NIHRDataInsights/HRCSData huggingface dataset:
Title: GO2-PRECISE: Defining the platinum sensitive sub-group of gastroesophegal cancer to optimise effectiveness and tolerability
Funder: Cancer Research UK

Abstract: Background: Achieving a better balance of cancer control, side effects and patient acceptability for palliative chemotherapy in Gastroesophageal adenocarcinoma(GOA) is a priority.Platinum based chemotherapy(PBC) has proven benefit but its effectiveness is limited by toxicity, especially in older or frailer patients that make up an increasing proportion.In the Phase III G02 trial we demonstrated that in older or frailer GOA patients lower PBC dose levels had non-inferior progression free survival(PFS) with less toxicity and improved overall treatment utility(OTU)- a composite endpoint of cancer control, tolerability and patient acceptance. We have also shown predictive impact for a 44 gene DNA damage immune response(DDIR)signature in perioperative PBC and in exceptional responders to palliative PBC.This implies that a good response to PBC, sustained once chemotherapy is completed , is due to pre-existing deficiencies in DNA damage repair associated with activation of an innate immune response to DNA damage. Together with the GO2 trial, this suggests in patients whose tumours are DDIR positive, that de-escalation of PBC dose with resulting reduction of associated toxicities, may be possible while still allowing a sustained response and so without compromising efficacy.This would benefit all, but especially those who are older and/or frailer. The DDIR signature may also be useful to stratify GOA patients for non-platinum based chemotherapy, immune checkpoint inhibitors and DNA damage repair inhibitors. Aims: Our primary aim is to define the role of the DDIR signature as a predictive biomarker for benefit from palliative platinum based chemotherapy at different dose levels in advanced gastroesophageal adenocarcinoma. We will also investigate the relationship between patient frailty, the DDIR signature result and treatment outcomes at different dose levels. Methods: DDIR signature will assayed on a representative cohort of 300 patient FFPE tumour samples already collected from GO2. Analysis of 100 samples from each dose level in GO2, will be performed -oxaliplatin and capecitabine Level A-100%;B-80% and, C-60%. PFS, OS and OTU will be investigated to enable an overarching assessment of benefit. How the results of this research will be used: This project will determine whether a prospective clinical trial is worthwhile with tumour DDIR signature used alongside the other objective health and frailty assessments, investigated in GO2, for personalised treatment selection in GOA patients.Depending upon results, this could include to optimise PBC dose levels; evaluation of immune checkpoint inhibitors and/or DNA damage repair inhibitors in DDIR positive GOAs; or use of platinum free chemotherapy regimens in DDIR negative GOAs.


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: Aggressive prostate cancer: understanding the aetiology through worldwide epidemiological and interdisciplinary collaborations - Studentship
Funder: Cancer Research UK

Abstract: Aims We propose an integrated and interdisciplinary programme of research to identify novel risk factors and elucidate mechanisms underpinning the aetiology of aggressive prostate cancer, to inform both population-based and stratified approaches to risk reduction. We aim to use recent developments in high-throughput technologies to provide detailed information on novel biomarkers and metabolic profiles, combined with tumour phenotyping, and state-of the-art methods for exposure assessment, statistical analysis and causal inference. Methods The research will be conducted in two international consortia which we lead, the EPIC-Prostate study in eight European countries and the Endogenous Hormones Nutritional Biomarkers and Prostate Cancer Collaborative Group in 38 studies in sixteen countries, as well as in UK Biobank and the PRACTICAL consortium. Together these resources provide exposure data on a wide range of biomarkers with detailed covariate and clinical characteristics for up to 25,000 cases of prostate cancer including up to 7,000 aggressive cases and 3,000 deaths, providing substantial statistical power. We propose systematic analyses of the roles of circulating proteomic and epigenetic factors as potential risk markers and mediators for aggressive prostate cancer, together with analyses of a new measure of free insulin-like growth factor-I, extended analyses of metabolomic, hormonal and nutritional profiles, and analyses of the mechanisms underlying the association of abdominal adiposity with risk. To assess causality we will conduct Mendelian randomization analyses, and interpret findings in relation to other types of evidence using the triangulation approach. We also propose establishing a new resource of prostate cancer tumour tissue to enable us to incorporate tissue markers in future collaborative research. How the results of this research will be used This integrated programme of research will provide information on novel aetiological markers and underlying mechanisms, and identify modifiable risk factors for aggressive prostate cancer. The findings will inform the development of evidence-based strategies for prostate cancer prevention, and enhance the resources available to the international cancer research community.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS
Title: Targeting the tumour-stroma crosstalk in pancreatic ductal adenocarcinoma
Funder: Cancer Research UK

Abstract: Our Laboratory focuses on identifying more effective cancer treatments for pancreatic ductal adenocarcinoma (PDA) patients that are based on the biological mechanisms that drive cancer. In particular, our research focuses on: Characterizing fibroblast and immune cell heterogeneity in normal, inflamed and malignant states. Pharmacologically and genetically dissecting cancer/fibroblast signaling interactions. Developing therapeutic strategies that target tumor-promoting stromal components of PDA. About Giulia I received my Master’s degree in Biomolecular Sciences and Genetics from the University of Pavia, Italy. My Ph.D. dissertation was completed with Sir Shankar Balasubramanian at the Cancer Research UK Cambridge Institute. During my doctoral training, I demonstrated the existence of RNA and DNA secondary structures called G-quadruplexes in human cells by developing a G-quadruplex-specific antibody. This antibody has become a standard tool for the study of these structures in homeostasis and cancer. During my post-doctoral training, I furthered my interest in characterizing the biochemical differences between normal and malignant cells by studying the signaling pathways active in the microenvironment of pancreatic ductal adenocarcinoma (PDA). In particular, using organoid and mouse models, I investigated the crosstalk between cancer cells and cancer-associated fibroblasts (CAFs). I co-led the establishment of a three-dimensional co-culture system of PDA organoids and fibroblasts, which recapitulated the extracellular matrix deposition and symbiotic interactions observed in vivo. Using this co-culture system and mouse models of PDA, I helped to identify two distinct CAF subtypes, with potentially different roles in PDA progression. I also demonstrated that these cell populations dynamically interconvert, depending upon spatial and tropic cues. Importantly, this cell plasticity represents a therapeutic opportunity as it may be more beneficial to convert, rather than just ablate, tumor-promoting CAFs into potentially tumor-restraining populations. In addition, I determined the critical ligands and receptors responsible for specifying these CAF subtypes in vitro and in vivo, laying the groundwork for the generation of new models that will allow to genetically dissect the roles of these populations.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: STING signalling as link between DNA damaging therapies and innate immunity in bladder cancer
Funder: Cancer Research UK

Abstract: Background: The immune system can help eliminate cancer cells. A pre-requisite for successful immunosurveillance and immunotherapy is the presence of a T cell-inflamed “hot” tumour micro-environment, which relies on the secretion of type I interferons and chemokines such as CXCL10 by tumour cells and infiltrating immune cells. A key signalling cascade that shapes anti-tumour immune functions involves the protein STING (Stimulator of Interferon Genes). STING is activated by the DNA sensor cGAS which detects cytosolic DNA during infection, or following DNA damage. We have recently discovered that DNA damage can also be detected in the nucleus by the DNA binding proteins IFI16 which leads to the cGAS-independent activation of STIG. This non-canonical mode of STING activation causes the production of a different, more pro-inflammatory, cytokine and chemokine profile. We hypothesise that the regulation of STING signalling in cancer cells may be a key factor in the response to DNA damage following radio- or chemotherapy, and has the potential to shape the immune microenvironment and subsequent responses to DNA damaging therapies. Aims: We will investigate the link between DNA damage, STING activation and innate immune responses to radio- and chemotherapy in bladder cancer. We aim to (i) find out how DNA damage shapes the innate immune response in normal urothelial cells and cells derived from muscle-invasive bladder cancer, (ii) determine how STING signalling is dysregulated, lost or re-wired in cancer cells, and (iii) generate a multi-parameter model for the personalised prediction of patient responses. Methods: We will employ mechanistic studies in primary human urothelial cells and cell lines derived from muscle-invasive bladder cancer, and investigate the innate immune response to radio- and chemotherapy using CRISPR gene targeting, cytokine/chemokine profiling and the molecular analysis of signalling complexes. In vitro findings will be supplemented with the analysis of patient samples by immunohistochemistry, and the mining of transcriptomic and genomic data sets from bladder cancers with associated information on treatment outcomes. Outcomes: This project will provide mechanistic insights into the regulation of STING signalling in human cancer cells, where STING can have both anti- and pro-tumour functions. We aim to integrate mechanistic insights with individual tumour data from patients, in order to provide a basis for personalised treatment decisions, based on the innate immune signalling capacity of the tumour. The project may also lead to the discovery of additional molecular targets for combination therapy approaches in solid tumours.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Next Generation T cell therapies for childhood cancers (NexTGen)
Funder: Cancer Research UK

Abstract: BACKGROUND: Current treatments fail to cure many children with solid cancers. Recent advances in adult cancers such as checkpoint blockade and targeted small molecules have made little impact in childhood disease. Engineered T-cell therapies can achieve durable responses in refractory lymphoid cancers without long-term toxicity. These are precisely the characteristics required for new treatments for pediatric solid cancers. In contrast to hematologic malignancies, solid cancers are challenging due to a lack of targets, tumor heterogeneity, and hostile tumor microenvironment (TME). We posit that through advanced cellular engineering we can overcome these challenges. Our vision is that engineered T-cell therapy for childhood solid cancers will become routine within a decade. Our central hypothesis is that coupling of advanced cellular engineering along with progressive clinical development is the fastest route to developing effective T-cell therapies for pediatric solid tumors. In NGTC we combine detailed studies of primary tumors to discover new targets and understand how the TME subverts T-cell function. This, along with a closely coupled clinical development programme will guide the progressive engineering of T-cells to result in transformative therapies. NGTC is composed of 6 inter-connected work-packages (WPs) with work initially focused on pediatric sarcomas and brain tumors. AIMS: WP1: To identify suitable targets for engineered T-cells. WP2: To understand the TME in pediatric solid cancers. WP3: To develop receptors and other engineering components which target tumor cells and resist or modulate the TME. WP4: To evaluate the function of engineered T-cells developed in WP3. WP5: To translate approaches from WP4 and test them in clinical studies designed for maximal impact. WP6: To promote data sharing across all WPs METHODS: Target discovery (WP1) and TME studies (WP2) will utilize mass spectroscopy and chip cytometry respectively. Component engineering (WP3) will use protein engineering methods. To model engineered cell function, WP4 will mostly use intact tumor models such as immune PDXs. In WP5, clinical product generation will involve autologous closed system semi-automated manufacturing. WP6 uses standard and custom databases and data sharing platforms. USE OF RESULTS: Tumor target and TME data from WP1 and 2 will be uploaded to databases developed by WP6 for widespread distribution. Engineering components from WP3 and functional data from WP4 will be available for incorporation into therapeutic T-cell strategies by the entire community. Clinical study data from WP5 should lead to registration studies, improving cure rates and mitigation of long-term toxicity to realize our Vision.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Evaluation of key Biomarkers for the prediction of successful treatment-free remission (TFR) in chronic myeloid leukaemia
Funder: Cancer Research UK

Abstract: Background: Many clinical trials have shown that patients with chronic myeloid leukaemia (CML) who obtain a stable deep molecular remission (DMR) after prolonged tyrosine kinase inhibitor (TKI) therapy may attempt TKI discontinuation, termed “treatment-free remission (TFR)”. Understandably, patients are keen to stop therapy to reduce side effects and potential long terms complications, resulting in improved quality-of-life. However, approximately 50% of patients attempting TFR have molecular relapse of CML, and require to restart TKI therapy. Currently, there are no reliable biological predictors of successful TFR, although, clinically, length of time on therapy and depth of response are associated with improved rates of TFR in multivariate analyses. Attempting TFR results in increased frequency of molecular monitoring and, hence, hospital visits, and increased psychological burden for patients who are concerned about molecular relapse. Aims: This study aims to understand what biological factors contribute to molecular recurrence in CML patients attempting TFR. To achieve this, we will determine if BCR-ABL1 transcript levels in bone marrow a better predictor of successful TFR compared to BCR-ABL1 transcript levels in peripheral blood; assess whether the presence of leukaemia stem cells (LSC) in the bone marrow of patients in DMR is predictive of TFR failure; explore whether there is a correlation between the immune cell repertoire in the bone marrow of patients in DMR and TFR success; and consider if there is a protein signature in the bone marrow predictive of successful TFR. Methods: This study will use bone marrow samples collected from patients enrolled in the DESTINY clinical trial. Quantitative real-time PCR will be used to evaluate BCR-ABL transcripts. Surface and intracellular flow cytometry will be used to enumerate LSC and define the immune cell repertoire, and SWATH MS and Luminex will be used to assess inflammatory proteins in the bone marrow plasma. How the results of this research will be used: Being able to accurately predict which patients will successfully remain in TFR would be a huge step forward in the management of CML. Identifying those patients that are highly likely to relapse on TFR attempt would enable those patients to be considered for alternative treatment strategies that may allow a successful TFR attempt in the future. The results of this biomarker research study will be used to design future clinical trials to prospectively assess the biomarkers identified before they can be adopted as standard-of-care to predict successful TFR.


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: Evaluation of the effect of RANKL inhibition on normal breast tissue - biopsy sub-study of the BRCA-P trial.
Funder: Breast Cancer Now

Abstract: Background BRCA1 pathological variant (path_var) carriers are at high risk of estrogen receptor negative breast cancers. These arise from luminal progenitor populations regulated by progesterone receptor (PR) induced paracrine signals, including receptor activator of NFkB ligand (RANKL). A large multi-national trial of the RANKL antagonist, denosumab, in this population is planned. Herein we propose a biopsy sub-study to determine the precise molecular effects of denosumab on breast tissue. Aims 1. To determine how denosumab treatment modifies the composition and cellular hierarchy of normal breast tissue in women with BRCA1 path_vars. 2. To determine the impact of denosumab treatment on DNA damage response and repair within specific subpopulations of the epithelial hierarchy, as a surrogate for preventive efficacy. 3. To compare the efficacy of RANK-L vs PR inhibition to determine the optimal preventive strategy in this population Techniques and Methodology 30 women carrying BRCA1 path_var will be recruited into the paired biopsy substudy of the BRCA-P trial. Vacuum assisted biopsies will be performed before and 4 weeks after the the first denosumab dose. Single cell RNAseq will be used as the most powerful unsupervised approach to determine how densumabo perturbs the overall cellular composition and epithelial hierarchy. Imagestream analyses in samples irradiated ex vivo will be used to determine the impact of denosumab on the specific subpopulations most at risk of DNA damage. We will compare transcriptional profiles of women treated with denosumab in BRCA-P and anti-progestin in a previous BCN funded study, with in vitro clonogenic and tissue microstructure assays to determine the optimal preventive approach in this population. Impact on breast cancer research Detailed maps of epithelial and stromal subpopulations in the normal human breast and the impact of denosumab and anti-progestin therapy will be provided. These data will help to determine the optimal chemoprevention strategy for such women.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Development of antibody technology for driving cancer immune receptor agonism
Funder: Cancer Research UK

Abstract: Background Monoclonal antibodies (mAb) are now central to the clinical management of many malignancies. However, further improvements in response rate and efficacy are required. Agonistic antibodies to immune receptors display great potential for driving effective immune responses and controlling tumour growth. However, these reagents have not delivered efficacy in humans either through toxicity and/or a lack of agonism. Therefore, we recently set out to explore a novel antibody technology to provide agonism with improved potency and safety. Aims Our aim is to develop and validate this approach for multiple immune receptors as a tool for delivering powerful and non-toxic agonism leading to anti-cancer immunity. We will: 1. Show that these molecules are capable of being stably produced for multiple targets and mAb 2. Assess their ability to drive agonism in a series of in vitro assays 3. Demonstrate efficacy in vivo using unique human knock-in mouse models 4. Confirm that these reagents are safe and with useful PK 5. Explore structure:function relationships to generate the most active molecules 6. Develop our most promising agent for exploration in Phase 1 clinical trials Methods We will use a combination of bespoke preclinical models together with a panel of established murine and human assays to assess the potential utility of the technology How the research will be used. This research will provide validation for the use of the technology to deliver powerful and non-toxic agonism. It will provide evidence that these reagents can be reliably generated, with broad applicability for multiple receptors, to deliver immunotherapy of cancer.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Studying the origins of mast cells to delineate their functions in melanoma progression
Funder: Cancer Research UK

Abstract: Mast cells (MCs) are myeloid effector cells abundantly found associated with melanomas. While immune cells are now widely recognized as critical elements shaping tumor microenvironments, the roles of MCs in melanoma have remained controversial. This currently represents a major hurdle for exploiting MCs for diagnostic, prognostic and therapeutic benefit. MCs can have a wide range of cellular functions, but were often considered a relatively uniform entity. This has now changed with the recognition that they are in fact highly specialized cells of which distinct populations can exist within the same tissue. One aspect that contributes to this heterogeneity is their origin: I have recently shown that MCs are first established during fetal development, and that for example in the skin, fetal-derived MCs can persist into adulthood, where they co-exist with MCs originating from hematopoietic stem cells (HSCs). In preliminary experiments, I have now found that melanoma-associated MCs have distinct origins, and that fetal-derived MCs are enriched compared to normal skin, suggesting active recruitment. Similar findings have been made for macrophages in other cancers, where fetal-derived MCs are recruited to early lesions to promote tumor growth and spread. Based on these observations, I hypothesize that fetal- and HSC-derived MCs may have antagonistic functions in the context of melanoma. This project addresses the following questions: Are developmentally distinct MCs recruited to melanomas with different kinetics? Do they occupy distinct niches within the tumor microenvironment? (How) are they different from MCs found in healthy skin? Do MCs with distinct origins differentially impact melanoma growth, and through which mechanisms? We will address these questions using a combination of in vivo melanoma models that recapitulate features of human disease and are normally refractory to immuno-therapy, state-of-the-art cellular (flow cytometry, confocal imaging), transcriptomic (single-cell, bulk RNAsequencing) and genetic tools (fate mapping, conditional targeting). This work will advance our understanding of how MCs impact melanoma growth, and may provide explanations for the current controversy. While fundamental in nature, this work has intrinsic translational significance: It will define molecular signatures and markers identifying specific types of MCs, which can be tested in patients and correlated with clinical outcomes. This has the potential to improve patient stratification and allow more tailored therapy choices. Ultimately, this project may also lay the groundwork for novel therapeutic approaches designed to more selectively target distinct MC populations.


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