NIHRDataInsights/HRCSData huggingface dataset:
Title: Characterising novel Phosphatase enzymes important in regulating Androgen Receptor function in the progression of Castrate Resistant Prostate Cancer
Funder: Prostate Cancer UK

Abstract: Proposal Outline: Numerous studies into the effect of co-regulators on androgen receptor (AR) function during advanced Castrate Resistant Prostate Cancer (CRPCa), have yet to identify a successful targeted treatment regime for this type of disease. Research has focused on the effects of post-translational modification of the AR in late stage disease and in particular, the mechanisms which regulate AR phosphorylation. But the processes of de-phosphorylation by phosphatase enzymes during the progression to CRPCa disease, are markedly understudied. Background: Using a high throughput siRNA library screen the expression of a panel of all 293 human phosphatase enzymes were suppressed by targeted siRNA (using 3 pooled oligos), in a modified PCa LNCaP cell line (LNCaP-7B7-PSA) and PSA expression assessed by luciferase assay. Target phosphatase enzymes which demonstrated repressor or activator function, were further tested in unmodified LNCaP cells, to confirm phosphatase mRNA knockdown and PSA expression by RT-QPCR. Seven novel phosphatases were identified as potentially influencing AR function (5 repressors and 2 activators). Expected Outcomes: To fully elucidate the mechanisms by which seven novel phosphatase enzymes influence AR function and progression to CRPCa. To identify therapeutic targets for advanced prostate cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Identification and validation of novel therapeutic targets in prostate cancer by investigating the cell killing mechanisms of the oncolytic adenovirus Ad∆∆ in combination with cytotoxic drugs
Funder: Prostate Cancer UK

Abstract: We previously demonstrated that our engineered oncolytic adenoviral mutant AdΔΔ synergises with chemotherapeutic drugs in prostate cancer cells, reduces tumour growth and prolongs survival in tumour models in vivo by potentiating drug-induced apoptosis. Efficacy was greatly improved in the highly treatment-resistant prostate cancer cells PC-3 while primary normal cells (NHBE, PrEC) did not support AdΔΔ propagation and were not sensitised to drugs. Ongoing work indicates that autophagy is highly induced in prostrate cancer cells and treatment with the cytotoxic drugs currently used clinically, docetaxel or mitoxantrone, further increases autophagy activity. The increased autophagy flux results in survival of the prostate cancer cells and partial rescue from drug-induced apoptosis, while simultaneous infection with AdΔΔ prevents autophagy-dependent survival and promotes drug-induced apoptosis. We have identified potential pathways and key factors that are regulated by adenoviruses and drugs using viral mutants defective in specific protein-binding regions and screening of a microRNA (miRNA) library. We will further investigate and validate the functional significance of key candidate cellular factors and identified miRNAs involved in the increased drug-sensitivity in the presence of virus. The ultimate goals are to identify novel therapeutic targets and develop novel therapies, particularly for advanced treatment-insensitive prostate cancers.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Development of a Transcriptional Repressor Based Approach for the Treatment of Prostate Cancer
Funder: Prostate Cancer UK

Abstract: Prostate tumours grow in response to androgens. Therapies for inoperable prostate cancer inhibit androgen signalling, by chemical castration or repressing activity of the androgen receptor, which mediates the actions of all androgens. However, tumours eventually recur in spite of such therapies, often due to alterations in the androgen receptor pathway. Also they are associated with side-effects in other androgen target tissues, which are many and varied. Androgen receptor activity can be modulated by binding of accessory proteins, often in response to binding of androgens or therapeutic antiandrogens. We aim to engineer transcriptional repressors which will be recruited to the receptor in the presence of androgens, but will inhibit its activity due. This approach is designed to address many of the concerns over existing therapies and to block the activity of the AR even in circumstances where conventional therapies would be predicted to fail, such as mutated or elevated androgen receptor, or increased coactivators. They also have the potential to be delivered in a targeted manner to prostate tumour cells.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Aldehyde Dehydrogenases in Prostate Cancer
Funder: Prostate Cancer UK

Abstract: There is an immediate need for biomarkers that distinguish aggressive from indolent prostate cancer (PCa). Aldehyde dehydrogenases (ALDHs) are identified as a characteristic of cancer stem cells (CSCs), however specific isoforms are thought to play important roles in tumourigenesis and metastasis. Currently it is not clear which ALDH isoforms are most relevant to PCa stem cell identification and which ALDH isoforms are involved in PCa tumourigenesis and drug resistance. This project will help elucidate (i) the role of hypoxic stress in the regulation of ALDH expression in malignant PCa vs benign PCa and (ii) important leads for identifying PCa specific ALDH(s) as biomarkers indicative of the aggressiveness of this disease.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Role of Stroma Microenvironments in Prostate Cancer Cell Migration and Metastasis
Funder: Prostate Cancer UK

Abstract: Metastasis of tumours to secondary sites including bone and lymph nodes has a very significant impact on patient outcomes. Through comparing primary human prostate stroma from benign prostatic hyperplasia and low and high Gleason grade tumours we have shown that adhesion molecules are up-regulated in high grade tumours. Analysis of prostate cancer cell migration capacity using tumour – stroma spheroids showed that adhesion had an essential role in regulating tumour cell migration out of the spheroids into the surrounding extracellular matrix. Using in vitro culture system we have shown that adhesion molecule expression is regulated by cytokine signalling. In this PhD project will build on these results focusing on how cytokine signalling pathway regulates the tumour microenvironment using primary human tissue biopsies, 3D human tumour cell-stroma-immune cell spheroids and an in vivo mouse syngeneic prostate cancer model. Using these technologies the project will investigate cytokines and adhesion molecules in the tumour microenvironment and how this regulates tumour cell metastasis. We will combine small molecule inhibitors and blocking antibodies with 4-Dimensional multiphoton confocal microscopy and small bore magnetic resonance imaging (MRI) to visualize the role of these molecules in advanced prostate tumour metastasis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Refinement of a polymeric system delivering super-potent cytotoxins to prostate tumours
Funder: Prostate Cancer UK

Abstract: Water-soluble polymers accumulate in solid tumours by the EPR effect. PSA is a peptidase which is active only in the extracellular space of the prostate and prostate tumours. A polymeric prodrug carrying drugs attached to the backbone through a PSA-cleavable linker peptide has two modes of selectivity. Exploiting the exquisitely potent cytotoxicity of the CBI DNA minor-groove-binding drugs, such as duocarmycin SA, we plan to refine our polymeric prodrugs comprising CBI precursors (seco-CBIs) attached to both ends of poly(ethylene glycol) (PEG) polymer molecules through short peptides (sequences cleaved selectively by PSA). The CBIs are exquisitely potent, so the low loading on the PEG polymer will deliver sufficient drug. The project builds on much previous work and proceeds in four stages (i) optimisation of chemical syntheses of the stereochemically pure CBI core for maximum potency; (ii) optimisation of the non-covalently binding “tail” attached to the CBI for maximum potency in DNA-binding and cytotoxicity; (iii) incorporation of a self-immolative clip between PSA-cleavable peptide and drug to speed PSA-triggered release; (iv) assembly and preliminary evaluation in vitro of poly­meric prodrugs for PSA-triggered delivery of the super-potent CBI. This project should lead towards a new approach to selective chemotherapy of prostate cancer.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: The role of Leukaemia Inhibitory Factor (LIF) in prostate cancer bone metastasis
Funder: Prostate Cancer UK

Abstract: Once prostate cancer metastasizes to bone it becomes incurable. Therefore there is a pressing need for early detection and treatment of bone-metastatic prostate cancer. We have identified an increase in the cytokine leukaemia-inhibitory factor (LIF) in patients with prostate cancer prior to bone metastases. We demonstrate that bone metastatic prostate cancer cells express higher levels of LIF, and that decreased LIF expression in prostate cancer cells reduces bone resorption in a murine model of prostate cancer bone disease. Our overall hypothesis is that LIF expression and secretion by prostate cancer cells promotes bone metastases and development of the mixed osteolytic/osteoblastic bone disease. To address this we propose to use a powerful combination of cellular and molecular biology and established murine models of prostate cancer bone metastasis. We will investigate the regulation and functional role of LIF in prostate cancer-induced bone disease in vitro and in vivo. We will also determine whether LIF expression can act as a biomarker to predict patients at risk of bone metastases and/or the extent of the bone disease. Our study will elucidate the mechanism of action of LIF in prostate cancer-induced bone disease and determine the potential for LIF as a prognostic biomarker.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: An investigation of the role of the ets factor ELF3 in prostate cancer aggressiveness.
Funder: Prostate Cancer UK

Abstract: My laboratory has pioneered techniques to fractionate prostate tumours and to enrich for the different cell types which comprise this complex cancer. We have studied patterns of gene expression in the minor tumour cell populations, one of which we have shown to possess the major tumour-inducing capacity, in contrast to the bulk of the tumour which simply forms a replicative mass, against which current therapies have been developed with limited long term success. In an Affymetrix array total gene expression screen of fractionated cell types, an ets family member (ELF3) was aberrantly expressed in a consistent manner across multiple patient samples. Since ELF3 was downregulated in the tumour-initiating population, it was not prioritised for study until 2 (largely cell line-based) functional studies were published in 2013, reaching opposite conclusions about the role of ELF3 (oncogene vs tumour suppressor) in aggressive prostate cancers. We believe that this conflict is due to tumour cell heterogeneity, and propose to examine the effects of manipulating ELF3 expression in the different tumour cell compartments, both in vitro and in new near-patient xenografts, to resolve its proposed aetiological role, and to determine whether the significant expression changes can be exploited as a novel, targeted treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Characterisation of mRNA isoforms as potential clinical biomarkers and molecular drivers of prostate cancer
Funder: Prostate Cancer UK

Abstract: Androgens play a key role in driving prostate cancer through regulating gene expression. Individual genes can produce multiple different mRNA isoforms, which can have quite different biological activities from each other. Not much is known about how androgens regulate different mRNA isoforms, but they are a huge potential source of biomarkers and therapeutic targets. We will use existing RNA sequencing data we have prepared to discover mRNA isoform switches occurring between triplicate androgen deplete and androgen-stimulated prostate cancer cells. Specific isoforms will be experimentally confirmed by RT-PCR. Using bioinformatics and molecular biology we will correlate this data with isoform expression in clinical prostate cancer before and after androgen-ablation therapy. We will monitor isoforms in hormone naïve and hormone refractory cancer, and in Tissue Microarrays from different Gleason grade cancers. Finally we will stably express these isoforms in LNCaP and DU145 cells grown in tissue culture, and ablate expression using SiRNA. Our expected outcomes are to comprehensively monitor the expression of these isoforms in clinical cancer of different grades, and determine their role and importance in cell growth, motility and signalling pathways. We will use this data to evaluate the potential of these isoforms as prognostic markers and potential therapeutic targets.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: TAZ & rhabdomyosarcoma: TAZ expression in human samples, TAZ transformation of myoblasts and YAP/TAZ drug discovery
Funder: Sarcoma UK

Abstract: Rhabdomyosarcoma (RMS) is an aggressive frequently childhood sarcoma where the causative cells resemble proliferating myoblasts. YAP and TAZ are transcriptional co-factors within the Hippo pathway and are now recognised as genuine oncogenes. In preliminary experiments we found that RMS generally have a YAP and/or TAZ gene expression signature. This means that genes which are known to be regulated by Yap and Taz are highly expressed in Rms Moreover, in embryonal rhabdomyosaroma (ERMS) and fusion gene-negative alveolar rhabdomysarcoma (ARMS) our preliminary data suggest that TAZ mRNA itself is highly expressed. In the proposed study we wish to investigate the role of TAZ in RMS further and to test whether TAZ is a suitable diagnostic marker for RMS and search for compounds that inhibit YAP/TAZ to potentially treat Rms We will first stain human RMS tissue arrays for TAZ protein to determine whether this marks specific types of RMS and correlates with clinical data. We also wish to conduct an extensive bioinformatics analysis to try to identify causes of TAZ signatures where TAZ expression is normal and correlate TAZ expression/signature with the expression of other RMS-related genes, histology, fusion gene status and clinical data. We then wish to over express TAZ and constitutively active TAZ S89A to test whether this can transform normal myoblasts and confer resistance to chemotherapy drugs as TAZ does in breast cancer. We also plan to screen a library of »300 natural compounds for YAP/TAZ inhibitors. To aid future drug discovery we will search for YAP and TAZ binding partners in different types of RMS as this is key for designing more RMS-specific drug screening assays.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Validation of clinically relevant oncogenic receptors in high grade human sarcoma as potential drug targets
Funder: Sarcoma UK

Abstract: The management of high grade soft tissue sarcomas remains a fundamental problem that requires novel strategies to improve outcomes. We aim to identify, using new generation proteomic platforms, candidate targets in high grade soft tissue sarcoma, against which future therapeutic strategies can be developed for targeted analysis and imaging to provide clinically useful prognostic and predictive information. We have obtained background data using iTRAQ mass spectrometry in paired normal and tumour samples of pleomorphic and high grade leiomyo- and liposarcoma, identifying differentially over-expressed receptors in sarcoma that represent dominant potentially druggable receptor classes. The lead candidate targets / biomarkers from the sarcoma samples will be validated in sarcoma cell culture to determine how inhibition or depletion affects growth, survival, and response to combined therapeutic drugs. Considering the accessibility of these candidate receptors to monoclonal antibodies, the impact of this work should we validate the receptors as being compelling drug targets, would be the formation in future of monoclonal antibody based diagnostic and therapeutic programmes to improve the diagnosis and treatment of high grade tissue sarcoma.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Evaluation of physical functioning in adults treated for bone and soft tissue sarcomas – a feasibility study of two new technologies.
Funder: Sarcoma UK

Abstract: Background: Assessment of physical functioning is important to understand the effects of treatment in survivors of bone and soft tissue sarcoma. There is lack of objective measures of physical functioning in this population. Aims: This project will investigate whether two new technologies (a patient Activity Monitor (Open Movement Motion Sensor) and the Xsens tracking device) which track movement in clinical and community settings could be used as objective measures of physical functioning in this group of patients. Methodology: Prospective non-randomised feasibility study in 20 survivors of bone or soft tissue sarcoma.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Determinants of locoregional recurrence and metastatic relapse in breast cancer: identification and development of novel biomarkers to inform clinical management
Funder: Chief Scientist Office (Scotland)

Abstract: Metastatic breast cancer remains an essentially incurable disease. Despite the sinister implications of development of distant metastatic disease, molecular changes driving metastasis remain relatively poorly defined and there have been very few studies analyzing matched primary and recurrent/metastatic lesions. Such studies would be valuable to facilitate a tightly controlled comparison of changes present in primary tumour and distant metastasis and those detected only in the metastasis with the opportunity to pursue novel therapeutic strategies. The proposed study will utilize established and well-characterized clinical series of paired primary and metastatic breast carcinomas. The goals of the proposed work are, therefore, i) to seek from de novo gene finding studies additional candidate genes involved in metastasis; ii) to analyze selected new candidates in paired primary: metastasis to assess their potential use as prognostic and predictive biomarkers iii) To similarly evaluate and compare these with reviousl identified candidate biomarkers in the same series.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: STAMPEDE Trial
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Abstract and summary of trial design. STAMPEDE is a multi-centre, randomised controlled trial for patients with locally advanced or metastatic prostate cancer who are about to commence androgen suppression (AS) therapy. Patients can have either newly diagnosed disease, or have been previously treated with radical radiotherapy or surgery but now have a rising prostate specific antigen (PSA) (further details on eligibility see section 4). The trial will assess the effects of adding three different agents, both as single agents and in combinations, to AS therapy. The investigational agents are (i) a bisphosphonate, zoledronic acid, (ii) a cytotoxic chemotherapeutic agent, docetaxel and (iii) a cyclooxygenase (Cox-2) inhibitor, celecoxib. The trial has six arms; the control arm of the trial is AS only, achieved through the use of luteinising hormone releasing hormone (LHRH) analogues or bilateral orchidectomy according to local practice. The trial will be conducted in FIVE stages: a Pilot Phase, Efficacy Stages I to III and Efficacy Stage IV. The primary outcome measure of the Pilot Phase is the safety of the investigational arms and 210 patients will be recruited. Investigational arms will only proceed to recruitment in the next stage if they have been shown to be both safe and feasible, although patient data from all patients and all stages will be included in the final analyses. In Efficacy Stages I-III the primary outcome measure is failure free survival (FFS). Further patients will be recruited until 115, 225 and 355 FFS events have been observed in the control arm. Some evidence of efficacy will be required for an research arm to proceed to further recruitment in each stage and guidelines are in place. In Efficacy Stage IV, patients will be recruited until 440 deaths have been observed in the control arm. Overall, approximately 3,300 patients will be recruited over 5-7 years although the exact number of patients and duration will depend on the observed accrual rate, observed event rate and the number of patients accruing at each stage. Patients will be assessed 6 weekly for the first 24 weeks after randomisation and then every 12 weeks up to 2 years. Assessments will then be 3-monthly for the next 2 years and then 6-monthly, thereafter. Patients will also be asked to complete questionnaires aimed at assessing the effects of the investigational treatments on their quality of life (QL) and on their use of health care resources (HE study). In addition, there is a molecular genetics substudy. Patients willing to participate will be asked to donate 8ml of blood which will be stored for either DNA and protein analysis in order to try to identify genes that are associated with response to therapy, side-effects or susceptibility to prostate cancer. There are separate patient information sheets for the QL and HE study, and the molecular genetics study (For further details of ancillary studies see section 16)


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS