NIHRDataInsights/HRCSData huggingface dataset:
Title: Identification, characterisation and therapeutic targeting of leukaemic stem/propagating cells in Acute Myeloid Leukaemia
Funder: Medical Research Council

Abstract: Our aim is to characterise the heterogeneous populations of leukaemia propagating cells (LPC) in adult and childhood Acute Myeloid Leukaemia (AML) at functional, genetic, epigenetic and molecular levels, eventually at a single cell level, to improve our basic understanding of leukaemia initiation and propagation. The ultimate aim is to translate this knowledge to improve survival rates in patients. Recent studies from our laboratory and other laboratories have shown that, within any one patient’s tumour, there is functional, molecular and genetic heterogeneity of tumour propagating populations. Though not yet formally demonstrated, layered upon this will likely be epigenetic heterogeneity. Thus, our key questions centre around understanding: a) the nature of this heterogeneity; b) how it arises and c) how different aspects of heterogeneity impact on each other. From a tumour biology perspective, a central hypothesis we will work towards testing is that there are specific molecular attributes present in AML LPC, but absent in downstream progeny, that explain LPC’s ability to propagate tumours whereas downstream progeny cannot. Experimentally, these studies will initially be cell population based. We will purify distinct immunophenotypic primary human AML populations, test their in vivo function, and determine their molecular, genetic and epigenetic profiles. This will be an iterative process. But, ultimately, these studies will have to be conducted at the single cell level,. To begin with, we will overlay single cell molecular and genetic analysis on the cell population-based studies. From a translational standpoint, our key hypotheses are: A) AML LPC are the chemoresistant relapse-driving populations. B) LPC can be therapeutically targeted. Only if both hypotheses are proven correct will be able to improve survival for patients. To test the first hypothesis, we will track LPC from diagnosis through therapy. To address the second hypothesis, we will continue work with Stanford to develop a combination of therapeutic antibodies targeting LPC antigens. Once again, there are huge challenges here, that include: a) defining a window between efficacy and toxicity given that many LPC markers are widely expressed b) defining cocktails of antibodies that target all chemoresistant LPCs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Defining stroma function in the developing tumour microenvironment
Funder: Medical Research Council

Abstract: Our immune system is our primary defence mechanism destroying both exogenous and endogenous threats, but tumours have developed strategies to interfere with almost every step necessary for a successful anti-tumour immune response. The recent success of immunotherapy platforms to harness and reactivate the immune response represent a major therapeutic advancement, however, current approaches are effective in just a few cancer types, and many patients still fail to respond or do not see lasting benefits. Increasing our understanding of anti-tumour immunity and the suppressive networks at play during the different stages of malignant transition will be fundamental to the development of improved strategies and design of new, targeted therapeutic platforms. The supporting tumour stroma, particularly cancer associated fibroblasts (CAFs) are emerging as key sources of tumour-promoting inflammation, but little is known about the mechanisms by which these cells act, when in tumour evolution these functions are acquired, or how they may contribute to therapeutic resistance. This programme takes a multidisciplinary approach, integrating experimental cancer models, complex in vitro and in silico systems, high throughput genomics and bioinformatics to explore the mechanisms and evolution of stromal-mediated immune dysfunction in the tumour microenvironment. Focusing on a subset of CAFs and their counterparts at tumour draining lymph nodes, which express the glycoprotein podoplanin, we aim to uncouple the immunoregulatory systems governing their suppressive function.


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: Investigation of the role of metabolism in tumorigenesis
Funder: Medical Research Council

Abstract: In order to proliferate, migrate, and survive under the harsh environmental conditions experienced in solid tumours, cancer cells undergo profound metabolic changes. Oncogenes and tumour suppressor orchestrate this metabolic reprogramming by activating cancer-specific metabolic pathways that optimise nutrients utilisation. The correlation between cancer and altered metabolism is mutual. Indeed, recent evidence suggests that small molecule metabolites accumulated under physio-pathological conditions support and, in some cases, promote cell transformation. These small molecule metabolites, also known as oncometabolites, have been shown to activate oncogenic signalling cascades by impinging on both transcriptional and translational processes in the cell. However, how cancer cells rewire their metabolism and how, in turn, metabolites contribute to tumorigenesis is still unclear. Our laboratory uses a multidisciplinary approach to understand the intricacies of cancer metabolism and to elucidate novel mechanisms of tumorigenesis driven by metabolic cues, including nutrient and oxygen availability. In particular, our approach encompasses the use of in vitro and in vitro models of cancer, their metabolic characterisation using metabolomics methods, and systems biology to model the results. We aim to exploit this knowledge to find novel pharmacological targets and to discover cancer biomarkers that can be used for early detection and for assessing disease progression. Our work has multiple implications for health and disease. First, it will improve our understanding of the process of cancer transformation, bringing a novel perspective to the field of oncology. Second, our work will investigate synthetic lethal pathways in cancer cell to find novel pharmacological targets for cancer therapy. Finally, by discovering novel biomarkers of cancer, our work will provide the community with tools for early detection of cancer and for patient stratification.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Molecular origins of metastatic cancer phenotypes
Funder: Medical Research Council

Abstract: Metastatic dissemination remains one of the most devastating complications of cancer. In the clinic, metastases often present as the final step of disease progression, but the molecular origins of metastases may be rooted in the early steps of carcinogenesis. Several lines of evidence suggest that instead of specific mutations, metastatic phenotypes can emerge from optimized output of the oncogenic pathways that drive tumour initiation and early progression. The molecular mechanisms as well as phenotypic consequences of such optimization of pathway output remain elusive. Yet, understanding how metastatic cancer phenotypes arise and persist, to what extent this is dependent on the pathways that drive tumour initiation and early progression, and what genetic vulnerabilities advanced cancer clones have could profoundly affect our ability to fight metastatic cancer. Using an integrative approach combining experimental cancer models, high-throughput genomics, functional genetics, bioinformatics and clinical association analysis, this programme aims at identifying genetic dependencies in metastatic cancer. With a focus on VHL mutant renal cancer, we will explore molecular mechanisms that modulate the phenotypic output of tumour-initiating mutations in support of metastasis, and test the hypothesis that this optimisation of oncogenic signalling results in molecular vulnerabilities in the most aggressive cancer clones. Understanding the origins of metastatic cancer phenotypes will provide insights into the fundamental requirements of cancer cell states and help identify functionally relevant biomarkers as well as therapeutic targets. Knowledge of the molecular networks that bolster the output of tumour-initiating genetic pathways in cancer progression may also have implications for early intervention strategies for cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Therapeutic target discovery and validation programme & the systems microscopy initiative
Funder: Medical Research Council

Abstract: There is a very high rate of attrition in the development of new classes of therapeutic agents that exploit our growing knowledge of the genetic basis of diseases like cancer, presenting a major impediment for academia and industry. Our ability to rapidly identify and validate of the best new therapeutic targets for drug development remains a a key challenge. To address this problem, we aim to build on the success of our recent work to develop novel approaches to systematically scrutinize cellular pathways altered in disease using large libraries encompassing diverse protein folds, and second, to extend using fragment-based and library-driven methods the discovery of chemical leads against novel molecular targets implicated in cellular regulation. In addition, our ongoing work to develop new approaches in light microscopy, such as hyper-dimensional imaging microscopy, to deconvolute complex cellular pathways will serve not only to advance understanding of disease-related derangements of these pathways, but also to validate diagnostic or therapeutic concepts for further development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Modelling of tissue level carcinogenesis through hybrid, biophysical, and executable approaches
Funder: Medical Research Council

Abstract: Cancer is an important and widespread disease, with roughly one in three adults developing the illness in their lifetime. However, the likelihood of a single cell from the hundreds of trillion cells in the adult human body at any one time developing into a tumour is very low due to intrinsic mechanisms of suppression. Stem cells in the body are made robust to deleterious mutations by a large number of poorly characterised mechanisms. One such mechanism for limiting the damage done by mutations is the competition of stem cells within a population. Whilst recent experimental evidence has given us insight into this competition, observing the dynamics of tissue development experimentally is arduous, and requires use of animals. The objective of this program is to develop models which give insights into experimentally inaccessible phenomena in the development of cancers, by coupling developmental and physical effects within cells. Some of these models will couple the physical dynamics of cells in the tissue with models of the underlying signalling networks to give us insights into the competition between different mutations. I will use these models to explore the nature of tissue growth and study how external events, such as wounding, can alter this competition and trigger stable populations of cells to develop into a tumour. By explicitly modelling the 3D structure of the tissue, the models will allow us to gain insights into the early stages of tumour formation by showing how changes in stratification rate and shape of the basal layer of stem cells are correlated to changes in cell proliferation rate. Alongside this, I will model cellular localisation processes, working on the dynamics and behaviours of mitochondria in the control of metabolic pathways in cancer cells. These insights will both suggest new experiments, and highlight the most fruitful lines of experimental enquiry. As such, this programme of work will involve extensive collaboration with different members of the cancer unit. By coupling the expertise of the group, with my own skillset, I will develop a set of approaches and discoveries which guide and support our understanding of cancer development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Chromosomal translocation genes and their protein interactions in cancer
Funder: Medical Research Council

Abstract: The programme will be a continuation of my current MRC programme grant and builds on some new observations about chromosomal translocations in cancer development. We will focus on three related areas involving chromosomal translocation genes, viz. the LMO2 translocation gene protein in cancer and in haematopoiesis and synergy with the IL2 receptor gamma common chain in leukaemia; cancer lineage control by chromosomal translocation fusion genes such as MLL-AF4, ENL and AF9 and BCR-ABL; cancer lineage control by mutant signaling molecules resulting in liver neoplasias and a new model of haemangioblastoma. We will refine further our de novo translocation (translocator) technology to incorporate reporter genes for tracking cancer initiating cells and to incorporate co-operating oncogenes to study the role of fusions genes. We will develop new approaches to study and interfere with protein-protein interactions in cancer. The new technologies proposed that will add further levels of complexity to more accurately recapitulate human disease counterparts and the new approaches will be transferable to other labs, for instance resources such as the proposed serially targeted ES cells. The research objectives are therefore to understand the function chromosomal translocation genes and their protein interactions in cancer and to solve basic problems in haematopoiesis and cancer biology. For exploitation of the research results, we will contribute knowledge for the unmet need of cancer target validation and corroborating protein complexes as targets for therapy. The programme is technology driven including new ways to produce highly specific and rapid models of the effects of chromosomal translocation genes, methods to identify natural components of protein complexes and approaches to confirm that chromosomal translocation genes or mutant proteins are valid drug targets. The latter is an important spin-off as a precursor to expensive and lenghty drug development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Mechanisms of mature B-cell tumour pathogenesis and of the interplay between host-immunity and these tumours.
Funder: Medical Research Council

Abstract: Mature B-cell derived tumours are the most frequent human haematological malignancy. Following antigen encounter, mature B-cells can differentiate into plasma cells through a reaction that exposes cells to DNA mutation and recombination in their immunoglobulin genes while rapidly dividing. Infidelity in these processes predisposes genetic lesions, including mutations that activate NF-kB and deregulate c-Myc expression, recurrently observed in the human activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) and in the plasma cell tumour multiple myeloma (MM). However, I found that co-induction of NF-kB signalling and c-Myc expression in mouse B-cells in-vivo, originates MM in 100% of the cases. In contrast, disruption of the plasma cell differentiation regulator Blimp1, promotes the development of ABC-DLBCL, consistent with its frequent inactivation in the human tumour counterpart. This work suggests that a block of B to plasma cell differentiation is required in ABC-DLBCL pathogenesis and I propose to assess alternative mechanisms by which plasma cell differentiation is blocked in the fraction of human ABC-DLBCLs, without Blimp1 inactivation. The final goal is to identify causative genetic mutations through interspecies comparative oncogenomics, which could function as prognostic biomarkers and/or therapeutic targets. In addition to oncogenetic lesions, it has become increasingly clear that host immunity plays a fundamental role in tumour formation and progression and regulatory T-cells (Tregs) may play a key role in this context. However, although in solid tumours Tregs aid cancer immune escape their role in haematological malignancies like ABC-DLBCL and MM remains controversial, warranting caution when attempting to extrapolate effective treatment strategies in solid tumours. I propose to investigate the role of Tregs in these diseases in order to gain insights on how and when to modulate their activity to stimulate the immune system to control tumour growth.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Understanding the essential requirement for HDAC1 and HDAC2 in tissue development and homeostasis: implications for disease and therapy.
Funder: Medical Research Council

Abstract: Histone deacetylases (HDAC) are important drug targets in the treatment of cancer and mental illness. However, the existing HDAC inhibitors used in the clinic (SAHA, valproic acid) inhibit all 11 Zinc-dependent HDAC enzymes (HDAC1-11) and their prescription is associated with a number of debilitating side-effects, including: fatigue, diarrhea, low platelet counts, and hyperammonemia, which can lead to brain damage. Knock-out (KO) mice and RNAi studies implicate HDAC1 and 2 (HDAC1/2) as the most clinically relevant targets, particularly in terms of growth inhibition and apoptosis. We propose that targeting HDAC1/2, rather than HDAC1-11, might retain the therapeutic benefits of current HDAC inhibitors while avoiding the side-effects associated with inhibiting the entire sub-family of enzymes. To explore this, we intend to identify the key pathways regulated by HDAC1/2 and determine the therapeutic value of specific inhibitors. Objective 1: Since HDAC inhibitors are used clinically to treat cutaneous T-cell lymphoma, we will assess the role of HDAC1/2 during T-cell development, using existing HDAC1/2 knock-out mice and a novel catalytically inactive HDAC1 mutant line. Objective 2: HDAC1/2 activity in vivo is regulated by incorporation into three specific co-repressor complexes: Sin3A, NuRD and CoREST. To determine molecular details of complex assembly we will solve the structures of MTA1-HDAC1/2 and Sin3A-HDAC1/2 using X-ray crystallography. Using this data, the functional necessity of complex incorporation will then be assessed by testing the ability HDAC1/2 mutants to rescue the viability of HDAC1/2 double KO cells. Objective 3: Define the physiological substrates and genomic targets of HDAC1/2 activity, using quantitative mass-spectrometry and ChIP-seq assays, in double HDAC1/2 KO cells. This multi-disciplinary program of work will clarify the essential roles of HDAC1/2, their mechanism of action and establish the therapeutic value of specific HDAC inhibitors.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Novel targeted contrast agent for early detection of brain metastasis: from animal to patient stage 2
Funder: Medical Research Council

Abstract: Metastasis to the brain is one of the most feared complications of systemic cancers, and prognosis is poor. Magnetic resonance imaging (MRI) is widely used for diagnosis of brain cancer, but the techniques are sensitive to late-stage disease when therapeutic potential is limited. Development of targeted MRI contrast agents, which detect specific molecules expressed early in disease, will overcome this limitation. We have demonstrated that our new contrast agent, targeting the endovascular adhesion molecule VCAM-1, enables detection of micrometastases in mouse brain when this pathology is otherwise undetectable. Our current DPFS award is funding us to create a fully humanised and biodegradeable version of our contrast agent, undertake toxicology and scale up the synthetic protocol. We now seek funding for cGMP synthesis of the agent, acquisition of regulatory and ethical approval and a Phase I/IIa trial in solid cancer patients with known brain metastases. In addition to obtaining safety and pharmacokinetic information, we will obtain some preliminary efficacy data thus maximising value of this Phase I/IIa trial.


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: Functional characterisation of a novel BRCA1-mRNA splicing complex that is mutated in multiple cancers.
Funder: Medical Research Council

Abstract: BRCA1 is mutated in a large proportion of familial breast and ovarian cancers. Additionally, BRCA1 is lost or inactivated in a large proportion of sporadic breast and ovarian cancers. BRCA1 deficient tumours are sensitive to a range of DNA damaging chemotherapies. Indeed BRCA1 mutation is currently being used as a means of enriching early phase clinical trials for response to PARP inhibitors, a novel class of agents that specifically target DNA repair deficient cancers. We have recently identified a novel BRCA1-mRNA splicing complex that is mutated in multiple cancer types. This complex is involved in mRNA splicing of a specific subgroup of genes following DNA damage and promotes cellular resistance to DNA damaging agents, DNA repair and maintenance of genomic stability. By carrying out these functions this complex broadly functions to suppress tumorigenesis. The main objectives of the proposed research are : 1) Identify if and how known pathogenic mutations in BRCA1 affect the functions of this complex. 2) Identify which splicing target genes of the complex are required for it's ability to promote resistance to DNA damage and DNA repair.3) Characterise how confirmed driver mutations identified within SF3B1, a component of this novel complex mutated in breast, ovarian, and myeloid malignancies, affect the function of this complex, particularly with respect to sensitivity to DNA damaging therapies. This last aim also has the potential to confirm SF3B1 mutations as potential predictors of response to DNA damage based chemotherapy. Our current finding suggest that mutations in components of the BRCA1-mRNA splicing complex may also predict response to DNA damaging chemotherapy or novel agents such as PARP inhibitors. In addition, the confirmation of functionally and clinically relevant targets modulated by this complex will add significantly to our understanding of BRCA1 biology and may open up additional opportunities for drug development in breast 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