NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigation of the molecular pathogenesis and therapeutic vulnerabilities of acute myeloid leukaemia using genome-editing technologies
Funder: Cancer Research UK

Abstract: Background Acute myeloid leukaemia (AML) is a devastating disease whose long-term survival remains poor at less than 30%. Progress in deciphering its molecular pathogenesis has accelerated dramatically in recent years, propelled in significant part by advances in cancer genomics. Despite such progress, the treatment of AML patients has remained largely unchanged for decades, with cytarabine, first described in 1961, representing the last major addition. This reveals a significant unmet medical need and to this end we have recently developed a powerful and flexible CRISPR-Cas9-based platform for the performance of genome-wide recessive screens to identify genetic vulnerabilities in leukaemia cells. We have gone on to adapt this platform to the study of AML cell lines and primary AMLs from geneticallyengineered mice. Our results so far have i) identified circa 500 genes that are essential to AML cells and have the potential to serve as therapeutic targets and ii) given novel insights into AML pathogenesis. From this work, it is evident that the unbiased nature of these screens makes their findings orthogonal and highly complementary to hypothesis-driven mechanistic studies that we and others have been conducting. Aims In the proposed work, I plan to build on our findings so far to identify gene targets of differentiation therapy, search for mutation-specific genetic vulnerabilities in AML, study AML drug resistance/sensitisation and investigate the pathogenesis of selected AML subtypes. Methods We will combine CRISPR-Cas9 screens with our bespoke mouse models and other reagents developed in my lab to: i) identify potential targets for AML differentiation therapy, ii) define genotype-specific vulnerabilities of selected AML subclasses, iii) derive mechanistic insights into the function of AML driver genes such as NPM1 and DNMT3A and iv) identify ways to enhance the effectiveness of existing therapies by overcoming drug resistance and also by finding genetic pathways whose co-inhibition can synergistically enhance AML cell killing. How the results of this research will be used I anticipate that this work will generate important insights into the pathogenesis of AML and also identify novel therapeutic approaches and candidate target genes, the most promising of which will be taken forward for the development of new treatments against AML and related malignancies. Given our experience so far, I expect that we will identify several novel potential therapeutic targets some of which we will pursue ourselves and others which will be pursued by others in the AML scientific community.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Hijacking FTase to degrade farnesylated onco-proteins
Funder: Cancer Research UK

Abstract: Background Farnesyl transferases (FTase) modify cellular key proteins by adding a farnesyl group to their C-terminus. Although this process is important in cancer development, FTase inhibitors have not been successful as expected as anti-cancer drugs. I propose a new and radical idea, in which FTases function will be modified, using small molecules, in order to degrade farnesylated onco-proteins. This method has the potential to eventually be able to target undruggable onco-proteins. Aims Designing small molecules that hijack FTase and use it to degrade farnesylated onco-proteins in cells Testing the efficiency of these molecules in cells Methods chemistry, molecular biology, and cell biology The results of this project will be published and made available for public. Furthermore the results will be used to position the project for possible translational opportunities.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Determining the effect of a highly penetrant mutation found in adult T cell leukaemia on the properties of PKCβ
Funder: Wellcome Trust

Abstract: Protein kinases are molecules inside cells which convey signals. For example, kinases can signal for a cell to divide or repair damage. If a kinase becomes mutated, the signals it conveys can be altered, which can contribute to the development of cancer. Adult T cell leukaemia (ATL) is a rare but aggressive cancer of the blood with poor prognosis and limited treatment options. In 33% of ATL cases, a specific mutation is found in a kinase called protein kinase C&beta; (PKC&beta;), indicating that an alteration in PKC&beta; contributes to ATL. The aim of my PhD project is to determine how this mutation alters the signals conveyed by PKC&beta;. I will compare the properties of mutant and normal PKC&beta;, including their structure, activity, localisation inside cells and impact on the growth of T cells. By understanding the effect this mutation has on PKC&beta;, this work will have an impact on future development of treatments for ATL, and could be relevant to similar mutations found in other protein kinases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Development of pan- and mutation specific-Ras inhibitors through Affimer-informed small molecule design
Funder: Wellcome Trust

Abstract: The most commonly administered cancer treatments rely on broad-spectrum combination therapies that follow a ‘one size fits all’ approach. Given this, movements towards personalised cancer therapies are underway that promise more successful, tumour-specific treatments without widespread side effects. It is known that 20-30% of all human cancers are associated with mutations in the Ras oncoprotein. Ras functions to control cell division, migration and proliferation; all features of the cell that if uncontrolled, lead to cancer. After three decades of research into this major oncoprotein, no treatments that target Ras have been successfully identified that have made it to the clinic. Nevertheless, recent advances in novel biological tools, known as Affimers, have renewed hope that Ras could in fact be successfully targeted. We aim to use Affimers to study Ras biology, and ultimately identify and characterise personalised drugs that specifically target the highly important protein. If successful, this project could demonstrate an exciting progression in modern science and personalised medicine, with a focus on cancer treatment.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: How do omental stromal cells (OSCs) assemble extracellular matrix to form the metastatic niche in high-grade serous ovarian cancer?
Funder: Wellcome Trust

Abstract: High-grade serous ovarian cancer (HGSOC) is the most common form of ovarian cancer. The 5-year survival rate is low, as patients are often diagnosed after cancer cells have spread from the ovary to other parts of the body. Their preferred site to spread to is the omentum, which is the fatty tissue covering the abdomen. The omentum provides an environment, named the metastatic niche, that supports cancer cell migration, growth and survival, enabling a tumour to form. Fibroblasts are a type of cell within the omentum which are partly responsible for forming this environment. They do so through the assembly of a protein fibre meshwork which surrounds the cancer cells, named the extracellular matrix (ECM). However, how fibroblasts in the omentum become able to assemble ECM in a manner which allows cancer cells to thrive is not yet understood. During my PhD project, I aim to develop a better understanding of how fibroblasts assemble ECM in this way to create a suitable environment for tumour formation within the omentum. To achieve this, I plan to use techniques including CRISPR, fluorescence microscopy and BioID in cell lines I will generate from ovarian cancer patient omentum samples.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Determining the mechanism of NKG2D-based chimeric antigen receptor (CAR) T cells and their efficacy against solid tumours
Funder: Wellcome Trust

Abstract: Cytotoxic T-cells are predominantly responsible for recognising cancerous and virally infected cells and removing them from our body. However, cancer cells can develop the ability to evade detection by immune cells, preventing their elimination. This inspired the idea of generating cancer immunotherapies, to aid the immune system in detecting cancerous cells, killing them, and stopping them from spreading. One such treatment is the use of T-cells genetically modified to express chimeric antigen receptors (CARs). We modify these receptors so that T-cells specifically find and kill cancer cells, but not healthy ones. Two of these "cellular therapies" are already FDA-approved for the treatment of certain haematological cancers, however they demonstrate poor efficacy on solid tumours. This project uses a receptor that can recognise eight different "signals" specifically found on cancer cells, activating T-cells and prompting them to kill cancerous cells and recruit other immune cells. We will generate different versions of this receptor to optimise their potency and efficacy on different solid tumours, whilst limiting any toxicity, ensuring safety. Considering the widespread expression of these eight signals on both blood cancers and solid tumours, there is potential for this cellular therapy to work in treating several different cancers.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Functional and evolutionary characterisation of chromatin organisation in endometrial cancer
Funder: Wellcome Trust

Abstract: Endometrial, or uterine, cancer affects roughly 9,000 women each year in the UK and has become considerably more common during the past two decades. Although more than 80% of affected women are cured by surgery and post-operative treatments, the prognosis for certain disease subgroups is considerably poorer. Improving this requires a better understanding of the evolution of this disease at a molecular level. We propose to do this by a detailed study of genetic (changes in DNA sequence) and epigenetic (changes other than DNA sequence) perturbations in endometrial cancers of different stages. Using a combination of human tumours, cell lines and experimental models (such as organoids - 3D cell cultures derived from the mouse uterus), we will apply advanced machine learning techniques and state-of-the-art experimental methods to understand the key events in tumour evolution and the underlying biology driving this process. In doing so we ultimately hope to improve prognostication and therapies for patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Investigating how Platelets and Inflammation Impact Cancer Cell Metastasis and Extravasation - Live Imaging in Zebrafish Larvae
Funder: Wellcome Trust

Abstract: Metastasis is the process by which cancer cells migrate from a primary to a secondary tumour site, with 95% of cancer deaths attributed to this metastatic spread. Cancer cells interact with a variety of host cells at the primary tumour location and as they invade other tissues, these interactions increase their survival and metastatic potential. Platelets are the smallest circulating cell type and are often the first cells to escape blood vessels into a growing tumour. As a cancer cell enters the vasculature it becomes further exposed to circulating platelets. Evidence suggests that platelet:cancer cell interactions mediate interactions with innate immune cells, which are beneficial for the survival and metastasis of cancer cells. My PhD project will use translucent zebrafish larvae to live image how platelets (thrombocytes in fish) might be pivotal at several stages of cancer metastasis. Specifically: • Do platelets mediate cancer cell:macrophage/neutrophil interactions at the site of primary tumours and impact tumour angiogenesis? • How might microclots enable innate immune cells to interact with circulating cancer cells to enable their extravasation to a secondary cancer site? • What role do other immune cells, including eosinophils and adaptive immune cells, play in each of these plateletmediated steps?


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Comparative Analysis of NFE2L-family Stress Responses in Cancer
Funder: Wellcome Trust

Abstract: The human NFE2L gene family encodes three proteins that drive expression of a range of genes that protect cells from different forms of stress. Under normal circumstances, these proteins are beneficial and protect cells from potential damage. Unfortunately, high levels of NFE2L activity can also be detrimental. In some cancers, enhanced activity of NFE2L family members allows cells to survive both chemo and radio therapy, leading to poor rates of survival. Therefore, we are keen to know if it is possible to target NFE2L proteins to make tumours more sensitive to treatment. Before we can do this, we need to know how NFE2L proteins work and how they may be controlled in health and disease. Therefore, we plan to show how human NFE2L proteins interact with other proteins, creating ‘molecular maps’ which will shed light on why NFE2L activity is increased in cancer, and how this activity may be inhibited. In addition, we will create genetically modified cell lines which we will use to see if blocking NFE2L proteins can make chemotherapy more effective in different cancer cell lines.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Elucidating the functional heterogeneity and fate dynamics of alveolar stem cells in lung regeneration and early oncogenesis
Funder: Wellcome Trust

Abstract: Lung cancer, of which adenocarcinoma is the most common subtype, is the leading cause of cancer-related mortality worldwide. Activating mutations in oncogenic KRAS account for approximately 25% of all lung adenocarcinoma cases, and for these tumours in particular, prognosis is poor and effective chemotherapies are severely lacking. Alveolar type II (AT2) cells act as the major stem cell population within the alveoli and are known to be key cells of origin of lung adenocarcinoma, but the molecular mechanisms and early cellular transformation events that drive their tumourigenesis remain elusive. Using a novel, oncogene-associated multi-colour reporter mouse model, I aim to label and track AT2 cells harbouring Kras mutations and compare their behaviour to wildtype AT2 cells. By analysing individual AT2 cell-derived clones over time, I intend to shed physiological insight into the initial steps of tumourigenesis and determine how dynamic cell-to-cell interactions present between mutant AT2 cells and their associated neighbours facilitate tumour propagation. Collectively, this work will help to devise early detection strategies and identify novel therapeutic targets for the treatment of lung adenocarcinoma, whilst simultaneously highlighting the mechanisms by which lung stem cell function can be hijacked during early disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Investigating the effect of colon cancer mutations on human intestinal stem cell dynamics
Funder: Wellcome Trust

Abstract: Intestinal stem cells are responsible for the regeneration and maintenance of the intestinal tissue. Due to the high proliferative potential of intestinal stem cells, mutations that disrupt the homeostatic regulatory mechanisms can result in cancer formation. Mouse intestinal stem cell dynamics have been widely studied but our knowledge of human intestinal stem cell dynamics has been lagging behind. now there is evidence to suggest that mutations in genes driving cancer formation can alter stem cell dynamics to achieve a high mutational burden in the normal human colon but so far only a few cancer-associated genes have been studied. As part of my PhD project I aim to develop an integrative approach by using a three-model system to assess how cancer-driver mutations are affecting human intestinal stem cell dynamics. I will use tissue sections of normal human colon, human intestinal organoids and a conditional knock-out mouse model to address this question. Multiple established methods will be employed including sequencing, immunohistochemistry, genome engineering and lineage tracing. This research will help me explore how stem cells are affected in a diseased context to ultimately understand more about the process of colon cancer initiation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The contribution of T cells to PI3Kδ and Bcl6-dependent B cell lymphomagenesis
Funder: Wellcome Trust

Abstract: Non-Hodgkin Lymphoma (NHL) accounts for 4% (14,100) of new cancer cases every year (UK) with a survival rate of 55% (2013-2017). Diffuse Large B Cell Lymphoma (DLBCL) is a common subtype of NHL which arises from high affinity B cells. The lipid signalling enzyme phosphoinositide-3 kinase &delta; (PI3K&delta;) is critical for the development of these B cells and is often mutated (hyperactive) in DLBCL. We identified that hyperactive PI3K&delta; cooperates with the oncogene B-cell lymphoma 6 (Bcl6) to drive lymphomagenesis and that this was accelerated in the absence of a functioning immune system. Furthermore, restricting PI3K&delta; hyperactivity to CD4+ T cells was sufficient to drive lymphoma progression. I aim to investigate the cooperativity between PI3K&delta; and Bcl6 in B cell lymphomagenesis by combining flow cytometry and transcriptomic approaches to identify and characterise B and CD4+ T cell populations in our lymphoma models. Transfer of selected populations into immunocompromised mice, followed by tumour analysis by histology, will allow me to identify the cellular origin of the malignant B cells and the CD4+ T cell populations responsible for driving lymphomagenesis upon PI3K&delta; dysregulation. This study will illuminate the cooperation between PI3K&delta; and Bcl6 in B cell lymphoma with important future therapeutic implications.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Genetic and non-genetic factors driving the expansion and progression of clonal haematopoiesis
Funder: Wellcome Trust

Abstract: Myeloid malignancies are a range of blood cancers caused by specific mutations in blood cells. These mutations cause affected cells to grow more rapidly and make up a greater proportion of our blood over time in a process known as clonal haematopoiesis (CH). Recent studies have shown CH is commonly found in otherwise healthy individuals with some fraction going on to develop myeloid malignancies. We have previously shown that some of these mutations are particularly common in elderly individuals, although how they lead to CH is currently unknown. My research will study human bone marrow samples and mice carrying these mutations to understand how they cause CH and why they are more common in the elderly. In particular, I hope to identify factors present in the bone marrow of elderly people that alters the behaviour of blood cells carrying these mutations and leads to CH. This could be used to determine which individuals carrying these mutations are at high risk of progression to myeloid malignancy and develop treatments to stop or reverse this process.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Understanding the genetic basis of radiotherapy toxicity
Funder: Wellcome Trust

Abstract: Patients differ in the way they respond to radiation treatment. Approximately 5% of patients are sensitive to radiotherapy and at risk of suffering long-term side-effects (1). However, there is no effective way to identify these patients. The REQUITE trial was established with the aim of reducing long-term side-effects from radiation (2). A total of 4438 cancer patients were enrolled in the study. Before receiving radiotherapy, patients completed a questionnaire and provided a blood sample which was analysed for genetic variants. The researchers tested for other biomarkers that might predict sensitivity to radiation. One example includes the radiation-induced cell death assay called RILA. This is a measure of the percentage of white blood cells that are killed by radiation (3). The researchers found that a low RILA score is associated with long-term side-effects. My research aims include finding possible genetic associations with the RILA assay. In addition to finding possible genetic associations to predict late side-effects in breast cancer patients and a genetic study on patient reported outcome measures such as quality of life scores. The overall long-term goal of this project is to integrate biomarkers, genetic and clinical data to help predict which patients will suffer from worse side-effects.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Targeting individual bromodomain and extra terminal domain (BET) proteins (BRD2-4) to modulate breast cancer angiogenesis
Funder: Wellcome Trust

Abstract: Tumour cells requires oxygen and nutrient to grow. As tumours outgrow their existing blood supply they develop regions that have low oxygen (hypoxia) and nutrient levels. These regions are often found in breast cancer and they are associated with resistance to chemotherapy and radiotherapy. Cancer cells exposed to low oxygen release chemical signals that stimulate the growth of new blood vessels which can then deliver the required oxygen and nutrients. There are four Bromodomain and extra terminal (BET) proteins that bind to sections of the DNA that has been chemically modified to indicate if a gene should be active or inactive. The BET proteins then recruit other proteins which are important for transcribing genes. It has been shown that drugs that inhibit the BET proteins change how the cells respond to hypoxia and reduce the growth of new blood vessels.I will investigate how the BET proteins regulate the growth of new blood vessels and identify which of the four BET proteins is the best target for new therapies. Regulating blood vessel growth can lead to the reperfusion of tumours and allow radiotherapy and chemotherapy to effectively treat patients with solid tumours.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Non-distancing: The role of direct cell-cell contact in cancer initiation and early progression
Funder: Wellcome Trust

Abstract: Cells must communicate with their neighbours, send, and receive various information as they build and regenerate tissues. This communication is often not well understood, for example during the very first steps of cancer growth. Pre-neoplastic cells (PNCs) (the first cells carrying oncogenic mutations that will lead to cancer) are surrounded by healthy neighbours and contacted by patrolling innate immune cells. I want to know how these interactions between healthy cells of the body and the very first cancer cells may lead to the arrest or support of tumour development.Evidence from the Feng group shows that neutrophils and macrophages contact emerging PNCs in the skin, and that this interaction results in increased proliferation of cancer-cell colonies (van den Berg et al., 2019). A new synthetic-biology tool called SynNotch allows us to precisely report on direct cell-cell contact at the single cell level (Morsut et al., 2016). I will engineer this tool into the zebrafish, where it will allow us to report on cell-to-cell contact in real-time, and in the living animals. Using this tool, I will study the effects of PNC-immune cell contact.Additionally, I will study the effects of contact between PNCs and healthy neighbour cells in cell culture.


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