NIHRDataInsights/HRCSData huggingface dataset:
Title: How tumour-cell killing by T cells is initiated
Funder: Cancer Research UK

Abstract: Background Receptor signaling underpins the new treatments transforming cancer medicine. However, there is almost no agreement about how these receptors are triggered, even though a proper understanding could extend the reach of immunotherapy, increase its efficacy, or curb its toxicity. We have proposed a mechanism in which receptor phosphorylation is kept low by an equilibrium between kinases and phosphatases, that is disturbed locally in favour of the kinases when the large receptor-type phosphatase, CD45, is sterically excluded from cellular contacts where receptors engage their ligands. We and others have demonstrated local kinase/phosphatase segregation at contacts of lymphocytes with model surfaces, and we have developed a quantitative treatment of signaling that predicts the relative signaling potencies of well-characterised receptor ligands. The important question now is: does the mechanism apply at authentic cell-cell contacts, especially those formed with tumours by T cells? Aims In the last few months we have begun to observe local regions of phosphatase depletion at contacts that T cells make with the U-2 OS osteosarcoma cell line. Our goal is to determine whether tumour-cell killing is initiated by the steric exclusion of the phosphatases and receptor dwell-time at these contacts. Methods U-2 OS osteosarcoma cells are unusually flat (3 micron thick) cells, which means that we can interrogate their upper surfaces when they interact with T cells, using ‘highly inclined and laminated optical sheet’ imaging. So that we can study primary T-cells, we will use bispecific T-cell ‘re-directors’ already in use in the clinic, called ImmTACs. To demonstrate the important role that molecular dimensions play for these and other therapeutics, including immune checkpoint blockers, we will use protein engineering. The mathematical model we have developed will be used to fit our measurements of triggering at cell-cell contacts, or refined to match the data. All of our work will be done alongside tumour killing assays in vitro and in vivo, confirming the therapeutic relevance of our observations. How the results of this research will be used A new understanding of receptor triggering could change how we approach immunotherapy, for example by placing more emphasis on the steric properties of drug-like molecules, or by suggesting new ways to move signaling molecules in and out of T-cell/tumour contacts. We will illustrate this by testing whether the activity of the immune-checkpoint blocker, nivolumab, could be enhanced by altering its steric properties.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Use of hormone replacement therapy and survival from cancer
Funder: Cancer Research UK

Abstract: Background Hormone replacement therapy (HRT) is widely used and has proven benefits in women with menopausal symptoms. The role of oestrogen in cancer progression is complex. Recent studies have suggested HRT could be protective in women with melanoma, colorectal and liver cancer. In contrast, there have been concerns that HRT could accelerate cancer progression in women with lung, bladder, gastric, and brain cancer. Consequently, some researchers have recommended against using HRT in women with these cancers. However, the survival of women using HRT after cancer diagnosis has not investigated by epidemiological studies in women with most cancers. Aims To determine whether HRT use after diagnosis of cancer alters the risk of cancer-specific mortality in women with a range of common cancers. Methods The study will utilise independent population-based data from England using QResearch, Wales using SAIL databank and Scotland based upon the national Prescribing Information System. The study will contain around 250,000 women newly diagnosed with common cancers from 1998 to 2016, identified from cancer registries. Women with breast and gynaecological cancers will be excluded. HRT will be ascertained using electronic prescribing or dispensing records. The primary outcome will be time to cancer-specific mortality from national mortality records. Time-dependent cox regression models will be used to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs) for cancer-specific mortality in HRT users compared with non-users after cancer diagnosis (with HRT use modelled as a time varying covariate), stratified by cancer site. Adjusted HRs and 95% CIs will be calculated including the following covariates in cox regression models: age, year, stage, cancer treatment, grade, comorbidities, hysterectomy, oophorectomy, other medication use, deprivation, smoking and BMI. Analyses will be conducted by HRT type and dose-response analyses will be performed. Analysis will be repeated investigating the impact of HRT use immediately before diagnosis, when the cancer was developing, on cancer-specific mortality. How the results of this research will be used Our study could provide evidence that: (a) HRT accelerates cancer progression in patients with a specific cancer, allowing patients to make an informed decision to use HRT or switch to alternatives (such as selective serotonin reuptake inhibitors and clonidine) and providing insights into cancer mechanisms; (b) HRT has no impact on cancer progression, providing reassurance to patients and GPs; or, (c) HRT delays cancer progression in patients with a specific cancer, providing mechanistic insights and highlighting the potential for hormone therapy in cancer treatment.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CANCER AND NEOPLASMS
Title: VISION Laboratory: Imaging oxygen and oxidative stress
Funder: Cancer Research UK

Abstract: Our mission is to devise new imaging approaches that will improve early cancer diagnosis. We are an international team combining physicists, engineers, chemists, and molecular biologists who work at the clinical interface. Our imaging innovations arise primarily from low cost optics and photonics technologies, applied both in cancer models and in patients. We are particularly interested in developing methods to interrogate cancer metabolism and the tumour microenvironment. Importantly, we place emphasis on biological validation of the imaging biomarkers that we measure, connecting our non-invasive imaging signatures with the molecular processes that generate them. We achieve developments in this area through a combination of: modelling, to understand the interactions between light and tissue; and innovative instrument design, integrating new technologies to enable spectral imaging. By applying such developments to preclinical disease models and ultimately in patients, we aim to better understand cancer progression, from early development through to treatment resistance.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: A pilot study of Positron Emission Tomography (PET) scanning with 89Zr-DFO-Atezolizumab in patients receiving pembrolizumab for non-small cell lung cancer
Funder: Cancer Research UK

Abstract: Background Lung cancer affects over 45,000 people per year in the UK with a 19% one-year survival for those with metastatic disease. In non-small cell lung cancer (NSCLC) immune checkpoint inhibitors (ICIPs/immunotherapy) are standard of care. NSCLC patients receive chemotherapy or ICIPs (e.g pembrolizumab) or chemotherapy-pembrolizumab combination depending on the baseline tumoural (biopsy) PD-L1 results. Tumoural PD-L1 is not a perfect biomarker of response with around 50% of patients expected to not respond to ICPI using this method of patient selection. ICPI carries a burden of toxicity with immune activation causing debilitating and potentially life-threatening toxicities. FDG-PET (Positon Emission Tomography) scanning utilises a radiolabelled tracer to give a read-out of metabolic cancer activity and, in combination with simultaneously acquired CT (computer tomography) images is a adjunct to response assessment. PET imaging with alternative labelled tracers is feasible. Immuno-PET with radiolabelled monoclonal antibodies (mAbs) to PD-L1 could enable a quantitative read out of the checkpoints on tumour and other cells (e.g. tumour-associated macrophages) and sequential measurements of PD-L1 expression over time without a need of repeated biopsies Aims We postulate that radio-labelled atezolizumab (89Zr-DFO-Atezolizumab) will provide a non-invasive and quantifiable measure of PD-L1 expression level that can ultimately become a biomarker for patient selection. Methods This single centre study of 10 patients with NSCLC receiving pembrolizumab as part of their standard of care. Patients will have a baseline 89Zr-DFO-Atezolizumab scan in the two weeks prior to commencing pembrolizumab. Scans will be repeated at 9 weeks and at progression. For each administration of 89Zr-DFO-Atezolizumab (37 MBq), imaging will be performed at 2 days and 4 days post-injection. The sub-therapeutic administration of the radiolabelled atezolizumab is considered to be safe and have low toxicity risk. The primary end-point is description of baseline SUV (PET read-out). Secondary end-points include comparison with baseline tumoural PD-L1, change in PET characteristics over time and against radiological response. How results will be used The following step is to use the PET read-out to change patient treatment decisions and relies on the results of clinical trials in which patients are randomised to ICIP trials on the PET results. Ultimately, implementation in the NHS will use existing PET imaging infrastructure and existing radiologist expertise. The cost of a PET CT scan is around £650 per scan. Given pembrolizumab costs £5260 per 3 weekly treatment the cost-benefit of an implementation that improves patient selection is likely to be large.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Integrative single cell time-series for tumor microenvironment remodeling
Funder: Cancer Research UK

Abstract: Immunotherapy has revolutionized cancer treatment by targeting tumor-immune interactions and providing durable objective clinical responses in advanced metastatic cancers. However, these therapies are only effective in a subset of cancer types and patients. For example, a large subset of lung adenocarcinoma patients obtain a durable response to immunotherapy, whereas immunotherapy is not effective in pancreatic ductal adenocarcinoma patients. The lack of response can be attributed partly to exclusion of T-cell infiltrates and poor cancer immunogenicity due to low mutational burden. Therefore, strategies to enhance T cell infiltration and tumor recognition are needed to potentiate immunotherapy. Single cell genomics has transformed our understanding of heterotypic cellular interactions in tumors and has revealed mechanisms of response and resistance to therapies such as immunotherapy mostly in preclinical models. We propose to characterize the mechanisms of response or resistance to the combination of senescence-inducing therapy and immune checkpoint blockade immunotherapy in lung and pancreatic adenocarcinomas by focusing on the tumor microenvironments remodeling effects. We will use single cell genomics analyses (transcriptome, epigenome, T-cell Receptor profiling, and spatial transcriptomics) of tractable and validated genetically engineered mouse models. Our preliminary data shows a dynamic process that involves dramatic changes in cell type composition, functional states and spatial organization of cells in the tumor microenvironment after senescence-inducing therapy. Thus, we propose to fully interrogate responses to senescence-based therapies in time and space at single cell resolution and in combination with checkpoint blockade immunotherapy. Despite the staggering rate at which single cell genomics methods are being developed, computational methods for the analysis of more complex scenarios like treatment response to therapy in space and time are still needed. In this project I will first develop robust computational methods to leverage longitudinal and spatial information at single cell resolution. Second, I will develop methods to integrate single cell transcriptomic and epigenetic data to tease apart the regulatory mechanisms underlying the remodeling upon treatment. Third, I will incorporate the clonal tumor evolution axis to the computational framework by leveraging single cell copy number alterations. Results from these analyses will provide mechanistic understanding of the senescence-based therapy response and identify targets that will be tested for tumor senescence and immunotherapy efficacy (targeting PD-1/PD-L1 receptors). Finally, the computational framework for single cell time-series will be further applied to spatiotemporal single cell cancer data from hundreds of human samples generated by the lung and pancreas Human Tumor Atlas programs and the TRACERx program.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/039: LCH-IV - International collaborative treatment protocol for Langerhans Cell Histiocytosis
Funder: Cancer Research UK

Abstract: Background Langerhans Cell Histiocytosis (LCH) is a rare disorder with highly variable clinical presentation and biological behavior. It is characterized by proliferation and accumulation of cells phenotypically and functionally similar to activated normal Langerhans cells. It can affect a single system/organ (SS-LCH) or multiple systems/organs (MS-LCH). Patients with SS-LCH of the skeleton, skin, or the lymph nodes have an excellent prognosis and may only need minimal or no treatment. The course of MS-LCH is unpredictable upon diagnosis, ranging from spontaneous resolution to rapid progression and fatal outcome. Patients with involvement of the haematopoietic system, liver, or spleen are at higher risk of death and these organs are referred to as ‘risk organs’. International studies over the last 20 years have shown that combination therapy with vinblastine and prednisone is an effective therapy for MS-LCH but 10% of patients still succumb to this form of the disease and more than a third of patients suffer disease reactivation. LCH patients may also experience serious permanent consequences including hormone deficiencies, a neurodegenerative syndrome and lung fibrosis. Aims The study aims to improve overall survival, reduce reactivation rates and reduce permanent consequences. Methods All LCH patients ( 18 years old) are eligible for enrolment. The study is designed to tailor treatment based on disease features at diagnosis and on response to treatment. There are therefore seven strata. In Stratum I, a prolongation (12 vs. 24 months) and intensification (addition of 6-mercaptopurine) of first line therapy (vinblastine and prednisolone) is the subject of a randomised study. In Stratum II, the response to a uniform initial second line therapy (prednisolone, Ara-C and vincristine) for those without risk organ involvement is studied followed by a randomised comparison of maintenance therapy with either indomethacin or 6-mercaptopurine + methotrexate (total treatment duration of 2 years). Stratum III (2-CdA/Ara-C based salvage treatment) and Stratum IV (reduced intensity haemopoietic stem cell transplant) are single arm studies of 2nd line therapy for those with risk organ involvement. Stratum V explores the course and treatment of CNS – LCH, Stratum VI the natural history and treatment on SS-LCH which did not require systemic treatment at diagnosis and Stratum VII the long term outcome of all patients diagnosed with LCH. Results The results of the trial will be used to inform standard practice worldwide and provide the standard arms for future LCH trials.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Growth Factor Signalling and Squamous Cancers
Funder: Cancer Research UK

Abstract: The transforming growth factor beta (TGFβ) superfamily comprises approximately forty related dimeric polypeptide cytokines including the bone morphogenetic proteins (BMPs), the growth and differentiation factors (GDFs), activin, nodal and the TGFβs (TGFβ1, TGFβ2 and TGFβ3). These growth factors play fundamental roles during mammalian development and act as homeostatic factors in adult life, regulating tissue repair, wound healing and the immune response. As well as having vital normal physiological functions, these factors play pivotal roles in disease pathogenesis, and the emerging importance of TGFβ and BMP signalling in cancer biology is the primary focus of our studies. Paradoxically, TGFβ can act as both a tumour suppressor and a tumour promoter. The tumour suppressor activities of TGFβ are ascribed to its ability to act as a potent negative regulator of cell proliferation and survival. As tumours progress they frequently avoid the tumour suppressive activities of TGFβ and switch their response to this cytokine and utilise it as a promoter of motility, survival, invasion, vascularisation, metastasis and immunosuppression. We have three fundamental questions that we are trying to answer in the laboratory using both in vitro cell biological and in vivo techniques coupled with analysis of primary patient tumour material: 1) How do TGFβ/BMP act as tumour suppressors and how do tumour cells avoid this? 2) How do TGFβ/BMP act on tumour cells to promote cancer progression? 3) When and where do these events occur? Our ultimate goals are to develop therapeutics that selectively target the pro-oncogenic actions of these cytokines and to identify patient selection criteria for their deployment. In collaboration with Owen Sansom’s laboratory, we have previously shown that both TGFBR1 and TGFBR2 are frequently mutationally inactivated in human cutaneous squamous cell carcinoma (cSCC) and that combined deletion of TGFBR1 coupled with activation of the MAPK pathway is sufficient to drive rapid invasive cSCC formation from the Lgr5+ve hair follicle bulge stem cells in the mouse. This has led us into studies profiling the molecular landscape of human cSCC. Our recent whole exome sequencing studies have identified driver genes and pathways that are implicated in cSCC progression and we are currently building upon these observations using whole genome sequencing and RNAseq in collaboration with Peter Bailey (University of Glasgow) and Irene Leigh (QMUL). There are striking similarities in the molecular landscape of all squamous cancers, and we are determining the biological roles of the genes, pathways and processes underpinning tumour progression in cSCC, head and neck SCC and the 'squamous' subtype of pancreatic cancer using in vitro, ex vivo and in vivo pre-clinical models.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Investigating mechanistic pathways linking adiposity to colorectal cancer
Funder: Cancer Research UK

Abstract: Background: Colorectal cancer (CRC) is a heterogeneous disease with both genetic and environmental risk factors contributing to its etiology. Obesity is a condition characterized by substantially dysregulated metabolism, and is an established risk factor for CRC indicating that the endogenous metabolic milieu is likely to play a major role in CRC development. Leading biological hypotheses to explain this relationship include alterations in insulin signaling, adipose tissue-derived inflammation and sex hormone pathways. Despite extensive experimental and molecular epidemiological research being undertaken, our knowledge of the biological pathways that mediate the adiposity and CRC association is relatively limited, as important questions remain unanswered. Aims: In this project, we will probe more deeply into the etiologic role of metabolic dysfunction on CRC development by investigating whether the association of obesity differs by tumour molecular subtypes defined by existence of tissue mutated pathways. We will also investigate whether obesity interacts with germline genetic variation in CRC development. Finally, we will investigate the potential causal role of obesity-related metabolic dysfunction pathways on risk of CRC. Methods: This study will leverage existing resources in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO, NIH U01 CA137088). GECCO includes 58,000 CRC cases and 67,000 controls from well-characterized cohort studies with prospectively measured data on adiposity indices (i.e. body mass index, waist and hip circumference), detailed germline genetic data from genome-wide genotyping arrays, and a database of clinical and epidemiologic variables harmonized across all studies. Furthermore, the majority of studies in GECCO have collected tumour samples for which targeted sequence data to define molecular subtype are available or are currently being generated for 7,000 CRC cases. The association of adiposity indices with CRC molecular tumour subtypes will be performed using subtype-stratified Cox proportional hazards regression models. The interaction of adiposity indices with germline genetic variation will be performed using genome-wide pathway-based approaches. Mendelian randomization will be used to investigate the causal role of obesity-related metabolic dysfunction pathways on CRC risk. How the results of this research will be used: Our large and well-characterized study population, combined with our experienced research team, established methodology, and integration of somatic and germline genetic data, provides a unique opportunity to better understand how obesity influences CRC tumorigenesis with possible relevance for other obesity-related cancers. Such insights have the potential to enhance CRC preventative and therapeutic strategies and will have an important public health impact.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS