NIHRDataInsights/HRCSData huggingface dataset:
Title: Targeting the connected metabolic and immune responses to pancreatic cancer to improve outcomes for patients
Funder: Cancer Research UK

Abstract: Background and aims Independent lines of research have led to advances in cancer immunotherapy, and in the understanding of the altered host metabolism that causes the fatal wasting syndrome cachexia. However, it was unclear if the host's immune and metabolic responses to tumors were linked. My work to date provides a causal connection of tumor-induced reprogramming of liver metabolism in cachexia to lack of anti-tumor immunity. As part of the proposed work, I will investigate the extend of the link between the host's metabolic and immunological response to cancer. I will conduct experimental medicine studies to demonstrate the translational relevance of my findings. Ultimately, I will test the hypothesis that the convergence of host metabolism and antitumor immunity offers a platform for biomarker-driven investigations of new combination therapies. Methods Experiments will be performed using syngeneic subcutaneous tumour models of cachexia inducing cancer (C26), genetically engineered mouse models of PDA (KPC), and organoid as well as orthotopically implanted organoid derived models. The effect of tumour associated reprogramming of the hepatic metabolism will be interrogated using mRNA sequencing, pathway analysis, functional assays, metabolomics, and genome editing techniques. Pharmacological reversibility will be tested, in part in collaboration with industry partners. The differential effect on tumours and host organisms will be studied using organoid technology. The effect of metabolic stress on the immune system will be tested using immunohistochemistry, immune fluorescence, flow cytometry, and reverse transcriptase quantitative PCR of immune cell marker genes. Pharmacological induction and reversal of treatment failure will be studied. How the results will be used If indicated, clinical trial protocols to investigate the most promising treatment hypotheses for cachexia will be developed, sponsored by Cambridge University Hospital and run through the accredited Cambridge Clinical Trial Unit, with the sponsor of this application and the director of the Cambridge Cancer Trials Centre, Prof. Duncan Jodrell. Ultimately, the results of this proposal are going to help improve the outcome for patients with PDA.


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: Mapping the constraints and selection pressures of lung cancer evolution
Funder: Wellcome Trust

Abstract: Lung cancer development is an evolutionary process, involving accumulation of mutations within a given environment. However, although driver alterations and mutational processes in lung cancer evolution have been elucidated, an understanding of the constraints and selection pressures that govern cancer development and their evolution and genomic regulation is unclear. Moreover, while studies have revealed that driver alterations can be present in ‘normal’ tissue, the differences between such somatic genomic evolution and cancer evolution is unclear. I hypothesise that knowledge of the genomic and transcriptomic mechanisms underpinning tumour evolution, coupled with an understanding of constraints and selection pressures that shape tumour development, can inform approaches to tackle cancer. I have previously developed bioinformatics methods to disentangle a cancer’s life history from multi-region sequencing data (e.g. de Bruin and MCGRANAHAN, 2014 SCIENCE; McGRANAHAN et al., 2016 SCIENCE), and developed tools to elucidate immune escape (MCGRANAHAN et al., 2017 CELL). I propose to extend these methods using normal tissue sequencing, public and private data from collaborators, to obtain a pan-cancer database of the evolutionary trajectories of thousands of tumours. Evolutionary maps, including immune micro-environmental and therapeutic selection pressures over space and time, will provide a systems level understanding of cancer evolution.

Lay abstract: Cancers develop through an evolutionary process, whereby ‘normal’ cells accumulate genetic faults. Although some of the key genetic events leading to cancers have been identified, why certain events occur in certain tissues at certain times and not others are not clearly understood. I hypothesize that by developing a deeper understanding of the processes that go awry during cancer development, coupled with a further investigation of the key selective forces shaping a tumour’s development, including the immune system, we may be better placed to tackle cancer. I propose to utilize data from thousands of cancers to obtain a large database of how tumours from different tissues evolve over time. This database will be used to help understand how tumours change during their development, and whether we can predict the next step they are likely to take. Ultimately, this work may lay the foundation for a new type of evolutionary guided therapeutics.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: CRUK/14/013: MyeChild01 - An international randomised phase III clinical trial in children with acute myeloid leukaemia
Funder: Cancer Research UK

Abstract: Background: Outcomes for children with acute myeloid leukaemia (AML) have improved little in the past two decades. Whilst advances in supportive care and better salvage therapy after relapse have led to a small improvement in overall survival, the relapse rate remains unacceptably high (35-40% for all major national groups) with relapsed disease the commonest cause of death. Strategies aimed at reducing the relapse risk without significantly increasing toxicity have the greatest potential for improving outcomes. This study plans to test a number of strategies reported to improve outcomes including intensive anthracycline induction , induction intensification by the addition of a new agent, intensification of consolidation therapy and evaluation of a reduced intensity conditioning regimen in allogeneic stem cell transplantion in 1st complete remission. DaunoXome, with it theoretical advantage of limited cardiotoxicity, may facilitate anthracycline intensification in children. Gemtuzumab ozogamicin is the most promising new agent in AML and has been reported to improve outcomes when added to induction chemotherapy in adult AML studies and more recently has been reported to reduce the relapse rate in paediatric AML (Gamis , Blood 2013). The optimum dose and schedule in combination with induction chemotherapy in children will be investigated after the highest tolerable dose has been identified in a dose finding study. Minimal residual disease (MRD) monitoring will be used to improve standard risk group stratification and guide treatment intensification and SCT. Aims: To improve the overall and event free survival of children with AML and reduce treatment related mortality and morbidity. Methods: An international, open label, stratified, phase III, randomised controlled trial is designed to recruit 600 patients with AML over 5 years. Patients will be treated during induction phase according to their risk group defined by cytogenetic and molecular characteristics and then later re-stratified by response to treatment as assessed by minimal residual disease monitoring. How will the results of the trial be used: The results will be published in peer reviewed journals and will inform best clinical practice for children with AML. Raw data from the trial will be made available to bona fide researchers for the purposes of evaluation of treatment efficacy via systematic reviews, meta-analysis, prognostic factor/biomarker development/validation and other relevant scientific projects. Requests for data sharing will be reviewed by the TSC to ensure they are scientifically appropriate. The appropriate regulatory and ethical requirements will be adhered to when data sharing.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK support to the Personalised Breast Cancer Programme
Funder: Cancer Research UK

Abstract: The Cambridge Personalised Breast Cancer Programme is pioneering whole genome sequencing for breast cancer patients. A new personalised breast cancer initiative which will map patients’ DNA and RNA to tailor treatment for individuals launches at the Cancer Research UK Cambridge Institute today. The project, which was launched with £1.1 million funding from Addenbrooke’s Charitable Trust (ACT), will analyse the genome and all expressed genes of tumour cells from 250 breast cancer patients to improve early diagnosis and tailor treatment. Finding out which genes have become faulty in breast cancer cells will help researchers understand more about how cancer develops and spreads. It will also help doctors choose the best treatment for their patients. Breast cancer patients are treated based on the broad types of cancer, for example, those that are likely to respond to hormone therapies, but it can be difficult to predict how individual patients will respond to treatment. The researchers hope to find out how this personalised diagnosis and treatment project could be implemented in the National Health Service’s (NHS) breast cancer unit in Cambridge and hope that one day this will extend around the UK.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: CRUK/19/014 CUBIC: A Phase I/II study of the CXCR2 inhibitor, AZD5069, in combination with Durvalumab, in patients with advanced Hepatocellular Carcinoma (HCC)
Funder: Cancer Research UK

Abstract: BACKGROUND HCC complicates chronic liver disease, the incidence of which is increasing dramatically in the UK, attributed to viral hepatitis, alcohol excess, obesity and type II diabetes - related liver disease. Tyrosine kinase inhibitors have modest benefits as either first- or second-line therapy in advanced HCC. Inhibition of the immune checkpoint interaction between PD-1 and PD-L1 has promising activity in HCC, but does not improve overall survival as monotherapy. Pre-clinical studies suggest that inhibiting neutrophil accumulation in chronic liver disease or targeting their tumour-promoting activities may offer therapeutic opportunities. The primary immune function of CXCR2, the receptor for a number of human chemokines, is the regulation of neutrophil migration and it also regulates the migration of myeloid-derived suppressor cells (MDSCs). In pre-clinical studies, CXCR2 inhibition reduces liver tumour burden and tumour score and synergises with anti-PD-1 inhibition to prolong survival in addition to reducing tumour burden. AIMS We will test the hypothesis that AZD5069, an inhibitor of CXCR2, by depleting MDSCs and neutrophils in the liver tumour microenvironment, can enhance the anti-tumour activity of durvalumab, an anti-PDL-1 antibody. We will determine the recommended phase II dose of AZD5069 in combination with durvalumab, and determine the anti-tumour activity of this combination in patients with advanced HCC. We will also investigate the pharmacodynamic effects of this combination in blood and tumour samples and explore predictive markers of tumour response to this combination. METHODS Eligible patients with advanced HCC will receive AZD5069 orally, twice daily, by continuous administration and durvalumab by intravenous infusion 4-weekly. Using a keyboard design, we will determine the maximum tolerated dose of AZD5069 (using 5 cohorts of n = 3, and 3 dose levels) in combination with a fixed dose of durvalumab. An additional cohort of patients will be recruited to determine anti-tumour activity, as measured by objective tumour response (RECIST 1.1), using a Simon’s two-stage design (n = 35). PD analyses will include biomarkers of CXCR2 inhibition, changes in expression of PD-L1, PD1 and immune cell markers, and drug-induced changes in expression of CXCR2, CXCR2 ligands and signalling pathway genes, T cell and myeloid cell pathways, and neutrophil-associated genes. Predictive marker studies will include analysis of the CXCR2/PD(L)1/immune axis, CXCR2-regulated signal transduction pathways, proliferation markers (Ki67), and tumour sequencing using a bespoke multiplex pan-cancer panel. FUTURE STUDIES We anticipate that the results of this study will lead on to Phase III trials in patients with advanced HCC.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Identifying the genetic and functional drivers of chemoresistant T-cell acute lymphoblastic leukaemia
Funder: Cancer Research UK

Abstract: Background Primary refractory (PR) T-cell acute lymphoblastic leukaemia (T-ALL) that is resistant to induction therapy represents a high-risk subtype of this aggressive haematological malignancy. Despite improved characterisation of T-ALL, the mechanisms governing refractory disease are largely unknown and effective treatments remain elusive. This proposal sets out to address this unmet need through detailed genomic and functional analyses of primary samples to ascertain the true drivers of resistance and provide targets for novel therapies. Aims 1. Characterise the coding mutations and aberrant pathways enriched in primary refractory T-ALL 2. Discover and validate novel non-coding enhancer mutations using an innovative bioinformatic pipeline 3. Identify functional drivers of resistance by employing genome-wide CRISPR screens in in vitro and in vivo systems Methods I will conduct whole exome sequencing (WES) and RNA sequencing on paired diagnostic and FACS-purified post-induction PR T-ALL samples to uncover the baseline mutational and transcriptional profile and permit appreciation of the clonal dynamics of refractory disease and the genes and pathways enriched in refractory subclones. Given the recent discovery of novel non-coding oncogenic mutations in T-ALL, I will explore this mechanism as a driver of PR T-ALL using an innovative in-house bioinformatic pipeline combining WES, RNA-seq and ATAC-seq to identify novel cis-acting sites, which drive aberrant expression of genes involved in chemoresistance. To pinpoint essential drivers of resistance, I will adopt a parallel functional approach using genome-wide CRISPR screening to identify genes which induce resistance in a sensitive T-ALL cell line in a co-culture system mimicking the bone marrow microenvironment. The most promising candidate genes will be taken forward into a targeted CRISPR screen in patient-derived xenografts (PDX) engrafted into NOD/SCID/IL-2Rgc-null mice to confirm in vivo functional relevance. The potential of novel agents to target aberrant pathways and to overcome resistance will be tested in refractory cell lines and PDX models. How the results of this research will be used This project aims to improve understanding of the processes driving refractory T-ALL with the hope that this will lead to identification of novel agents to improve outcomes in this high-risk disease. On a wider level, appreciation of whether an inherently resistant clone exists at diagnosis or if subclones develop in response to therapy has broad implications to other forms of cancer. Greater understanding of the processes that govern refractory disease could permit earlier detection of resistance and allow more accurate allocation of targeted therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: A phase II, randomised feasibility basket trial of a tailored, home-based exercise programme on disease-free survival among early stage high-risk recurring cancers in Yorkshire
Funder: Yorkshire Cancer Research

Abstract: More people in Yorkshire are diagnosed with lung, breast, and bowel cancer than in many other parts of the UK, with some specific types at higher risk of returning after treatment. Within each type of cancer, some diagnosis have a higher risk of recurrence. There is some evidence to suggest that regular exercise after cancer treatments can help increase the chances of surviving breast and bowel cancers by almost 40%. The evidence is not strong because it comes from observational studies and there is not enough among lung cancer to say if there is a survival benefit. Good quality, long-term clinical trials are needed to better understand if exercise should form part of cancer treatment. This study will compare a personalised home-based exercise programme with support from exercise professionals to NHS standard care. People who have recently finished their primary treatments and are at higher risk of their cancer returning will take part for 2 years. Results from this study will inform the design of a larger scale trial and provide initial evidence of whether more active people have longer, healthier lives without cancer returning than those who are less active after cancer treatments.

Lay abstract: More people in Yorkshire are diagnosed with lung, breast, and bowel cancer than in many other parts of the UK, with some specific types at higher risk of returning after treatment. Within each type of cancer, some diagnosis have a higher risk of recurrence. There is some evidence to suggest that regular exercise after cancer treatments can help increase the chances of surviving breast and bowel cancers by almost 40%. The evidence is not strong because it comes from observational studies and there is not enough among lung cancer to say if there is a survival benefit. Good quality, long-term clinical trials are needed to better understand if exercise should form part of cancer treatment. This study will compare a personalised home-based exercise programme with support from exercise professionals to NHS standard care. People who have recently finished their primary treatments and are at higher risk of their cancer returning will take part for 2 years. Results from this study will inform the design of a larger scale trial and provide initial evidence of whether more active people have longer, healthier lives without cancer returning than those who are less active after cancer treatments.

Research activity codes: 6.7 PHYSICAL
Health categories: CANCER AND NEOPLASMS
Title: IMPACT: Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in men at higher genetic risk and controls - A multicentre international targeted prostate screening study based on genotype: application to CRUK for the UK component of the study
Funder: Cancer Research UK

Abstract: Background The IMPACT study commenced in 2005 and is the first Prostate Cancer (PrCa) screening study targeted at men with a known genetic predisposition to the disease. The study has successfully established an international network of 65 centres in 20 countries offering a targeted PrCa PSA screening programme to men based on germline genetic status. Mutations in BRCA1/2 and mismatch repair (MMR) genes (MSH2, MSH6 and MLH1) are reported to be associated with a higher risk of both developing and dying from PrCa. The study offers screening to men with BRCA1/2 and MMR gene mutation carriers and their controls (men who have tested negative for a family mutation). The study has recruited 3245 men to date. Aims & Objectives The IMPACT study aims to: 1. Establish a multi-national targeted PrCa screening study in BRCA1/2 and MMR gene mutation carriers and controls 2. Determine whether there are differences between the cohorts in: -incidence of raised PSA -incidence of abnormal biopsy -pathology 3. Determine sensitivity, specificity and positive predictive value of PSA screening and prostate biopsy for PrCa in these cohorts 4. To gain a better understanding of the pathogenesis of PrCa due to a genetic predisposition. Methods Men aged 40-69 years from families with BRCA1 or BRCA2 or MMR (MLH1, MSH2, MSH6) germline mutations and their matched controls are offered annual PSA screening for 5 years. In addition biological samples are taken for banking for new marker studies. After 5 years of screening all men in the BRCA cohort are offered a prostate biopsy irrespective of PSA level. How the results of this research will be used This work will demonstrate the use of genetics to target screening to identify those at higher prostate cancer risk. It has translational opportunities to move forward the use of genomic medicine in healthcare policy. It is also an invaluable infrastructure to allow for future screening of any other high risk genetic mutations.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Chemokine dependent immune tumour cell cross-talk in chemotherapy resistant early triple negative breast cancers
Funder: Cancer Research UK

Abstract: Background: Majority of patients with Triple Negative Breast Cancer who do not achieve a complete pathological response at surgery after neoadjuvant chemotherapy have a very poor outcome. Relapse rates are particularly high with metastatic disease during the first few years following surgery with a peak recurrence risk at 3 years post-surgery. The contribution of the immune response, or editing of this response, within the treatment naïve and chemotherapy resistant disease remains unclear. Aim: This study aims to understand the contribution of chemokines in the microenvironment of chemotherapy resistant TNBC, and to inform strategies to enhance effector immune cell trafficking into tumours to improve anti-tumour therapy in TNBCs. Methodologies: I will use both multiplexed gene expression (nanostring nCounter® platform) from FFPE extracted RNA and protein expression (Vectra Quantitative Pathology Imaging platform) analyses in intact FFPE tissue sections to perform an in-depth study of the immune cell composition of post-neoadjuvant chemotherapy resistant residual disease. Next, I will use “Liquid Tissue” methodology for mass spectrometry from “NantOmics” to characterize the chemokine profile within this resistant disease; identifying which chemokines are important in recruiting e.g. effector as compared to suppressive immune cells. Next, we will investigate if corresponding chemokine receptor expression on the infiltrating immune cells is upregulated and how this overexpression may play a role in recruitment and/or retention of those immune cells into the tumour. I will use 3D-patient-deried cancer organoid and TNBC BLG-Cre;Brca1f/f;p53+/- mouse model to investigate how manipulation of specific chemokine profile affects the immune cell trafficking into tumour and their immunological processes within the TME. How the results of this research will be used: This project will inform directly on strategies to enhance effector immune cell trafficking into tumours to improve anti-tumour therapy in TNBCs and play a key role in the future development of a TNBC residual disease pre-surgical window trial platform called “PHOENIX”. PHOENIX is a peer-reviewed and CRUK EMERP/CRC committee endorsed clinical trials platform initiative.


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