NIHRDataInsights/HRCSData huggingface dataset:
Title: Characterization of the non-catalytic functions of AKT and other AGC kinases in cancer
Funder: Cancer Research UK

Abstract: Background Aberrant activation of the PI3K pathway is one of the most common oncogenic events in human tumours. The serine/threonine kinase Akt is a critical PI3K effector that promotes a number of cancer-associated phenotypes, including cell survival. We recently identified a novel pro-survival function of Akt that is independent of kinase activity, but dependent on the presence of a functional pleckstrin homology (PH) domain. Consistent with the catalytically-independent nature of this function, cancer-associated AKT mutants that lack kinase activity and exhibit altered phosphoinositide binding profiles and constitutive plasma membrane localisation, promote cell survival. Interestingly, additional members of the AGC family of kinases (e.g. SGK3 and GRK2) with a domain structure similar to AKT (i.e. a sub-cellular localisation domain linked to a catalytic domain), are also targeted by putative catalytically inactivating mutations in a variety of human cancers. Given the links of these genes to cancer, the presence of these alterations raises the question of whether these kinases, similar to AKT, have catalytically-independent functions that may be potentiated by mutation, and whether these types of lesions, as a group, represent a novel mode of oncogenic conversion. Additionally, a number of pseudokinases, which naturally lack enzymatic activity, are also targeted by mutations, some of which confer transforming ability. These observations further lend support to the notion that enzymatic activity might be dispensable for the oncogenicity of certain kinases. Aims: The goal of this project is to 1) characterise the molecular basis of the non-catalytic functions of AKT, 2) to determine whether these functions are oncogenic and whether they can be constitutively “activated” by mutation (both in AKT and in other members of the AGC kinase family), and 3) to explore the therapeutic opportunities afforded by targeting these functions. Methods: We will use mass spectrometry, RNA expression profiling, and computational approaches to 1) characterise the proximal and distal effectors of kinase-independent AKT activity, 2) assemble a signalling map of this novel branch of the pathway, and 3) identify useful biomarkers of non-catalytic AKT function. Mediators of non-catalytic pro-survival AKT function identified through molecular profiling will be validated genetically and pharmacologically using isogenic AKT-addicted cell line models (Breast cancer, lung cancer, melanoma). This information will provide: 1) critical insight into previously unknown aspects of PI3K signalling, 2) new therapeutic strategies to more effectively target AKT function in defined genetic contexts, and 3) new information to more accurately classify oncogenic mutations based on their ability to “activate” non-catalytic functions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Evolutionary forecasting of prostate cancer recurrence within a clinical trial
Funder: Cancer Research UK

Abstract: A significant proportion of localised or advanced localised prostate cancers can be cured with radiotherapy with/without Androgen Deprivation Therapy (ADT) or radical prostatectomy. Nevertheless, a substantial group of patients have recurrence. Can we distinguish potentially lethal cancers that need additional treatment, from those that need localised treatment only? Predicting relapse is difficult and current clinical standards for risk stratification are inadequate to determine the preferred treatment for individual patients. Therefore, patient risk stratification is a significant unmet clinical need in prostate cancer. Cancers are governed by evolutionary rules, but understanding tumours in the light of evolution remains challenging and with current approaches we are still unable to analyse patient genomic data in a clinically impactful manner. I argue that this is because we need a new type of genomic analysis that accounts for the mathematical rules constraining tumour evolution, in order to make sense of the data. I propose to identify new types of prognostic biomarkers based on the dynamic patterns of tumour evolution that may provide unprecedented power in predicting recurrence in prostate cancer. I will combine rational tumour sampling and genomic profiling, with mathematical modelling of tumour evolution to predict recurrence within a clinical trial. The integration of theory (mathematical modelling) with experimental observations (data) led to remarkable predictive power in fields such as physics (e.g. weather forecasting). The absence of a coherent mathematical framework prevents similar forecasting in cancer. Specifically, I propose to forecast prostate cancer recurrence by linking the dynamic rules of tumour evolution in 62 patients to progression-free survival within the IMRT clinical trial (up to 12 years followup) conducted at the Royal Marsden Hospital by Prof Dearnaley. My specific objectives are: 1. Map intra-tumour heterogeneity in prostate cancer at unprecedented resolution using multi-region whole-genome sequencing, and reconstruct the phylogenetic history in each patient. 2. Measure the dynamic rules of tumour evolution in each patient, such as where and how clonal selection operates in the cancer (identifying emerging subclones), the mutation rate, the mutational timeline, the level of clonal intermixing, and the presence of punctuated versus gradual evolution. 3. Link the measurements from Objective 1 and 2 to progression-free survival. These "evolutionary biomarkers" are based on mechanistic predictions of patient outcome rather than simple correlations between static signatures. Such predictions derive from the understanding of the underlying evolutionary processes, encapsulated within a mathematical model that allows uncovering the biology “locked” within the data.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: City of London Centre Clinical Academic Training Programme / Year 2
Funder: Cancer Research UK

Abstract: Traditionally, people view cancer researchers as scientists in white coats working in laboratories and making discoveries, and cancer doctors as working in hospitals or GP surgeries, treating and advising patients. In reality, many doctors are also research scientists and spend as much time in the laboratory as they do in the clinic. These are Clinician Scientists who very often are at the heart of new cancer discoveries. This City of London Centre’s (COL) Clinical Academic Training Programme (CAT) maximises opportunities for doctors to become Clinician Scientists. The COL is one 14 CRUK research centres in the UK delivering world-class cancer research. It is the first time such major London institutions have partnered to tackle cancer on such a large scale, bringing together over 350 researchers at Barts, the Francis Crick Institute, KCL and UCL. It has one of the most successful research environments in which to train and nurture the next generation of researchers. With a pedigree in training doctors dating back to 1123, with some of the oldest medical schools in the world, we have what it takes to inspire doctors to become clinician scientists. To become a clinician scientist is not easy and requires much more extensive training, so in addition to attending medical school, which is what all doctors do, clinician scientists must also undertake additional studies and typically obtain both a science degree (BSc) and a PhD. The COL’s new CAT programme maximises the available opportunities to do this: Medical students can complete their additional studie before they finish their medical degree, via an MB/PhD training course. These students will leave medical school with a medical degree (MBBS), a BSc and a PhD. As qualified doctors, then will continue their medical training, with ongoing encouragement to remain involved in cancer research Qualified doctors, training in a hospital to become a consultant, may suspend this specialist training for three years to come a Clinical Research Training Fellow (CRTF). A CRTF will complete their PhD in cancer research and then return to the hospital where they finish their specialist training, typically becoming a consultant. Ultimately, the COL CAT aims is to increase the number of doctors who choose a career in cancer research, so that the best clinicians and the best scientists can come together to tackle cancer and together push the boundaries of research, and develop new discoveries that improve treatment and increase survival of cancer patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Targeting mitochondrial metabolite transport in pancreatic cancer
Funder: Cancer Research UK

Abstract: Background Remarkable cancer cell metabolic flexibility and plasticity drive tumour progression and contribute to stubborn therapeutic resistance. Metabolic programming is particularly important in pancreatic cancer development, which is an aggressive disease with an appalling survival rate. The pleiotropic mitochondria are dynamic organelles that take centre stage in pancreatic cancer metabolic programming. For instance, pancreatic ductal adenocarcinoma (PDAC) cells tune their mitochondrial function to facilitate their adaptation to a nutrient deprived and hypoxic microenvironment. An essential but poorly understood facet of tumour metabolism is the coupling of cytosolic and mitochondrial metabolic reactions by tightly regulated metabolite transporters across the mitochondrial inner membrane (IM). Aims The overall goal of this research programme is to reveal and exploit the metabolic vulnerabilities of pancreatic cancer cells by targeting metabolite transport and nucleotide metabolism in the mitochondria. Firstly, we will identify and describe the mitochondrial metabolite transporters that control PDAC cell growth and survival. Secondly, we will specifically focus on chemotherapy resistance in pancreatic cancer and ask whether mitochondrial nucleotide transport and metabolism regulates PDAC cell response to nucleotide analogue therapeutics. Finally, we will move closer to the clinic by targeting candidate solute transporters and nucleotide metabolism in a mouse model of pancreatic cancer. Methods We will employ a mitochondrial metabolite transporter CRISPR interference and activation screen in a 3D PDAC model to identify transporters that regulate PDAC progression. Screen hits will be validated in patient derived PDAC cell lines using PDAC-stroma coculture systems to model the disease in vitro. We will describe transporter role in PDAC using compartmentalized metabolomics and will use super-resolution imaging to reveal their dynamic distribution in the mitochondrial network. Mitochondrial quantitative proteomics will reveal mitochondrial metabolite transporter regulation at the protein level in PDAC cells and patient biopsies. PDAC cell proliferation and survival in response to nucleoside therapeutics will be analysed in cells with inhibited and activated mitochondrial nucleotide transporters. In order to translate our findings in vivo, we will use adeno-associated virus-driven CRISPR- Cas9 editing of metabolite transporters in a PDAC mouse model to test the effect of overexpression or depletion of candidate transporters in developing pancreatic tumours. How the results of this research will be used The results of this research will improve our basic understanding of mitochondrial programming in cancer. They will be used to identify novel therapeutic targets in pancreatic cancer at the interface between mitochondrial and cytosolic metabolic pathways.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Investigating the impact of amplified centrosomes in cancer
Funder: Cancer Research UK

Abstract: Centrosome abnormalities, in particular supernumerary centrosomes, are commonly observed in human tumours. Recent in vivo work established that centrosome amplification is not a bystander in cancer but instead plays an active role in tumourigenesis by directly contributing to genomic instability and invasion. However, because these abnormalities occur only in a subset of cancer cells, the impact of centrosome amplification to cancer remains elusive. We recently uncovered that cells with amplified centrosomes undergo a stress response that culminates with altered secretion. The identification of an extra centrosomes associated secretory phenotype (ECASP) suggests that centrosome amplification could have a broader impact in tumours via paracrine signalling. Paracrine signalling via secretion of cytokines, growth factors and extracellular vesicles can impact tumour microenvironment (TME) and tumour clonal architecture and thus it is key for tumour progression and resistance to therapy. Thus, understanding what leads to secretion dysregulation in cancer and how this impacts tumourigenesis is critical. Here, we will elucidate how subpopulations of cancer cells with extra centrosomes impact tumours via ECASP. We aim to determine: 1) The mechanisms of extra centrosomes-induced secretion in cancer. We will use a combination of proteomics to systematically characterise the secreted factors induced by centrosome amplification in a panel of cancer cell lines. Imaging and cell biology techniques will be used to investigate the secretory mechanisms and signalling changes leading to ECASP. 2) TME remodelling in response to cells with amplified centrosomes. TME changes will be characterised in breast cancer mouse models and human tumours containing extra centrosomes using mass cytometry and imaging approaches. Established heterotypic 3D cultures and microfluidic chambers will be used to identify the secreted factors responsible for specific TME changes. 3) The consequences of centrosome amplification for tumour evolution. We will use mouse models to investigate how cancer cells with amplified centrosomes and associated ECASP impact tumour clonal architecture using single-cell barcoding methods, whole exome sequencing and mathematical modelling. The combination of all three aims will shed light on how centrosome amplification impact cancer cell secretion and its role on shaping the TME and tumour evolution. Our overarching goal is to use our findings to define therapeutic strategies that block crucial cell-cell communication pathways in tumours. The ambition of this proposal is that it can be applied to many tumour types and thus could broadly impact patient care.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Investigating the role of PRMT5 in cancer
Funder: Cancer Research UK

Abstract: BACKGROUND Arginine methylation is an emerging protein post-translational modification that has been implicated as a major regulator of tumourigenesis. This is particularly true for PRMT5, the main symmetric arginine di-methyltransferase, which is attracting significant attention for therapeutic intervention. We have found that PRMT5 regulates key cancer pathways, including gene expression and stem cell biology. However, somewhat paradoxically, PRMT5, via methyl-RUVBL1, is also required to maintain genome stability, a potent tumour suppressor pathway. It is therefore clear that if PRMT5 is to be a tractable drug target, a comprehensive mechanistic understanding into the role of PRMT5 during malignant progression, and the ability to stratify patients likely to respond to anti-PRMT5 directed therapy is urgently required. AIMS Given our extensive expertise in arginine methylation and tumour biology, we are in a unique position to explore the mechanism by which PRMT5 is promoting malignant progression. Specifically, we aim to: 1) Establish the significance of PRMT5 and methyl-RUVBL1 for drug resistance. Can methyl-RUVBL1 stratify patients suitable for PRMT5 inhibitor treatment, particularly in BRCA1 wildtype triple negative breast cancers? 2) Explore the mechanism by which PRMT5 is regulating breast cancer stem cells, particularly in the context of the DNA damage response and epigenetic-mediated gene regulation. 3) Better understand how PRMT5 contributes to oncogenesis. METHODS Using breast cancer as a model, with a focus on triple negative disease, we will use a combination of molecular, cell biology, proteomic and genomic approaches to fully explore our aims. Importantly, we will use the most appropriate model(s) to answer our questions, e.g. drug screening will utilise 3D cell cultures, translational potential will be assessed using patient derived tumour xenograft and primary resected tumour material. Collaborations with industrial partners will enable comprehensive in vivo analysis of pre-clinical PRMT5 compounds. Generation of a conditional PRMT5/MEP50 transgenic mouse will serve as a vital tool for genetic evaluation and in vitro discovery validation. HOW THE RESULTS OF THIS RESEARCH WILL BE USED This programme will generate essential new knowledge into how PRMT5 regulates tumourigenesis and drug resistance, identify pathways that could be exploited for therapeutic targeting, and decipher whether methyl-RUVBL1 is a biomarker for PRMT5 inhibitor therapy. The development of a novel murine model will be fundamental as a pre-clinical tool facilitating drug screening for PRMT5-directed therapies (e.g. EPZ015666), both in the breast and in other organs associated with PRMT5 overexpression (e.g. pancreatic cancer, glioma, colorectal and stomach cancer).


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Accelerating new treatments in clinical trials in bowel cancer
Funder: Yorkshire Cancer Research

Abstract: Through i) developing new methods and investigating the quality of surgery, radiology and pathology in bowel cancer we will improve routine care and obtain better outcomes. ii) By testing new methods of assessing the response to treatments we will develop an understanding of which ones to use before surgery for bowel cancer and also speed up their evaluation by novel clinical trials. iii) We will investigate the changes seen in the tumour genetic code on treatment to identify which tumours will and will not respond, how they fail and whether short treatments before surgery help to predict later response.

Lay abstract: Through i) developing new methods and investigating the quality of surgery, radiology and pathology in bowel cancer we will improve routine care and obtain better outcomes. ii) By testing new methods of assessing the response to treatments we will develop an understanding of which ones to use before surgery for bowel cancer and also speed up their evaluation by novel clinical trials. iii) We will investigate the changes seen in the tumour genetic code on treatment to identify which tumours will and will not respond, how they fail and whether short treatments before surgery help to predict later response.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.4 SURGERY;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: UCL ECMC
Funder: Cancer Research UK

Abstract: UCL ECMC is committed to performing world-class clinical cancer research to discover and develop new treatments and improve the outcome for patients. Our Centre will integrate fundamental scientific advances with optimised patient care in high quality clinical research performed in a patient focused environment. We will foster collaboration between ECMC Centres contributing expertise, education and data sharing to deliver the strategic aims of the Network.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: The Roles of Transposable Elements as Oncogenic Regulators in Acute Myeloid Leukaemia
Funder: Cancer Research UK

Abstract: Background: Acute myeloid leukaemia (AML) is a highly aggressive cancer caused by the accumulation of genetic and epigenetic alterations, which result in dysregulated transcriptional networks. One understudied but very important source of transcriptional regulators are transposable elements (TEs). Comprising half of the human genome, TEs are a rich source of tissue-specific cis-regulatory elements and have the potential to control cellular processes. Therefore, their aberrant activity could contribute to oncogenesis. Despite extensive functional genomic analyses of AML, crucially the contribution of TEs to AML pathogenesis is largely unknown. Using cell line models, I previously identified AML-specific regulatory TEs and demonstrated their impact on gene expression and cell proliferation. Building on this work and using primary patient cells, I will define the contribution of TEs to oncogenic networks in AML subtypes with genetic modifications in chromatin regulators. Aims: 1. Identify TE-derived cis-regulatory DNA elements in AML 2. Determine the role of regulatory TEs in chromatin organisation and gene expression in AML 3. Assess the impact of TE inactivation on AML cellular phenotype Methodology: Aim 1. To identify AML-associated TEs that are activated in oncogenesis, I will provide an in-depth epigenomic characterisation of regulatory elements across all TEs by profiling the chromatin accessibility, enhancer/promoter-specific histone modifications and DNA methylation status in primary AML cells. Aim 2. To determine which genes are directly regulated by TEs, I will perform promoter capture Hi-C (PCHi-C) in primary AML cells. Combining PCHi-C maps with transcriptome data, I will determine the exact contribution of TEs to transcriptional networks in AML. Aim 3. I will target regulatory TEs using three approaches and determine the subsequent impact on gene expression and cellular phenotype: 1) I will perform pooled CRISPRi screens in AML cell line models to target TEs identified in Aim1&2; 2) I will target TEs identified based on preliminary analysis and CRISPRi screens in primary patient cells using a CRISPRi system; 3) I will target TE-initiated transcripts and TE-derived enhancer RNAs ex vivo using antisense oligonucleotides and test the leukaemic activity of key TEs in patient-derived xenograft models. How the results of this research will be used: This project will provide the first comprehensive understanding of the roles of TEs as crucial regulators of gene transcription in AML patients. Understanding how the dysregulation of TEs contributes to oncogenesis will lay the groundwork for the development of novel prognostic and therapeutic strategies to improve the survival of patients with AML.


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