NIHRDataInsights/HRCSData huggingface dataset:
Title: Discovering new sources of endogenous DNA damage and their consequences in the haematopoietic lineage
Funder: Cancer Research UK

Abstract: Blood stem cells (also known as haematopoietic stem cells; HSC) must produce a constant supply of essential blood cells throughout a person’s lifetime. A threat to healthy HSCs can come from damage to their DNA, which can mutate the genetic message and lead to abnormal function or death of the stem cell. This can have serious consequences to health, for example causing inadequate production of normal blood cells, or aggressive blood cancers such as leukaemia. To understand what causes these blood disorders, we must discover the origins of DNA damage in the HSCs, and understand how can these stem cells protect themselves from DNA damage? Recent research has demonstrated that chemicals produced from within our own body can be an important source of DNA damage. One potential source of these DNA-damaging chemicals could arise from inflammation, a normal body response to injury. Therefore my aims will be to investigate whether inflammation is a source of DNA damage in HSCs, and how HSCs protect their DNA from such chemical attack. This knowledge can help us to understand why our HSCs decline with age and develop blood cancer, and potentially lead to development of new ways to prevent and treat blood cancers.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Mutographs of Cancer: discovering the causes of cancer through mutational signatures
Funder: Cancer Research UK

Abstract: Description of the proposed research Overall Goal Through study of the mutational signatures present in the genomes of cancer and normal cells we aim to comprehensively catalogue the mutational processes that cause human cancer, to understand their causes and to apply this knowledge to cancer prevention. Research strategy ? We will address three Specific Aims in order to advance towards the Overall Goal: 1. To elucidate the causes of major global geographical and temporal differences in cancer incidence through mutational signatures. 2. To identify, characterise and understand the biological processes underlying mutational signatures. 3. To survey and monitor mutagenic exposures in normal cells in humans through mutational signatures. ? We will combine expertise, approaches and technologies from the constituent scientific disciplines of cancer epidemiology, cancer genomics, environmental mutagenesis and DNA damage and repair biology. ? Central to our proposal will be a major initiative to collect, DNA sequence and analyse for mutational signatures 5,000 epidemiologically characterised human cancers. This will be complemented by work-streams underpinning, informing and developing the findings of the central study. ? We will develop an international network of collaborations and work closely with existing collaborative groupings to produce a scientific collective of complementary expertise that we anticipate will be world-leading. ? We will generate open data resources and computational tools enabling the wider scientific community to pursue research into mutational signatures and the causes of cancer. ? We will make fundamental scientific discoveries relating to cancer causation and commence applying them towards public health goals.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Understanding how alcohol and endogenous aldehydes promote carcinogenesis
Funder: Cancer Research UK

Abstract: We discovered that reactive aldehydes are a common source of endogenous DNA damage. More specifically, the metabolism of alcohol unleashes acetaldehyde, in addition, certain biochemical pathways emit formaldehyde. A two-tier protection mechanism prevents these two aldehydes from damaging DNA. Tier-one consists of their enzymatic clearance by Aldehyde Dehydrogenase 2 (ALDH2) or Alcohol Dehydrogenase 5 (ADH5). Tier-2 protection is provided by the Fanconi anaemia DNA repair pathway. When we inactivated this two tier protection mechanism in mice then blood production ceased and certain cancers emerged. Furthermore, such animals were unusually sensitive to alcohol. The aim of this research proposal is to understand how DNA damage caused by these two aldehydes promotes the emergence of cancer and whether this new understanding can be therapeutically exploited. We will build on our recent work by developing new refined two-tier deficient animal and cellular models. These model systems should give us finer tissue and temporal control of two-tier protection. We will also study how the p53 protein senses and responds to aldehyde stress, and restrains aldehyde driven malignancy. Many people accumulate acetaldehyde when they consume alcohol. We will create specific mouse models that mimic these human genetic situations, and we will then study these animals to determine how two-tier protection limits DNA damage and carcinogenesis associated with alcohol consumption. We recently discovered that formaldehyde is released by the one carbon folate cycle, through oxidation of certain folic acid derivatives. These molecules effectively deliver formaldehyde into cells, and therefore are strikingly cytotoxic to DNA repair deficient cancer cell lines. We plan explore this synthetic interaction further to develop it as a potential therapeutic approach to treat cancer. Combined inactivation of Aldh2 and Adh5 in mice causes premature ageing and cancer predisposition. This striking result indicates that aldehyde accumulation leads to widespread damage despite intact DNA repair. We need to understand the genetic physiology responsible for this striking phenotype since it argues that intact DNA repair may not be sufficient in preventing aldehyde driven cell damage and carcinogenesis. Finally we will aim to develop biomarkers for aldehyde damaged DNA, and with strategic collaborations gain better insight into how aldehyde cross-linked DNA is repaired. We will also uncover the mutagenic scars that such damage leaves in the DNA of stem cells and cancers obtained from our mouse models. Ultimately we want to determine whether reactive aldehyde driven endogenous DNA damage leaves a distinct mutation signature in our genomes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Investigating the molecular mechanisms of cellular responses to replicative stress and their exploitation in cancer therapy
Funder: Cancer Research UK

Abstract: Background: Genome stability and the faithful duplication of genetic information are constantly challenged by genotoxic stress. To preserve chromosomal integrity, cells have evolved a complex network of pathways collectively called the DNA damage response (DDR), which is governed by the PI-3-kinase-like kinases (ATR, ATM, DNA-PK). The importance of the DDR is underscored by the fact that many diseases, including cancer, are linked to mutations in genes within the DNA damage and genome maintenance pathways. Moreover, many commonly used anticancer agents mediate cellular toxicity by inducing DNA damage. Accordingly, targeting individual components of the DDR has emerged as a successful approach to selectively kill cancer cells in a synthetic lethal manner. Therefore, understanding the mechanism by which the DDR preserves genetic integrity is of enormous fundamental and medical importance. Aims: The aims of this proposal are to understand how cells repair damaged DNA during genome duplication, and deliver knowledge that could be exploited to improve cancer treatment by facilitating novel synthetic lethal approaches that hold considerable promise for selectively eliminating cancer cells. Methods: Aim 1: Dissecting the cellular responses to replicative stress. We have recently identified EXD2 as a novel factor required for DNA double strand break repair. Our preliminary data shows that this protein is also crucial for maintenance of genome stability at replication fork. We aim to define how EXD2 functions in suppressing replicative stress and characterize its role in processing stressed replication forks using state-of-the art techniques established in the lab. Aim 2. Our preliminary observations indicate that EXD2 is required for efficient activation of ATR signaling. We aim to define how EXD2 functions in ATR activation and what is its relationship with other components of the replication fork protection pathway. Aim 3. Exploiting EXD2 in the treatment of cancer. We have recently identified that EXD2 is essential for survival of BRCA1 and BRCA2-deficient cells. We aim to investigate the underlying mechanism of this synthetic lethal interaction in vitro and validate it in vivo using xenograft mouse models. We will also investigate the impact of an EXD2-associated DNA repair defect on development as well as survival of prostate cancer. How the results will be used: The work outlined above will increase our knowledge about how cells respond to replicative stress, which could lead to the development of novel treatment strategies for cancer. Furthermore, this work has the potential to define new therapeutically exploitable cases of synthetic lethality.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Institute of Cancer Research ECMC
Funder: Cancer Research UK

Abstract: Over the next 5 years, we will address these challenges with ECMC infrastructure support being key to our delivery. We will: • Design and conduct biomarker-rich, hypothesis-testing, early phase clinical trials. These will focus on first-in-human studies of novel anticancer agents and include developing ICR discovered drugs in parallel to companion biomarker studies, translating hypotheses described by ICR scientists, as well as developing drugs and strategies discovered by other scientists/industry in collaboration with other ECMC centres. • Develop a suite of analytically validated biomarkers for clinical qualification in early phase clinical trials. These will include biomarkers that are predictive of response and pharmacokinetic-pharmacodynamic modelling evaluating target engagement, both being critical to early drug development. This enables the acceleration and prioritisation of novel anticancer drug development by both SMEs and large companies within the pharmaceutical sector. • Focus on improving clinical trial designs of novel anticancer drugs to accelerate the drug development process in order to rapidly improve patient outcomes while decreasing research costs. • Sponsor investigator-initiated clinical trials of promising novel anticancer drugs deprioritised by the pharmaceutical industry, and explore novel combinations that may otherwise not be evaluated, to generate clinical evidence that will lead to further development of these drugs for patient benefit. Patients would not benefit from the eventual registration of these drugs unless these academic trials, which are supported by ECMC funding, are run. • Develop new approaches to prevent, anticipate or overcome the evolution of drug resistance through the study of drug combinations. We will also add value to early phase studies by gaining insights into resistance mechanisms through the study of circulating biomarkers (plasma cfDNA; single CTC studies), which can impact future drug discovery efforts. • Foster national and international scientific collaborations to expedite the translation of the best science to improve cancer care. • Expand our collaborations with national and international pharmaceutical companies to conduct trials in the UK to deliver patient benefit, resources and research output to the NHS. • Continue to train the next generation of British-based and international clinician-scientists with expertise in drug development and effectively engage with patients, their relatives and the public about research relevant to this ECMC.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Targeting Post-transcriptional Regulators to Eradicate Leukemic Stem Cells in Acute Myeloid Leukemia
Funder: Cancer Research UK

Abstract: Background While abnormalities in genetic and epigenetic pathways in tumorigenesis are intensively studied, little is known about how alterations in post-transcriptional regulation (PTR) impact cancer development. Acute myeloid leukemia (AML) is propagated by leukemia stem cells (LSCs) which are responsible for drug resistance and disease relapse. I have identified a novel post-transcriptional regulator MYBBP1A to be important in AML. MYBBP1A was previously reported to bind several types of RNA, but its precise functions in RNA biology is not known and its role in normal and malignant hematopoiesis is not understood. My preliminary data show that MYBBP1A is important for survival and function of human and mouse AML cells. Aims: This proposal aims to uncover the functional relevance of the RBP MYBBP1A in AML and to elucidate the underlying molecular basis for MYBBP1A function, with the ultimate goal of targeting it for AML therapies in the near future. AIM 1: Determine the requirement of MYBBP1A in AML leukemogenesis; AIM 2: Define the role of MYBBP1A in normal hematopoiesis; AIM 3: Identify the molecular basis for MYBBP1A function in AML LSCs. Methods Towards aim 1 and 2, I will investigate the consequences of MYBBP1A loss and gain-of-function in leukemia and normal hematopoiesis. Firstly, I will utilize shRNAs and recombinant protein expression in cell lines, normal hematopoietic stem and progenitor cells (HSPCs), and AML primary patient samples. Secondly, I will analyze the effects of MYBBP1A loss on leukemogenesis and hematopoiesis in the Mybbp1a conditional knockout murine model that I have developed. Finally, to elucidate the molecular basis underlying MYBBP1A functions in LSCs, I will map MYBBP1A-bound transcripts using my recently adapted HyperTRIBE approach. I will identify the gene expression program controlled by MYBBP1A using integrative analyses at multiple regulatory levels including transcriptome, translatome and proteome in LSCs. These approaches will define MYBBP1A’s role in normal and malignant hematopoiesis and determine whether MYBBP1A is differentially required for AML LSCs. Finally, they will uncover MYBBP1A mechanism of action in leukemia. How the results of this research will be used This study will identify MYBBP1A and its functional downstream pathways as potential therapeutic targets in AML. Once validated, these can be employed to design innovative drugs, including small molecules, antibodies and RNAi, that specifically eradicate LSCs in AML while leaving normal hematopoiesis intact. Moreover, this study will significantly enhance our understanding of cancer stem cell biology, thus contributing to our efforts to prevent and treat cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Defining the molecular anatomy of the Bloom syndrome tumour suppressor complex
Funder: Cancer Research UK

Abstract: Background: Mutations caused by DNA damage enable a normal cell to become cancerous, and individuals with disorders caused by mutations in many DNA repair genes are predisposed to cancer. One such disorder is Bloom syndrome, which results from mutations in the gene encoding the BLM helicase. Apart from surgery, the most effective cancer treatments work in tumour cells by inducing DNA damage. Exploiting knowledge of the DNA damage response is therefore likely to lead to more effective and personalised cancer therapies in future. Like all biological pathways, DNA repair relies on protein-protein interactions to function. However, in any protein network it is a major challenge to identify functionally important peptide motifs and the protein domains that recognise them. Thus, we still lack a comprehensive understanding of which DNA damage response proteins functionally interact with each other and, crucially, how they are regulated. Methods: We will address this issue by using a bioinformatics pipeline that can predict functional peptide motifs and post-translational modifications with a high degree of accuracy. After applying this method, interacting proteins for novel motifs identified this way will be determined using a proteomics approach. The physiological importance of newly identified protein-protein interactions will then be validated in human cells using cutting-edge CRISPR-Cas9 gene-editing methods. As proof-of-principle, we will concentrate initially on the proteins that make up the Bloom syndrome complex. Preliminary analyses using the pipeline have identified a novel motif in BLM centred around Ser304, which we have found is required for maintenance of genome stability by binding to the DNA replication and checkpoint protein, TopBP1. Aims: 1. To identify and characterise novel and functionally important peptide motifs in the Bloom syndrome complex, and the protein domains that recognise them; 2. To establish the mechanistic and structural basis for the phosphorylation-dependent interaction between BLM and TopBP1, and how it is regulated in cells. How the results of this research will be used: By exploiting recent advances in molecular phylogenetics and genome editing, this work will provide new insights into the underlying mechanisms that control a key DNA repair complex. In addition, the novel methods described here will provide an experimental framework that could readily be applied to investigate other biological pathways and thus have significant impact in other fields of cancer research.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: CHROMATIN REPLICATION AND CANCER
Funder: Cancer Research UK

Abstract: Since decades, cancer etiology is considered as a key step to find innovative treatments. Indeed progress in understanding tumorigenesis mechanisms has proved its therapeutics potential, yet most of them remained elusive or unknown. The research plan presented here is in line with this ongoing effort, proposing to explore promising new mechanisms in tumorigenesis using cutting edge technologies. Cancer cells are characterized by the presence of genetic and epigenetic alterations that lead to loss of cell identity, uncontrolled cell proliferation, cell invasion and metastasis. However, upstream events that drive the appearance and selection of these alterations remain poorly understood. Past two decades has revealed the key function of epigenetics mechanisms in maintaining cell identity and genome stability whereas their corruption is a hallmark of tumorigenesis and cancer progression. Epigenetic information relies on a combination of DNA modifications, nucleosomes positioning and modification, and many proteins that define, maintain and functionally translate this information. Therefore to maintain cell identity, faithfully duplication and transmission of epigenetic information to daughter cells is as important as duplication and transmission of the genetic information. However, little is known about how the epigenetic information is propagated during the cell cycle and recent findings raise the question of its potential implication in tumorigenesis. In S phase, the progression of DNA replication forks provokes a genome-wide disruption of the epigenetic information. This proposal aims to reveal how cells restore epigenetic information after DNA replication and to explore the interplay between these mechanisms and tumorigenesis. To this end, I will combine Nascent Chromatin Capture (NCC), a technology for purification of newly synthetized chromatin that I have developed, with mass spectrometry, high-throughput microscopy and screening technologies in normal and cancer cells. Newly identified players that are subjected to deregulation in cancer will be next characterized in order to understand their role in cancer development and their therapeutic potential.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Dysregulation of protein kinase and phosphatase networks required for genome maintenance and cell division in human cancers
Funder: Cancer Research UK

Abstract: Background Investigation of protein kinases alone cannot explain the complex patterns of cell regulation required to regulate normal cell growth and division, or the changes seen in human cancers. Both protein kinases (Aurora and Polo)) and serine/threonine phosphatases (PP2A and PP6) are mutated or dysregulated in cancers, and the interlinked relationships of these enzymes therefore have to be understood at a molecular level. This is crucial if we are to effectively target these pathways in human cancers. Despite the availability of drugs targeting Aurora and Polo kinases, the circumstances in which they would be effective remain ill defined. Furthermore, serine/threonine phosphatase inhibitors, although commonly used in the laboratory, have not been viewed as suitable for widespread clinical use. This is in part due to the complex regulatory networks formed by kinases and counteracting phosphatases, complicating understanding of their effects at a cellular level in either the normal or cancer states. Major aims of this proposal are to explain how specific PP6/PP2A dephosphorylation and Aurora/Polo protein phosphorylation pathways, and regulated proteolysis govern the complex series of events necessary for cell division, and how these networks are dysregulated in cancers. Aims 1. Dissecting the PP6-Aurora A pathway in normal and cancer states 1.1 NHEJ – the Achilles’ heel of PP6-deficient cancer cells 1.2 PLK1 regulation of PP6 activity towards Aurora A 1.3 Analysis of the BORA-Aurora A-PLK1 pathway 1.4 PLK1-PP6-Aurora A function in DNA damage signalling 1.5 Cell-cycle stage substrate specificity of PP6 2. Molecular basis for Aurora B regulation by KIF20A/B 2.1 Structure of the KIF20A-Aurora B transport complex 2.2 Analysis of KIF20A/B function in tumour cell lines 3. Cell cycle regulation by PP2A phosphatases 3.1 PP2A-B55 function and regulation 3.2 Greatwall substrates – moving beyond ENSA 3.2 PP2A-B56 substrate recognition and regulation 4. Dephosphorylation and proteolysis during mitotic exit 4.1 A quantitative proteome/phosphoproteome of mitotic exit 4.2 Establishing the molecular basis of rapid and slow substrate proteolysis Methods This research uses quantitative biochemical and cell biological methods to understand interlinked networks of protein kinase and phosphatase function. CRISPR gene editing, high-resolution microscopy and mass spectrometry underpin this work. These approaches are complemented by structural and biophysical characterisation of protein complexes in vitro using X-ray crystallography and cryo-electron microscopy. How the results of this research will be used By identifying deficiencies arising from dysregulation of protein kinases and phosphatases, this research will provide a foundation for new strategies targeting tumours.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE