NIHRDataInsights/HRCSData huggingface dataset:
Title: Colorectal cancer reduction through risk stratification of screening, follow-up and treatment
Funder: Cancer Research UK

Abstract: Background We have shown that by combining genetic information with age, gender and family history we were able to identify those from the general (asymptomatic) population likely to maximally benefit from chemoprevention of colorectal cancer (CRC) disease or from earlier introduction in the CRC screening programme. In regards to symptomatic patients, there is a need to identify those in higher risk for prioritization of follow-up investigations, as it has been estimated that less than 4% of symptomatic patients have a bowel tumour or high risk adenoma. Finally, it is crucial to target interventions to CRC patients most likely to benefit within a stage, given the cost and side effect implications. Aims I aim to develop and evaluate prediction models to stratify the asymptomatic population, symptomatic patients and stage 2 and 3 CRC patients for targeted CRC screening, follow-up and treatment. I will include more than 6,400 CRC cases and 18,740 controls from the UK Biobank and the Scottish Colorectal Cancer Study and aim to recruit 5,000 symptomatic patients from the Western General Hospital in Edinburgh, Scotland. Methods I will first assemble the risk factors to be included in each prediction model. I will include genetic variants, novel markers, demographic items and risk factors. In addition I will use the GENOSCORES open access library of genetic scores for traits and omic markers that are not measured in the included studies. I will then construct prediction models for CRC risk and survival. To estimate predictive performance, I will use several measures including discrimination (Area under the ROC Curve), calibration, model fit, and re-classification, plus cross-validation and handling of competing risks. I will apply parametric and non-parametric meta-models to optimize the combination of risk scores and to account for correlations among the predictions. I will develop methods for partitioning patients into subgroups so as to optimize predictions for each subgroup. I plan to internally and externally validate the prediction models. Finally, health economic models will be constructed using standard methods for cost-effectiveness analysis, based on a state transition cohort modelling approach. How the results of this research will be used The success and cost-effectiveness of targeted CRC screening, follow-up and treatment strategies will directly benefit the health of the British population. Furthermore, there is considerable potential for translation into clinical practice by facilitating the uptake of our findings through active engagement with the Scottish CRC screening programme from the beginning of the project.


Research activity codes: 4.4 POPULATION SCREENING;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: CRUK/17/012 Myeloma XV: RADAR: Risk Adapted therapy Directed According to Response comparing treatment escalation and de-escalation strategies in newly diagnosed patients with multiple myeloma (NDMM) suitable for stem cell transplantation (TE)
Funder: Cancer Research UK

Abstract: Multiple Myeloma (MM) is the second most common haematological malignancy with almost 5000 patients diagnosed in the UK each year. Over the last ten years patient outcomes have improved. Although still incurable in the vast majority, median survival in fitter patients who are transplant eligible is over 6 years. In addition, treatment approaches in MM now include continuous therapies which can impact on patient quality of life, partly due to treatment-related toxicity. Adaptive clinical trials are needed that can evaluate multiple novel treatment strategies in a timely manner for relevant patient subgroups, defined by genetic risk and treatment response.<br/><br/>The study is designed to for newly diagnosed MM patients who are transplant-eligible (TE), with stratification of standard and high-risk patients at the start. The overriding principle in Myeloma XV is precision medicine: a risk platform based on underlying genetics to stratify to different therapeutic approaches at the start of treatment, and a second, response-based stratification. For genetically defined standard risk disease the key objectives are to evaluate treatment escalation and de-escalation stategies as defined by disease response, in a randomised multi-arm multi-stage (phase II/III) controlled trial. For high-risk disease the objective is to provide access to high intensity treatment and assess their activity in phase II clinical trials. <br/><br/>All patients will receive the first cycle of carfilzomib, lenalidomide, cyclophosphamide and dexamethasone (KCRD). When the results of their baseline genetic tests are available (after one cycle), approximately 20% will be assigned to the high-risk pathway, with the remaining 80% continuing in the standard risk pathway. The standard risk pathway follows a response-adapted design where patients are allocated to a more, or less, intensive pathway depending upon their level of minimal residual disease (MRD) following initial chemotherapy and stem cell transplant. Treatment escalation options utilise agents targeting the tumour micro-environment, including immunotherapy drugs, whereas de-escalation strategies test the possible option of stopping continuous therapy in patients who have achieved and maintained the deepest response.<br/><br/>Results of this study will be used to design better protocols for patients, where treatment intensity and duration are adjusted according to diagnostic risk factors, and subsequently adapted according to response. Standard risk patients who have responded well will benefit by avoiding toxicities from unnecessary treatment, while those at greater risk due to genetic background or residual disease will have the opportunity to receive therapies with new mechanisms of action, to improve outcomes.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Dissecting the earliest steps in pancreatic cancer by genomic analyses of normal and precancerous tissue
Funder: Cancer Research UK

Abstract: Background Pancreatic cancer is a devastating disease with a five-year survival rate of just 5% – the poorest prognosis of all major solid tumours. Poor survival is largely due to late-stage diagnosis; therefore methods for early detection may help to improve patient outcomes. In just a few years, cancer genome sequencing has provided a detailed understanding of the genetics of cancer and promises to revolutionise clinical practice. However, very little is known about the earliest cellular changes that lead to cancer, a critical question newly amenable to genomic analysis. Aims In this study, I aim to characterise the earliest changes in the evolution of pancreatic cancer by studying the mutation and selection landscape in normal pancreatic tissue and precancerous lesions of different grades. Following my work on skin (Martincorena et al., Science 2015), I first plan to study the mutation burden, mutational signatures, clonal dynamics and driver mutations in normal pancreas. Second, I will explore how these processes are affected by epidemiological factors associated with pancreatic cancer, such as age or smoking history, by studying individuals with a range of ages and medical histories. Finally, I aim to characterise in detail the genetic changes that characterise precancerous lesions of the pancreas at different histological stages of progression to malignancy. Methods I plan to use laser capture microdissection of histopathological specimens followed by deep targeted sequencing of a panel of 300 cancer genes, an extension of the design I used in my recent work in skin. I propose to sequence and analyse ~3,500 microbiopsies from 100 resected pancreases, 75 from healthy individuals and 25 from pancreatic cancer patients. Whole-genome sequencing (Illumina HiSeq XTen) of ~100 selected biopsies will be used to obtain a more comprehensive understanding of the mutational landscapes and the clonal relationships between biopsies. How the results of this research will be used Understanding how normal cells accumulate specific mutations in their progression towards cancer is a critical step in better understanding the origin of cancer. Further, the work has important practical implications, as identifying the combinations of mutations that characterise precancerous lesions of different grades will guide efforts for early diagnosis of pancreatic cancer.


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: Deep molecular profiling of minimally invasive samples and tissue biopsies to select patients for invasive procedures and identify potentially lethal prostate cancer at an early stage
Funder: Cancer Research UK

Abstract: Background Prostate cancer incidence is predicted to increase by 12% over the next 20 years, with estimates of over 50,000 new prostate cancer cases, resulting in 12,000 prostate cancer deaths per year by 2035. The current diagnostic pathway for prostate cancer (mpMRI) misses 1-in-10 clinically significant cancers and 1-in-5 men still undergo invasive biopsies for benign lesions. We urgently need better tests to identify potentially lethal cancers at an early stage and distinguish these from benign or indolent lesions, to avoid a concomitant rise in healthcare costs, co-morbidities and cancer deaths. Aims 1. Systematically test circulating tumour DNA (ctDNA) analysis in early stage prostate cancer 2. Develop multi-modal prospective marker panels for pre-biopsy analysis in blood and urine samples 3. Test liquid biopsy analysis in large diagnostic sample cohorts, to evaluate this as a ‘pre-biopsy test’ in the diagnostic pathway for prostate cancer 4. Probe driver gene and phenotypic heterogeneity to identify features of non-indolent prostate cancers Methods We will determine a ‘ground truth’ for ctDNA levels using large patient-specific panels in early stage prostate cancer. This ‘ground truth’ will be used to benchmark a multi-parameter ‘prospective ctDNA panel’. Promising combinations of markers will be taken forward to test ctDNA analysis in large collections of diagnostic plasma samples. Finally we will probe the driver gene and functional heterogeneity in prostate cancer using a combination of tissue microdissection with targeted deep sequencing, single cell profiling, in situ hybridisation and error suppressed deep sequencing on mpMRI-guided diagnostic biopsy samples. In these projects we will apply cutting edge technologies, develop new workflows and leverage world-class infrastructure to provide deep insights into the signal space in early stage cancers with a clear focus on patient benefit. How the results will be used These clinically focussed projects aim to address the unmet need of reducing unnecessary tissue biopsies in men with benign prostate disease. We will also explore features of aggressive disease in contemporary diagnostic biopsy samples, with the aim of stratifying non-indolent prostate cancers to reduce unnecessary radical treatments. We will work closely with local GCPL facilities to ensure that useful tests can be implemented in future prospective clinical trials along side mpMRI and clinical prognostic scores to rigorously test the combined value for diagnosis and patient stratification.


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: Targeting of aberrant epigenetic circuitries and associated DNA damage response in acute myeloid leukaemia
Funder: Cancer Research UK

Abstract: While advance in DNA sequencing technology has provided important insights into the genetic makeup of cancer cells, it is evident that cancers are also driven by epigenetic deregulation and tumour environments beyond the hardwired DNA mutations. In acute myeloid leukaemia (AML), the most common initiating mutations involve transcription factors and their associated epigenetic modifiers such as retinoic acid receptor alpha, the core-binding factors (e.g., AML1 or CBF?), the mixed lineage leukaemia protein (MLL), and DNA methyltransferase 3A with clear distinctive epigenetic functions. The importance of epigenetic deregulation in AML pathogenesis is further underscored by the discovery of 1) leukemic stem cells with identical genetic makeup but distinctive gene expression profiles and immunophenotypes as compared with their short-lived progenies; and 2) genetically indistinguishable but transcriptionally distinctive AML stem cells originates from normal haematopoietic stem cells (HSC) versus committed early myeloid progenitors (e.g., CMP, GMP) exhibited contrasting cancer biology and treatment responses. While key epigenetic factors, polycomb group (PcG) proteins are frequently deregulated in various cancers including AML and their inhibitors have also been developed for potential cancer therapeutics, we are still in our infancy in understanding their roles and functional involvements in leukaemia development. Intriguingly, many of their family members and associated factors also emerge as important players in governing DNA damage responses (DDR), which has been the key to the recently proposed synthetic lethality approach for AML treatment. By applying various biochemical, molecular and cellular biology approaches in combination with sophisticated mouse disease models together with relevant patient derived leukaemia cell and xenograft models, my research programme will study the roles of epigenetic factors and DDR in AML pathogenesis with an overarching goal of developing more effective leukaemia treatments. The programme will be divided into four major interactive sections where we will 1) investigate the roles of YY1/non-canonical polycomb repressive complex (PRC)1 and Skp/Cullin/F-box (SCF) complex in MLL-AML and other AML; 2) define the functions and downstream molecular targets of BMI1/PRC1 in malignant and normal haematopoiesis; 3) dissect the mechanisms underlying contrasting EZH2/PRC2 functions in different AML; and 4) explore the link between epigenetic regulation and DDR that may be exploited as novel cancer therapeutics. The end product of these endeavours will be an in-depth understanding of the epigenetic regulation and transformation mechanisms underlying AML pathogenesis, which will also provide novel targets for development of better therapeutic strategies that can potentially be directly translated into patient’s benefit.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Realising the potential of genetics to prevent colorectal cancer
Funder: Cancer Research UK

Abstract: Background Colorectal cancer (CRC) is a common, but largely preventable, cause of cancer death. The genetic contribution to CRC risk comprises rare high-penetrance alleles and many common genetic variants of individually modest effect. Gender and vitamin D may interact with genetic factors to influence CRC risk. Identifying rare mutations is challenging, but achievable, by studying unusually young cases without a family history. We are nearing completion of the largest-ever GWAS meta-analysis with UK/US/Asian collaborators, gaining new insights into the contribution of common genetic risk factors (120 SNPs now known). However, GWAS has reached a “glass ceiling” due to sample/effect-size considerations. Hence, we focus on exploiting our accumulated genetic/expression data to develop new strategies to understand/modulate CRC risk. We are identifying new associations between CRC risk and genes/methylation marks by exploiting our RNAseq and methylation data from normal mucosa to build TWAS and MWAS prediction models. Aims We propose a bold, but deliverable mix of “post-GWAS” discovery, investigative and translational science to enable application of genetic knowledge to benefit human health. We will integrate functional genomic interrogation of selected CRC risk loci with genetic and other manipulations in model systems, including human epithelial organoids, genetically engineered mouse models (GEMMs) and clinical patient studies. Methods Workpackage-1: Whole-genome sequencing of family trios to search for de novo, and recessive, high-penetrance mutations, cross-referenced to our GWAS/TWAS/MWAS/SMR datasets. Pilot sequencing already identifies promising leads, implicating new genes in CRC aetiology. Sample-size estimates indicate 500 trios gives good study power. Candidate mutant genes will be studied by gene manipulations in cell lines, human colorectal mucosa organoids, and GEMMs. Workpackage-2: We will study modification of GWAS/TWAS/MWAS main effects by vitamin D/gender in gene-environment interaction analyses. Using gene-editing in human colorectal epithelial organoids, we will study vitamin D GxE effects and cell biological consequences. We will study expression/methylation in rectal biopsies from CRC patients before/after vitamin D supplements to inform a future RCT of vitamin D stratified by genotype, with survival as endpoint. Workpackage 3: We will generate GEMMS for a shortlist of target genes by prioritising from trio sequencing, GxE and/or TWAS studies to study gene-specific mechanisms. The SHROOM2-deleted model that we generated, only male mice develop rectal tumours. GEMM colonies are in progress for SMAD9 and FUT2 (genes we identified by TWAS). How the results of this research will be used. Our aim is to devise strategies to ameliorate/abrogate CRC risk in GEMMs, organoids and people.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS
Title: The MBL DNA Repair nucleases – from basic biology to therapeutic inhibition
Funder: Cancer Research UK

Abstract: Background - DNA damage, including double-strand breaks (DSBs) and interstrand cross-links (ICLs) are generated by drugs and radiation during cancer therapy. The human metallo-ß-lactamase (MBL)-fold DNA repair factors, SNM1A, SNM1B/Apollo and SNM1C/Artemis are nucleases that counteract therapeutic DNA damage. By virtue of containing a highly conserved, relatively well-understood MBL-fold active site, they are potentially readily druggable. Aims - Building on collaborative achievements, we will further our understanding of ICL and DSB repair via a comprehensive functional, mechanistic and structural understanding of the MBL-fold DNA repair nucleases, enabling their therapeutic targeting for cancer treatment. Through targeting the MBL-family of nucleases we aim to sensitise tumours to DNA damage induced by drugs of major therapeutic importance (e.g. cisplatin), and radiation, and to exploit several-tumour-relevant synthetic interactions we have recently discovered. We will address major unresolved questions via three integrated work fields. First, we will define the precise role SNM1A and SNM1B play in ICL repair and the repair of of damaged replication forks. We will extend our recent advances in identifying synthetic-genetic interactions between SNM1A (and SNM1B) and potentially exploitable tumour defects. Second, we will extend early-stage work on the mechanisms and inhibition of SNM1A/SNM1B to identify proof-of-concept inhibitors with novel mechanisms of action that selectively inhibit cellular SNM1A/SNM1B; we will also break new ground by targeting SNM1C/Artemis, a key player in the repair of radiation-induced DSBs. The third field emerges from our recent discovery of a role for SNM1A in the repair of DNA damage produced by radiomimetic drugs, that are associated with chemically damaged termini, interfacing with our work on Artemis. Methods – We will employ a powerful combination of cell biology, genetics, structural biology and chemical biology to define the mechanism of action of human MBL nucleases, and to fully explore their potential utility as anticancer therapeutics. How the results of this research will be used – The results of this work will be used to enable the selective targeting of MBL-fold nucleases as a novel approach to anticancer therapy, either as standalone therapies in tumours with specific genetic defects, or in combination to enhance the effectiveness of chemotherapy, radiotherapy and potentially the more recently developed targeted and immunotherapy approaches. We anticipate that by defining the mechanism of the MBL-fold nucleases and identifying strategies for their inhibition we will enable efforts by industry and others to exploit this druggable family of enzymes in future.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Exploiting cell cycle vulnerabilities to develop novel therapeutic strategies for ovarian cancer
Funder: Cancer Research UK

Abstract: Background High-grade serous ovarian cancer (HGSOC) is an insidious disease, with most patients diagnosed harbouring advanced and disseminated disease. Treatment options are limited, yielding survival rates well below CRUK’s visionary target. However, the discovery that PARP inhibitors selectively kill cancer cells with homologous recombination (HR) defects has led to a paradigm shift: with up to half of all HGSOC cases being HR-deficient, PARP inhibitors are driving unprecedented improvements in progression-free and, more recently, overall survival. However, most cases are HR-proficient and unlikely to benefit from PARP inhibitors. This leads to our central question: how can we improve outcomes for women with HR-proficient disease? Aims Our hypothesis is that HR-proficient tumours have other cell-cycle vulnerabilities that can be defined and exploited to develop novel biomarker-driven therapeutic strategies. Our overarching aim is to test this hypothesis by exploring three interconnected cell cycle processes, namely PAR dynamics and DNA replication stress; MYC/SUMO signalling in executing faithful cell division; and mitotic vulnerabilities to overcome paclitaxel resistance. Methods To exploit PAR dynamics and DNA replication stress, we will determine the molecular mechanisms underlying PARG inhibitor sensitivity, a potential novel treatment for HGSOC. We will focus on TIMELESS, a fork protection complex component, which we propose integrates the opposing forces of PARP and PARG to regulate replisome speed. To exploit oncogenic MYC, we will determine why inhibition of the SUMO E1 enzyme SAE2 causes cell division failure in cells overexpressing MYC. We will interrogate the SUMOylation machinery to identify the relevant E3 ligase, and test whether pharmacological inhibition of SUMO signalling selectively kills patient-derived HGSOC cells overexpressing MYC. To exploit mitosis, we will triangulate clinical data, multi-omics parameters and ex vivo drug-sensitivity profiling to define the molecular determinants of paclitaxel sensitivity, then determine whether HGSOC cells can be re-sensitized to paclitaxel by rationally targeting pro-survival factors and drug efflux pumps. Each project will be underpinned by a living biobank of ~200 ex vivo cultures, each annotated with clinical data; RNAseq and SWATH-MS profiles; and drug sensitivity to paclitaxel and inhibitors targeting PARG and SAE2. How the results of this research will be used: All three work streams will deliver novel insight into the fundamental biology underlying intrinsic cell cycle vulnerabilities in HGSOC, allowing us to develop mechanistically-driven biomarkers that predict sensitivity to emerging drugs and drug combinations, in turn informing the design of future clinical studies designed to improve outcomes for women with HR-proficient HGSOC.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS