considerable variation in practice and inpatient experience, with some people with PPC missing out on the benefits of care and others receiving end-of-life care that is inappropriately medicalised. By using real-world data from a range of national and regional datasets, this project run by the University of Edinburgh will examine clinical pathways and outcomes for people with PPC in Scotland, with the aim of improving the standard of care they receive. The study will examine cancer audit and registry data from around 10,000 people with PPC across three health boards in south-east Scotland. It will also perform in-depth linkage analysis on clinical and administrative data for one of these health boards in order to describe patient management in detail. Patient-reported experiences from five Scottish cancer centres will provide meaningful insights into aspects of care that are important to people with PPC and their families. This will feed into the development of dedicated patient and carer information resources, and support tools to inform shared decision making. The comprehensive evidence base generated by the study will educate policymakers, clinicians, patients and carers about the likely outcomes of treatment options in PPC, and help to develop new standards of care that have the potential to be extended throughout the UK.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CANCER AND NEOPLASMS
Title: Novel Immunotherapeutics for Natural Killer-cell and Gamma Delta T-cell cancers
Funder: LifeArc

Abstract: Most patients with lymphoma can receive treatment which effectively cures or controls their disease. However, certain rare types of lymphoma such as Natural Killer cell (NK-cell) lymphoma/leukaemia (NKL) and hepatosplenic gamma-delta (γδ) T-cell lymphoma (HGDTCL), can be very difficult to treat. New treatments are urgently required because very few patients with advanced stage NKL or HGDTCL are cured. The overall survival of patients with HGDTCL is only 10 months and in patients with relapsed, advanced stage NKL, overall survival is only 4.9 months. The research team believes that CAR-T therapy has a potential role in NKL and HGDTCL lymphomas. CAR-T therapy is a powerful immunotherapy treatment which takes T-cells – key immune cells – and re-programmes them through gene therapy, giving them a ‘chimeric antigen receptor’ (CAR) which can recognise a specific protein on the surface of cancer cells. These engineered T-cells are then returned to the patient. The therapy already works well in common forms of lymphoma, such as Diffuse large B-cell lymphoma (DLBCL) and those which are resistant to chemotherapy. Moreover, most patients with DLBCL who go into remission after CAR T-cell therapy stay in remission. This is unusual since most treatments for patients with resistant cancers extend life, but do not cure the disease. The team has identified in laboratory work a cell surface protein called CD160 which is present on the surface of NKL and HGDTCL lymphomas. Having made CAR T-cells which recognise CD160, the team’s early laboratory experiments show these cells can kill NKL and HGDTCL cells. The team is using LifeArc funding to: Make the best possible chimeric antigen receptor (CAR) for the CD160 protein Test the CAR in the laboratory and in mice with lymphoma Study as many cases of NKL and HGDTCL as possible to measure how much CD160 protein they express on the cell surface. It is hoped this laboratory work will demonstrate that CAR T-cells that target CD160 can eliminate NKL and HGDTCL lymphomas. This would allow the team to seek funding for a Phase I clinical study of CD160 CAR-T in patients with NKL and HGDTCL lymphomas. The team has a large programme of Phase I CAR-T studies running at their centre already and is confident it has the infrastructure and expertise to bring new CAR-T therapy projects swiftly from bench to bedside.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Personalized Treatment For Pleural Mesothelioma Patients By Taming The Hippo
Funder: LifeArc

Abstract: Mesothelioma is an aggressive type of cancer that most commonly starts in the layers of tissue covering the lungs. It is usually linked to asbestos exposure. Sadly, it is very difficult to treat and more than half of patients will lose their lives within one year of diagnosis. There is an urgent need for effective new treatments that can help improve survival for people with the disease. This research focuses on a key cellular communication cascade – the Hippo pathway – which controls many aspects of cell growth and development. In around four out of ten mesotheliomas, faults in components of this pathway are known to drive tumour growth and development. Developing drugs that can target this pathway could help to slow down or stop cancer cell growth, helping to improve outcomes in these patients. Dr Carsten Hansen and his team have screened more than 83,000 compounds using patient mesothelioma cells, selecting a shortlist of candidates with encouraging activity against the Hippo pathway. The researchers will now carry out a series of laboratory tests to further evaluate each compound – to examine their activity, specificity, and safety profile. They hope their results will unlock new opportunities for the onward development of effective new personalised treatments for mesothelioma.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Determination of uptake and response to preventive treatment with tamoxifen or raloxifene in women at moderate or high risk of breast cancer
Funder: Breast Cancer Now

Abstract: Background:Recent NICE guidelines indicate that tamoxifen or raloxifene may be offered/prescribed to women at moderate/high-risk of breast cancer with the aim of reducing risk. Reduction in breast cancer risk using tamoxifen/raloxifene is approximately 30-40%. However we do not know the proportion of women who wish to be treated nor how to determine those most likely to benefit. We have identified two large groups of predominantly postmenopausal women in the Manchester Breast Screening programme (NHSBSP) and in the Genesis Family History Clinic (FHC) at moderate/high-risk of breast cancer (5-8/>8% 10-year risk). Aims:The first aim of this study is to assess the uptake to preventive agents raloxifene or tamoxifen in these women; the number who take up the offer will inform the NHS concerning likely national uptake. The second aim of this study is to test the hypothesis that we can predict which women will benefit from preventive treatment. In a previous study (IBIS-I Tamoxifen Prevention Trial) we demonstrated that reduction of visually assessed mammographic density (>9%) predicted women who benefitted from tamoxifen; women with lesser density change had no benfit from tamoxifen. Methods:We will perform automatic measures of dense volumes (Quantra and Volpara) and a new method of breast texture analysis to detect change in mammographic density after one year of treatment. One year is a long time to take potentially ineffective treatments, so we will attempt to predict benefit in a shorter time period (12-weeks) by measurement of electrical impedence of the breast and changes in breast parenchymal enhancement, fibroglandular volume and diffusion-weighted imaging characteristics using MRI of the breast. We will assess whether changes detected by these techniques at 12-weeks predict mammographic density change at one year. Impact:These studies will indicate the number of eligible women wishing to take preventive therapy and women most likely to benefit from treatment.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS
Title: A pilot breast cancer (BC) prevention study of the antiprogestin Ulipristal Acetate (UA) in women at increased BC risk
Funder: Breast Cancer Now

Abstract: There is an urgent need for novel BC chemopreventative agents. Progestins increase proliferation, mammographic density and BC incidence. In preclinical models reduction in progesterone signalling markedly reduces BC incidence. Ulipristal acetate (UA) is a novel antiprogestin licenced for treatment of uterine fibroids with minimal toxicity. Aims1. To evaluate the potential BC preventative effects of UA on the epithelia and stromal compartments of the normal breast2. To correlate these effects with dynamic changes on breast imagingMethodology30 premenopausal women at increased BC risk will receive UA for 3 months. Dynamic MRI and vacuum assisted breast biopsy will be performed pre and on treatment. Biopsy samples will be subjected to:a. proliferation, clonogenic and FACS analyses for stem/progenitor populationsb. RNA-sequencing with validation of individual gene/protein expression through qRT-PCR and IHCc. analysis of extracellular matrix composition and stiffnessDynamic MRI: image segmentation to determine fibroglandular and overall breast volumes, background parenchymal enhancement, fibroglandular apparent diffusion co-efficient and T2 relaxation times.ImpactWe will define in detail the biological effects of antiprogestin therapy on the normal breast and will identify potential biomarkers of activity that may be used for patient selection in future randomised prevention studies.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS
Title: NEO-RT: Pre-operative breast intensity modulated radiotherapy in patients receiving neo-adjuvant hormonal treatment for breast cancer
Funder: Breast Cancer Now

Abstract: Background Increasing breast conservation rate improves cosmetic appearance and avoids reconstructive surgery. Intensity modulated radiotherapy (IMRT) targets tumour, whilst minimising dose to non-target tissue. Given pre-operatively, this may increase the chance of breast conservation in patients receiving neo-adjuvant hormonal treatment for early breast cancer with minimal side effects. Delivering radiotherapy in the neo-adjuvant setting also provides an ideal opportunity for pilot translational research. Aims To test the feasibility of neo-adjuvant breast IMRT and hormonal treatment in patients with borderline conservable breast cancer and also explore: Indication of a decrease in mastectomy rate Possible predictive immunohistochemical/molecular and imaging biomarkers of response Evidence of modulation of immune infiltrate in tumours after radiotherapy Techniques and Methodology Study design and sample size Single arm feasibility study with 43 patients. Endpoints: Primary: proportion of patients successfully completing neo-adjuvant radiotherapy and hormonal therapy followed by breast surgery as per study protocol. Secondary: Peri-operative complications Mastectomy rates Residual Cancer Burden and pre-operative endocrine prognostic index (PEPI) Acute and late normal tissue radiation-induced toxicity Eligibility Patients with invasive breast cancer planned for treatment with neo-adjuvant hormonal therapy and considered as borderline for breast conserving surgery. Neo-adjuvant treatment IMRT to the breast will be delivered over 3 weeks, followed by 20 weeks of hormonal therapy prior to surgery. Exploratory translational research The unique study design will investigate radiation effect directly on breast tumour. Serial blood tests and tumour biopsies paired with functional imaging before, during and after radiotherapy will enable exploration of potential molecular/radiological biomarkers of response and assess radiation-induced immune modulation. Impact on breast cancer research A potential benefit to patients will be reduction in mastectomy rates. Results will inform the design of larger studies investigating predictive biomarkers of response to breast irradiation ± novel agents including immunotherapy, which may increase local control and survival.


Research activity codes: 6.1 PHARMACEUTICALS;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Characterizing the in vivo functions of P-Rex1 and Rac1b in breast development and tumorigenesis
Funder: Breast Cancer Now

Abstract: Background: P-Rex1 and Rac1b are highly expressed in ER+ luminal and Her2+ breast tumours and probably are responsible for the increased Rac1-GTPase activity seen during breast tumourigenesis. P-Rex1 activates Rac1 downstream of ErbB/Her-signalling, whereas Rac1b is a constitutively active splice-variant of Rac1. My preliminary data demonstrate that P-Rex1 and Rac1b are required for the self-renewal and plasticity of breast cancer stem cells (Br-CSC), respectively. Although these findings suggest that targeting P-Rex1 and Rac1b would be a potential Br-CSC therapy, their requirement during normal mammary gland development and clinical relevance still needs to be validated in vivo. Aims: This project aims to characterise the in vivo functions of P-Rex1 and Rac1b in breast development and in breast tumourigenesis. Techniques and Methodology: I will determine the phenotypes of P-Rex1-/- and Rac1b-/- mouse lines at different stages of mammary gland development; the Rac1b-/- mouse line will be generated by Crispr-mediated targeting in mouse ES cells. To determine the P-Rex1 and Rac1b functions in breast tumourigenesis, I will perform phenotypic analyses of the (MMTV-Neu;P-Rex1-/-) and (MMTV-Neu;Rac1b-/-) mouse lines. All phenotypic analyses in this project will be performed at: tissue level by whole-mount staining, histology and flow cytometry, cellular level by primary cell culture, including mammosphere, colony-formation and matrigel assays, molecular level by lentiviral expression of mutant P-Rex1 forms and determination of Rac1b-associated signalling pathway activities. To determine whether P-Rex1 and/or Rac1b are required exclusively in epithelial cells and not systemically, cleared-fat pad and whole-breast transplantations will be performed. Impact on breast cancer research: This project will enhance our knowledge of the molecular mechanisms underpinning breast development and their contribution to breast tumourigenesis. Importantly, analysis of the P-Rex1 and Rac1b loss-of-function phenotypes in a wildtype background and a mouse model of breast tumourigenesis will validate their clinical relevance as Br-CSC-specific targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: ROLO: Phase II study of ROS1 targeting with crizotinib in advanced E-cadherin negative, ER positive lobular breast cancer, diffuse gastric cancer, triple negative lobular breast cancer or CDH1-mutated solid tumours
Funder: Breast Cancer Now

Abstract: Background: Lobular breast cancers are characterised by loss of function of the cell adhesion molecule, E-cadherin, due to mutations or epigenetic alterations in the tumour suppressor gene CDH1 (Christigen et al., Breast Cancer Res, 2015). In addition to the roles of E-cadherin in cell architecture and migration, the protein also appears to mediate signalling through EGFR and the Wnt pathway (Jeanes et al., Oncogene 2008). Lobular cancers are typically ER and PgR positive and HER2 negative (Bertucci et al., Oncogene 2008), and hormonal therapy is the mainstay of treatment for advanced lobular breast cancer before chemotherapy is necessary after the development of resistance. Lobular breast cancers respond less well to chemotherapy than ductal carcinomas (Cristofanilli et al., J Clin Oncol 2005), therefore there is a real need to develop new agents for patients with disease progression despite prior hormonal therapy. There are currently no recruiting studies worldwide investigating novel therapies specifically for advanced lobular breast cancer patients. Aims: This two stage phase II translational trial has been designed to evaluate whether crizotinib has activity in advanced lobular breast cancer that has progressed on prior endocrine therapy, aiming to confirm the activity seen in prior pre-clinical studies. The primary endpoint is confirmed response rate of the combination of crizotinib and fulvestrant, with the combination proposed to ensure concurrent blockade of ER signalling and to maximise potential for tumour control. A metastatic biopsy will be required for all patients for sequencing, with optional biopsies at day 15 and disease progression. Each cycle, blood will be collected for ctDNA analysis. This will allow us to identify candidate biomarkers of sensitivity and resistance.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Elucidating the clinical potential of novel therapeutic combinations in models of breast cancer bone metastasis
Funder: Breast Cancer Now

Abstract: Background: To improve breast cancer outcomes it is essential to develop more effective therapies for metastatic disease. This project represents a unique opportunity to identify new schedules for treatment of skeletal metastases, the most common site of spread in advanced breast cancer. Based on our proteomic studies, which for the first time highlighted the importance of CDK4/CDK6 in bone metastasis development (including in triple negative breast cancer), we will focus on the role of the CDK4/CDK6 inhibitor palbociclib, alone and combined with tamoxifen and/or the bone-targeted agent zoledronic acid, in modifying bone metastasis. Aims: To use in vivo model systems of ER+ve and ER-ve breast cancer, complemented by proteomic studies, to determine how palbociclib, alone and combined with zoledronic acid/tamoxifen, affects different stages of bone metastasis from tumour cell colonisation (early stage) to progression (late stage). Methods: Effects of palbociclib will be determined in established in vivo models where Luc2 expressing breast cancer cells labelled with lipophilic dyes are injected via the intra-cardiac route (ER-ve) or implanted in the mammary fat pad (ER+ve) in BALBc/nude mice. Tumour cell homing to bone will be detected by 2-photon microscopy and subsequent colonisation and progression by in vivo imaging (IVIS). Palbociclib (50-100mg/kg/day), alone or combined with zoledronic acid (100ug/kg/week) or tamoxifen (0.8mg/kg/day), will be administered for up to 3 weeks, commencing at different stages of tumour growth. Effects on tumour and bone will be analysed ex vivo (histology, bone histomorphometry, uCT) complemented by proteomic studies comparing the response to palbociclib/zol treatment in bone-homing and non-bone homing tumour cells. Impact: The effect of palbociclib specifically on bone metastasis has not been investigated in patients. This project will provide pre-clinical evidence for its potential in this setting, and hence a strong mechanistic rationale for subsequent clinical trials in advanced breast cancer including triple negative disease


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Exploiting ROS1 kinase inhibitors in breast cancer
Funder: Breast Cancer Now

Abstract: This project aims to develop novel approaches to targeting breast cancer using ROS1 kinase inhibitors such as crizotinib and lorlatinib. E-cadherin defects are common in breast cancer. We recently discovered a profound and robust synthetic lethal interaction between defects in E-cadherin, and inhibition of the receptor tyrosine kinase ROS1 with the Pfizer drug crizotinib, an effect that operates both in vitro and in vivo models of the disease. These observations are particularly pertinent, given the relative frequency of Ecadherin defects in invasive lobular cancers (ILCs) and other forms of the disease including triple negative breast cancer. Mechanistically, ROS1 inhibitors cause mitotic and cytokinetic defects in breast tumour cells with E-cadherin defects. On the basis of this work we have designed and instigated a BCN-Catalyst funded phase 2 trial (ROLo – ROS1 inhibitor in Lobular Breast Cancer, PI Dr. Nicholas Turner, Translational Lead, Dr. Chris Lord) to assess the efficacy of crizotinib in Ecadherin negative, ER positive lobular breast cancer. Aims: - Dissect at the molecular level, the mechanistic basis of E-cadherin/ROS1 synthetic lethality in order to understand therapeutic responses in the ROLo trial. - Use this information to refine predictive biomarkers of crizotinib sensitivity in breast cancer. - Identify new approaches for using crizotinib in combination with other targeted agents in breast cancer that could be used to inform the design of new clinical trials in breast cancer. - Assess whether ROS1 inhibitors could be used to target difficult to treat breast cancers, such as leptomeningeal metastases. - Assess whether the novel ROS1 inhibitor lorlatinib, which has improved PK properties, can be used to target breast cancer with a view to designing novel phase 2 clinical trials. - Assess whether other breast cancer patients, such as those with p120 catenin defective invasive ductal carcinomas (IDCs) could be treated with ROS1 inhibitors such as crizotinib or lorlatinib.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Investigating immunogenic cell death mediated by the anti-PTK7-ADC and harnessing this to overcome treatment resistance in Triple Negative Breast Cancer
Funder: Breast Cancer Now

Abstract: Background Following prolonged mitotic arrest, breast cancer cells typically die in mitosis or exit without dividing and survive. What dictates the balance between these two fates, and how cells sense mitosis arrest, and in response trigger cell death remains unclear. Mitosis poisons, such as Taxol and the Auristatin0101 payload of PF-06647020 (the anti-PTK7-ADC) arrest cells in mitosis, however both the mechanisms that lead to cell death and to acquired therapy resistance are poorly understood. We now have identified the molecular link that connects cell death to mitosis progression. We have uncovered an unanticipated function of the ripoptosome (RIPK1/caspase-8 complex) in cell division, actively promoting faithful chromosome alignment during mitosis, and eliminating those cells that exhibit defects in mitosis progression. Aims: The aim of this proposal is to exploit the complex relationship between mitosis, cell death and immunology, and harness this to stimulate long-lasting immunological protection and prevent tumour relapse and overcome tumour resistance. The idea addressed by this application is that cell survival and chromosomal instability of tumours are supported, at least in part, by avoidance of ripoptosome engagement, and that this can be targeted by re-activating the ripoptosome in mitosis to drive immunogenic cell death. Methods: We will exploit our knowledge of ripoptosome regulation and harness ripoptosome function to sensitise breast cancer cells to the targeted anti-mitotic agent PF-06647020 (the anti-PTK7-ADC) and improve treatment response. We aim to induce a type of tumour cell death that is immunogenic and in combination with immune checkpoint blockade, such as that induced by Avelumab (anti-PD-L1 mAb), may lead to long-lasting anti-tumour immunity. How the results will be used: Results from this programme will have significant impact on the development of novel treatment combinations aimed at sensitising breast cancers to anti-mitotic agents and improving cancer immunotherapy. It will also allow us to stratify patients with breast cancer into responders and non-responders based on each patient’s ability to trigger ripoptosome formation and ripoptosomedependent cell death.


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