NIHRDataInsights/HRCSData huggingface dataset:
Title: A pilot study to assess the feasibility of immune monitoring in neuroblastoma patients receiving anti-GD2 monclonal antibody immunotherapy
Funder: Children with Cancer UK

Abstract: Neuroblastoma is one of the commonest childhood tumours, and accounts for 15% of paediatric cancer deaths. It is frequently metastatic at diagnosis, resulting in poor long-term prognosis despite intensive, highly toxic, conventional therapies. Anti-GD2 antibody immunotherapy offers a more tumour-specific treatment and has been shown to offer survival benefit (68 vs 48% 2 year EFS) in a recent study by the US Children’s Oncology Group. Anti-GD2 therapy is now offered to all children in the UK with high risk neuroblastoma, as part of the European SIOPEN-HRNBL-1 study. However, anti-GD2 therapy does not cure all children, and many still relapse and die from their disease. In the COG study, anti-GD2 was given with IL-2 and GM-CSF, with the aim of enhancing immune effector function. However, the in-vivo mechanisms of action are not fully understood and the role these cytokines play in enhancing efficacy is uncertain. The aim of this study is to establish the methodology and infrastructure to allow robust, validated, immunomonitoring in children receiving anti-GD2 therapy within the UK in current and future Phase I, II and III immunotherapy trials. This will include quality assurance within the UK of assays already established within Europe (Greisfwald), as well as the development and validation of novel functional methodology, using minimal blood volumes. It is anticipated that such immunomonitoring will provide prognostic biomarkers, as well as a better understanding of the mechanisms of action of anti-GD2, and how these may be enhanced, allowing the rational design of more effective (and less toxic) immunotherapies.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Development of a novel screening method for leukaemogenic reintegration reactions
Funder: Children with Cancer UK

Abstract: The majority of childhood cancers are leukaemias and lymphomas with over 600 new cases each year in the UK alone1. Notably, between 35 and 40% of these cancers appear to have arisen from mistakes in the reactions that generate antigen receptor genes2. These recombination reactions are essential to generate a diverse immune system but because they involve the cutting and joining of DNA, mistakes can lead to genome instability and cancer. The main way in which these reactions were thought to cause cancer was via chromosome translocations. Recently, however, a new mechanism has been proposed by which V(D)J recombination causes cancer: By-products of the recombination reaction re-integrate back into the genome, triggering oncogene activation3. This has been proposed to cause a substantial fraction of T-cell leukaemias and follicular lymphomas but since the reintegration can occur at millions of potential sites and since it causes no gross cytogenetic abnormality, it is extremely hard to detect. This project aims to develop a novel screening method for cancers triggered by reintegration: The newly developed TALE (transcription activator-like) effector system4 will be used to generate DNA binding proteins that specifically detect the unique 14 bp sequence formed during reintegration. This will enable the sites of reintegration to be isolated and identified via high throughput sequencing. This also has the potential to identify the specific oncogenes activated in each individual patient, which could ultimately lead to personalised and therefore more effective cancer treatments.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Optimisation of circulating tumour cell detection in osteosarcoma
Funder: Children with Cancer UK

Abstract: Background Detection of circulating tumour cells (CTCs) is an established technique which provides additional information on disease behaviour in patients with common solid cancers such as breast and prostate carcinomas. The ability to detect such rare cells in patients with osteosarcoma could provide teams treating these patients with invaluable detail on disease progression and treatment response prior to, during and after therapy. Methodology Detection of CTCs in carcinoma patients utilises epithelial markers to identify the cells. This is not possible for osteosarcoma due to their mesenchymal origin. Using fluorescence activated cell sorting (FACS) we are therefore developing a ‘signature’ of osteosarcoma cell lines using an array of markers including mesenchymal stem cell markers and a membrane bound matrix metalloproteinase highly expressed in osteosarcoma. Using this signature we will attempt to identify CTCs in osteosarcoma patients. Objectives 1. Optimisation of the osteosarcoma cell line signature using the various cell surface markers as well as spiking known numbers of these cells into donated healthy volunteer blood followed by detection with FACS. 2. Detection of CTCs in current patients with osteosarcoma regardless of treatment stage, particularly those with known metastatic disease as they will have the highest disease burden. 3. Detection of CTCs in newly diagnosed osteosarcoma patients recruited from multiple centres (to include serial sampling).


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Pilot project to study the expression of the meiotic regulator, PRDM9, by childhood leukaemias
Funder: Children with Cancer UK

Abstract: The aetiological origins of childhood acute lymphoblastic leukaemia (ALL) are obscure. Studies demonstrate a significant increase in the frequency of rare variants of the PRDM9 gene in European American parents of children who develop ALL, and among patients themselves, compared to controls. PRDM proteins have been shown to contribute to oncogenesis and rare variants of PRDM9, which has an important role in meiotic recombination, are associated with germline chromosomal alterations. This study will determine the frequency of variants at PRDM9 among UK ALL patients and population controls by genotyping patients, parents and siblings for a SNP known to tag rare variants at the locus. In addition, we will investigate the precise nature of identified PRDM9 variants in samples from patients with B-cell precursor (BCP) and T-cell ALL by direct sequencing and will determine whether alleles are expressed in leukaemic blasts and matched remission blood samples by quantitative RT-PCR. We will also compare levels of PRDM9 expression between: 1. Diagnostic and remission samples; 2. PRDM9 alleles in heterozygous samples; and 3. Samples carrying non-A-type PRDM9 alleles and those that are A-type homozygous. The project will, therefore, determine the frequency of rare PRDM9 alleles observed in UK ALL families and the levels of PRDM9 expression in leukaemia and control cells.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: EML proteins in microtubule regulation, cell division and cancer
Funder: Worldwide Cancer Research

Abstract: <p>Microtubules (MTs) are the target of several widely used cancer chemotherapeutics. These drugs work through interfering with mitotic cell division and, possibly, perturbation of interphase MT dynamics. Whilst the relevant mechanisms of action remain unclear, it is well accepted that MTs are effective targets for cancer treatment. Unfortunately, though, resistance develops quickly to drugs that bind MTs directly, and alternative targets that regulate MT dynamics are being sought. EML proteins represent one such potential target. EMLs are MT-binding proteins that were discovered as major components of sea urchin mitotic spindles. They are conserved in human cells and localize to microtubules during interphase and mitosis. However, very little is known about their requirement for cell division or how they might regulate MT dynamics. Importantly, preliminary experiments in our laboratory have revealed that EMLs may be important substrates of the NIMA-related kinases (Neks) that contribute to mitotic spindle assembly and cell division, and which we are also currently investigating as potential targets for new cancer therapeutics. Furthermore, chromosome translocations have been found in different tumours that express fusions of EMLs to tyrosine kinases. Here, we propose to test the hypotheses that EML proteins contribute to the response of cancer patients to MT-targeted drugs and have important functions in the oncogenic fusion proteins. This will be achieved through (1) defining the function of EMLs in MT dynamics and cell division, (2) determining the contribution that EMLs make to Nek kinase function, and (3) testing how EML expression influences sensitivity to microtubule poisons and what role the EML moiety plays in the transforming properties of EML fusions.</p>


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Conditioning macrophages and dendritic cells to recognise epithelial tumour cells.
Funder: Worldwide Cancer Research

Abstract: <p>There is evidence that recognition and destruction of cancers by the immune system is mitigated by molecules expressed by tumour cells. Interventions that overcome the ability of tumours to inhibit immune recognition may therefore provide a powerful and specific approach to the immunotherapy of cancer. We have found that a ligand, associated with cytokeratins 8 and 18, that is specifically expressed on the surface of epithelial tumour cells, engages an inhibitory receptor, LILRB3, on macrophages and dendritic cells. We propose to exploit this observation to characterise a mechanism of potential use in anti-tumour therapy. Specifically, we will: 1. Investigate expression of the tumour ligand and its recognition by LILRB3. 2. Raise monoclonal antibodies (mAb) to human LILR and their ligands on tumour cells that block inhibition of immune recognition. 3. Investigate the extreme variation in LILR gene sequences in relation to cytokeratin binding and the clinical outcomes of patients with cancer.</p>


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Design of inhibitors of S100P, a protein implicated in pancreatic cancer progression
Funder: Worldwide Cancer Research

Abstract: <p>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with an exceedingly low survival rate and to date no truly effective therapy exists for patients with this malignancy. The calcium binding protein S100P is expressed at high levels in PDAC, where it is implicated in cell growth, survival, migration and invasion, and thus represents a promising novel therapeutic target. High levels of S100P also correlate with poor patient outcomes in several other cancers. The anti-allergy drug cromolyn, which binds to S100P, has been shown to inhibit pancreatic tumour growth and invasion <em>in vivo</em>, but has relatively low potency and bioavailability, and is therefore not potentially useful clinically. Computational<em> </em>modelling of cromolyn-S100P will highlight the requirements for drug-protein binding and will present the opportunity for rational design of improved and novel S100P inhibitors.</p> <p>The aim of this research is thus to identify potential novel chemotherapeutic agents for the treatment of pancreatic cancer, which specifically target S100P. Our approach is based on integrated computational drug design, synthesis and formulation, in tandem with established bioassays. Virtual high-throughput screening of commercially available compounds docked into the experimentally derived three-dimensional structure of the S100P structure will be used to identify potential inhibitors. &nbsp;The activity of the candidate compounds will be assessed by <em>in vitro</em> studies of biological effects on S100P-expressing cancer cells. &nbsp;Low aqueous solubility of compounds will be addressed <em>via</em> our formulation expertise, which we have previously used to achieve site specific delivery to tumours. A programme of analogue synthesis for active hits will be used to optimise activity, thereby to identify potent candidates for further development and <em>in vivo</em> studies, with the ultimate goal of a novel, clinically effective therapy for pancreatic cancer patients</p>


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Targeting protein-protein interactions involved in aberrant STAT3 signalling in human cancers
Funder: Worldwide Cancer Research

Abstract: <p>The targeting of protein-protein interaction surfaces (PPIs), particularly by small molecule ligands, has been a challenging field of development, therefore frequently avoided despite the therapeutic potential. With advances made in our understanding of structural factors that modulate protein-protein interactions, along with the exploration of naturally occurring ligand inhibitors of PPIs, it became clear that structural investigations are key components in any successful programmes involving these challenging targets. In the project proposal presented here we aim to structurally explore factors controlling PPIs of the Signal Transducer and Activator of Transcription (STAT3) protein containing the Src-homology 2 (SH2) domain.&nbsp; Specifically, we will focus on factors controlling protein dimerisation, structural basis of duplex DNA binding, and inhibition of these STAT3 functions through ligand binding, leading to downstream gene inactivation. In response to cellular stress, cytokines and growth factors, STAT3 proteins are rapidly activated through phosphorylation and other mechanisms, with inappropriate activation playing a pivotal role in inflammatory diseases and various cancers. In a proof-of-principle experiment down-regulation of STAT3 by siRNA resulted in cancer regression in animals. Utilising our in-house high-throughput (HT) screening data (CR-UK, programme grant), newly constructed protein variants and our crystallographic expertise we aim to: 1) structurally validate small molecule hits that have been shown to interfere with STAT3 function through the modulation of SH2 dimerisation supporting &nbsp;development of these compounds to lead molecules; 2) investigate direct protein/DNA interactions using structure-based site-directed mutation analysis; and 3) structurally rationalise the role of clinically observed mutations in STAT3 mediated signalling. We believe that the significantly different approach of our investigations will lead to the identification of new inhibitors (hits), validate known hits (small molecule and peptidomimetics), advance our understanding of PPIs, and expand the diversity of agents for future therapeutic use in cancer treatment.</p>


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Characterization of the GATA2 gene expression network in non-small cell lung cancer
Funder: Worldwide Cancer Research

Abstract: <p>Non-small cell lung cancer (NSCLC) is the most commonly diagnosed cancer worldwide, with over 1.4 million <br />deaths per year. Mutations in Ras pathway components occur in nearly half of all patients. Despite their <br />prevalence, therapeutic targeting of Ras has proven intractable and receptor tyrosine kinase inhibitors inevitably <br />engender resistance. Thus, there is a profound need to develop novel strategies targeting Ras-driven lung <br />cancer. To this end, we performed an RNA interference screen for factors required in Ras-driven cancer cells <br />and found these cells depend on the transcription factor GATA2. Through integrated transcriptome and genome <br />occupancy analysis, we defined a GATA2 transcriptional network composed of the proteasome, IL-1, and Rho <br />signaling pathways. In an autochthonous mouse model of Kras-driven lung carcinogenesis, Gata2 loss triggered <br />profound tumour regression. Moreover, combined inhibition of the proteasome and Rho signaling cascades with <br />clinically licensed compounds led to marked clearance of Kras-driven lung tumours. In total, these findings <br />suggest the GATA2 transcriptional circuit constitutes a druggable network in Ras-driven lung cancer. <br />Here we propose to use genetic, pharmacological, and molecular cell biological approaches to explore GATA2 <br />and its pathways in lung cancer. We will use the autochthonous mouse model of Gata2 loss in Kras-driven lung <br />tumours to explore the effect of GATA2 depletion in both tumour cells and the lung tumour microenvironment. <br />Moreover, we will test inhibition of the proteasome and Rho pathways in a mouse model of Kras-driven <br />metastatic lung adenocarcinoma, examining the impact on both response rate and survival. Finally, we will use <br />both the adenocarcinoma mouse model and lung cancer cell lines to determine mechanisms of resistance to <br />inhibition of the GATA2 network. Taken together, these approaches should allow us to systematically probe the <br />role of GATA2 and assess its inhibition with clinical therapeutics in Ras-driven lung cancer.</p>


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Targeting TRRAP as a Therapeutic Strategy against Malignant Brain Tumors
Funder: Worldwide Cancer Research

Abstract: <p>Our research focuses on an undifferentiated cell population in adult brain tumors &ndash;termed brain tumor stem cells (BTSCs). BTSCs have the ability to &lsquo;renew&rsquo; themselves, thereby helping the cancer to evade therapy. Eliminating BTSCs through specific tretament is a desirable goal that requires suitable molecular drug targets. Our previous work and clinical data indicate that the TRRAP protein critically promotes BTSC growth. Importantly, publically available clinical data also link TRRAP to a poor disease outcome in brain tumor patients. Therefore, TRRAP is a relevant factor in brain cancer progression/aggressiveness and may be exploited as a future therapeutic drug target. However, the complex molecular features of the TRRAP protein and its exact role in BTSCs during brain tumour growth are not well understood and this currently hinders the exploitation of TRAPP as a therapeutic target.</p> <p>Here, we aim to overcome this critical knowledge gap in targeted brain tumour therapy by validating TRRAP as a potential drug target in a pre-clinical setting. We will elucidate which domains of the TRRAP protein are responsible for promoting the growth of BTSCs. This knowledge may provide a basis for developing novel small molecule inhibitors targeting the malignant function of TRRAP. Moreover, we will determine whether elimination of TRRAP has a beneficial effect during the critical phase of brain tumor invasion which is a crucial factor for the poor prognosis of malignant brain cancer. We will also investigate whether targeting TRRAP is a suitable therapeutic option in combination with standard chemotherapy that is already used in the clinic.&nbsp; Overall, our study is expected to benefit patients by obtaining the necessary data to provide a basis for developing new clinical treatments against yet incurable types of brain cancer such as Glioblastoma multiforme.</p>


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Epigenetic disregulation in endometrial stromal sarcoma caused by the JAZF1-SUZ12 fusion protein
Funder: Worldwide Cancer Research

Abstract: <p>Cancers exhibit abnormal patterns of chromatin modifications that are thought to contribute to tumourigenesis by fixing cells in a normally transitory differentiation state. Polycomb protein complexes modify chromatin to repress developmental regulator genes and are emerging as key drivers of the epigenetic changes that occur in cancer.</p> <p>One of the clearest links between disruption to polycomb function and tumourigenesis is found in endometrial stromal sarcoma (ESS). ESS can arise from the waves of proliferation and differentiation that stromal cells undergo as they differentiate into decidual cells during each menstrual cycle. Women with ESS are most often treated by hysterectomy but many patients have late recurrence or metastases, which are not responsive to chemotherapy.</p> <p>ESS commonly displays translocation of chromosomes 7 and 17, fusing JAZF1 in place of the N-terminus of the polycomb protein SUZ12/JJAZ1. This JAZF1-SUZ12 fusion protein promotes proliferation and inhibits apoptosis, indicating a role in cell transformation. How this fusion event regulates polycomb function during decidualisation and how it contributes to ESS tumourigenesis is unknown.</p> <p>We have found that JAZF1-SUZ12 fusion removes SUZ12 non-coding RNA binding activity, which functions in targeting polycomb to chromatin. We hypothesise that this alters polycomb targeting, leading to changes in epigenetic modification and to cell transformation. To test this, we will use genome-wide measurements of protein-DNA interaction (ChIP-Seq) to identify the changes in epigenetic modifications caused by JAZF1 fusion in endometrial stromal cells. We will then determine whether these chromatin changes are associated with cell transformation and seek to identify the genes disregulated by JAZF1-SUZ12 that are driving this process. This work will define the epigenetic changes that govern endometrial stromal cell tumourigenesis and provide a model for developing a broader understanding of the role of polycomb proteins in cancer.</p>


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