NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigating the regulation and effects on androgen receptor expression using culture models of castration resistant prostate cancer that induce embryonic stem cell gene expression
Funder: Prostate Cancer UK

Abstract: Androgen receptor (AR) activity plays a central role in castration resistant prostate cancer. New evidence demonstrates activation of embryonic stem cell (ESC) gene expression signatures are also important in prostate cancer and that they may regulate AR expression. This novel interaction between ESC genes and AR requires further investigation and is the focus of this proposed work. To dissect the mechanisms of this interaction we have developed novel culture models of castration resistant prostate cancer that up-regulate AR and ESC gene expression. Two potential mechanisms for increased AR transcription will be explored: (1) recruitment of ESC transcription factors (OCT4, SOX2 and Nanog) to novel promoter response elements of the AR gene; and (2) competitive binding of ESC transcription factors to a recently identified suppressor androgen response element within the AR gene preventing repression of transcription. Furthermore, the effects of ESC gene expression on AR action in stem cell cultures mimicking castration resistant disease will be compared to standard culture of hormone dependant prostate cancer. Specifically, a global search for differential AR binding sites using ChIP-Seq will identify novel geneexpression programs Finally, candidate treatment targets will be functionally validated by knockdown studies and correlated with clinical expression using a tissue microarray.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Development of a first-in-class preclinical drug candidate for the treatment of castrate-resistant prostate cancer
Funder: Prostate Cancer UK

Abstract: There are few effective therapeutic agents available for treatment of castrate-resistant prostate cancer (CRPC). Of the 1 in 6 men diagnosed with prostate cancer, 1 in 33 will die of metastatic disease. Once diagnosed with CRPC, docetaxol treatment prolongs life expectancy by an average of 6 months. The regulatory kinases of the NFB pathway control the expression of pro-inflammatory and growth promoting proteins and we proposed previously that IKK and  represent viable therapeutic targets in CRPC which has been vindicated in mouse models of prostate cancer. Through access to a unique matched hormone-naïve and CRPC cohort, we have linked these laboratory-based findings with real clinical data to highlight the central role played by IKK in the development of CRPC and metastasis. Our Drug Discovery Group has generated a potent IKK selective lead series with <40 nM activity against the target isoform and selectivity over IKK ranging from 1:10 to 1:100 in favour of IKK. We are currently in the lead optimisation phase of combining desirable ADME properties with potency for efficacy studies in vivo to drive a further round of optimisation as we progress towards a first-in-class pre-clinical candidate to treat CRPC.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Identifying novel mechanisms of androgen-mediated growth control as new targets for intervention and prognostic biomarkers in prostate cancer
Funder: Prostate Cancer UK

Abstract: High throughput transcriptome screening is a powerful new tool to identify disease pathways in cancer and potential biomarkers/therapeutic targets. We recently determined how almost every exon in the prostate cancer cell transcriptome responds to androgens (Rajan et al, PLoS ONE, 2011;6(12):e29088). We have now meta-analysed this dataset with genes known to be mutated/mis-regulated in prostate cancer, and shortlisted for investigation PIK3R1 and PI3KR3 (normally repressed by androgens and frequently mutated in prostate cancer), PTPRR and a novel isoform of the tumour suppressor TSC2. To test whether expression switches in these genes might be critical events in prostate cancer progression we will “force” their expression in prostate cancer cells, and reciprocally deplete their expression using siRNA, monitoring effects on cell growth, division and important signalling pathways. We will monitor gene and protein expression in hormone sensitive and castrate resistant prostate cancer to evaluate these genes as potential prognostic markers and targets for clinical intervention. Secondly we will use RNAseq to identify further direct androgen regulated molecular switches (particularly mRNA isoforms). We will comprehensively stratify the role of such newly identified genes in PCa cell growth and disease using the same meta-analyses, functional assays and clinical expression analysis established above.


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: Quantitative shear wave elastosonography in the detection and characterisation of prostate cancer
Funder: Prostate Cancer UK

Abstract: Diagnosis using transrectal ultrasound (TRUS) shear wave elastography (SWE) - hereafter abbreviated as TRSES - potentially offers a novel approach for men with prostate cancer. TRSES will allow for precise location of cancer foci within the gland, and also provide a method for quantification of tissue stiffness. The latter can further be used as a biomarker for differentiating aggressive cancers from indolent lesions. Grey scale TRUS is offered in current clinical practice and is generally limited to measuring prostate volume and to guiding needles into the desired region as per the biopsy protocol. It does not actually differentiate between normal and cancerous tissue in up to 50% of cases. This proposal addresses this key issue of poor specificity and sensitivity of current ultrasound imaging by evaluating the role of SWE in the detection and differentiation of aggressive from indolent cancers. This approach could provide a new and easy to deploy, elastography-based paradigm, for improving integrated disease management and personalised cancer care.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Using circulating plasma DNA as a multi-purpose biomarker to identify aggressive prostate cancer and mechanisms of drug resistance
Funder: Prostate Cancer UK

Abstract: We hypothesise that men with prostate cancer have significant levels of tumour-associated circulatingplasma DNA (cpDNA) that is representative of the overall tumour population and genomic aberrations associate with tumour aggressiveness and progression. We therefore aim to use whole-genome SNParray profiling and targeted next-generation sequencing to identify genomic aberrations that associate with tumour aggressiveness in DNA from tumour and plasma from 1. castration-resistant prostate cancer (CRPC) patients progressing on abiraterone and 2. men undergoing both template and trans-rectal ultrasound-guided biopsies of the prostate in the PROMIS study. Data from both cohorts of men will be integrated with other studies to identify candidates that associate with aggressiveness. We shall then develop low-cost, high-throughput digital PCR for evaluating somatic copy number aberrations of candidate genes and test the accuracy for 1. identifying men recommended to undergo a prostate biopsy who are at highest risk of having clinically-significant prostate cancer and 2. distinguishing patients with aggressive from those with indolent prostate cancer. Finally, we shall functionally evaluate aberrant candidate genes/pathways identified as associating with resistance to castration and abiraterone through analysis of sequentially collected samples and obtain data to support novel biomarker-driven therapeutic strategies for CRPC.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Identification of DNA Repair gene mutations as a predisposition to early onset and aggressive prostate cancer
Funder: Prostate Cancer UK

Abstract: There is evidence for genetic predisposition to prostate cancer (PrCa) from epidemiological studies. To date genome-wide associations have identified 77 common variants (>5% frequency) which predispose to PrCa. We have identified the majority of these in our group. However these only account for 30% of the familial risk and so further variants remain to be found. We have shown that mutations in some DNA repair genes are important in PrCa causation and such variants have implications for targeted screening and treatment. BRCA2 is mutated in the germline of 1.2% of cases at <65 years and such individuals have a higher proportion of spread of disease and targeted screening identifies a higher proportion of aggressive disease than population screening. We therefore analysed 22 DNA repair genes in 191 affected men with a family history of PrCa and found 7.3% have germline loss of function mutations in these genes and are associated with more aggressive disease with more nodal spread. We therefore propose to analyse a more extensive panel of 193 DNA repair genes in a larger sample set to identify genes which can be tested in men with PrCa to identify those who are at risk of more aggressive 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: Functional analysis of the role of the Stem Cell Control Gene Latexin in prostate cancer invasion and metastasis
Funder: Prostate Cancer UK

Abstract: An unbiased analysis of gene expression in malignant prostate cancers has shown that latexin (LXN: a stem cell control gene in mouse haematopoiesis) is completely repressed in prostate tumour initiating cells from high Gleason grade tumours. We have also recently reported that LXN expression in LXN- cells results in a loss of colony forming ability, consistent with both effects on stem cell self renewal and metastatic capability. LXN protein was also localised for the first time in cell nucleus, implying a function distinct from its proposed carboxypeptidase inhibitory activity. The aim of this proposal is to elucidate the mechanism of action of LXN, by finding protein binding partners, exploiting existing and novel native, mutated and epitope tagged LXN proteins. We shall determine the genes and the signalling pathways whose expression is modified by LXN expression thus influencing its biological properties in vitro and in vivo. We shall seek to identify the means by which LXN controls the expression of its target genes: and the genomic binding sites after transfection of tagged LXN protein, backed up by a bioinformatic prediction of potential protein interactions. The outcome will provide a fresh source of potential therapeutic targets for malignant prostate cancers.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Identification of aggressive prostate cancer driver genes
Funder: Prostate Cancer UK

Abstract: Tumour formation is a multistep process driven by the accumulation of genetic changes that lead to a more aggressive and fatal disease. Identifying and understanding the changes that drive prostate cancer progression will facilitate the development of novel targeted therapies for advanced disease and the discovery of biomarkers that distinguish between dormant and aggressive disease, only the latter of which needs to be treated. We have performed a functional in vivo screen to uncover genes that drive prostate cancer progression to an aggressive stage. We are proposing to use oncogenomic comparative analysis to identify genetic changes found in human prostate cancer that are most likely drivers of advanced disease. We will perform in vitro and in vivo assays using prostate cancer cell lines to validate the advanced cancer promoting function of candidate genes. We will analyse the expression of select candidate genes in samples derived from patients with localised disease to determine whether they can serve as biomarkers that distinguish between aggressive and indolent disease. In addition, these data may provide information relevant to targeted therapeutic regimes in patients with advanced disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Development of Legumain based therapeutic for the treatment of advanced prostate cancer
Funder: Prostate Cancer UK

Abstract: Legumain, a C13 clan cysteine protease, has been reported to be overexpressed in a number of poor prognosis cancers, including breast, glioma, pancreatic and prostate with Legumain expression levels correlating with poorer clinical outcomes. Knockdown experiments using siRNA show that Legumain plays a significant role in both cancer cell proliferation and invasion. Similar knockdown experiments performed on non-tumorigenic cell lines showed no effects on normal cell viabilities, suggesting that Legumain may be a 'cancer-specific' target. We have observed that when Legumain is expressed on the cell surface, via colocalisation with ?-intergrins, it plays an important role in the stability and activation of MMP2 (a known Legumain substrate and oncogenic target). Direct targeting of MMP2 has proven problematic due to off-target toxicity, attributed in part to poor selectivity against other MMPs. Indirect modulation of MMP2 function would be seen as a major step forward in developing anti-cancer treatment options. The development of a highly potent and selective Legumain inhibitor would therefore be of considerable interest in the Fight against poor outcome prostate cancers. In this proposal we describe our identification and characterisation a novel series of Legumain inhibitors with tractable SAR and how we will progress their development.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Multi-parametric Ultrasound Imaging to Detect and Rule-out Clinically Significant Prostate Cancer
Funder: Prostate Cancer UK

Abstract: The diagnosis and risk stratification of men at risk of prostate is subject to error due to the current strategy of using transrectal ultrasound guided biopsies. We propose to test the hypothesis that multi-parametric Ultrasound has the ability to detect and rule-out clinically significant prostate cancer. Multi-parametric ultrasound, in a very similar manner to multi-parametric MRI, uses different modalities of ultrasound to visualise different aspects of tissue. It can incorporate B-mode greyscale images for anatomy, Power Doppler and Contrast enhanced Ultrasound for vascularity, Real-Time Elastography for tissue strain and density and Tissue Characterisation for tissue architecture. We propose a large prospective blinded, cohort validating study of up to 500 men who will undergo multi-parametric ultrasound, multi-parametric MRI and followed by template mapping biopsies, an accurate reference test that can be applied to all men recruited. This will allow us to compare the new test to the reference standard as well as the existing state-of-the-art imaging test, multi-parametric MRI. This study will represent level 1 evidence. If successful, multi-parametric ultrasound could lead to an accurate test that can be used at less cost with wider dissemination in healthcare systems


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Localising Occult prostate Cancer metastases with Advanced imaging TEchniques (LOCATE)
Funder: Prostate Cancer UK

Abstract: Locally advanced (T3/4; Tany, N1-2) and metastatic prostate cancer is a lethal disease and mortality within this group is primarily from prostate cancer rather than from other causes as previously thought. Whilst locally advanced disease is often treated with local therapies (external beam radiotherapy (EBRT) / brachytherapy), biochemical failure of therapy occurs in 25% of treated men at 5 years. Failure of local therapy initiates an imaging based assessment for metastatic disease; yet metastatic disease is difficult to detect on conventional imaging (CT and bone-scan) unless PSA level are very high (PSA > 40ng/mL), and so most men within this group have negative imaging findings and irrespective of biochemical failure undergo expectant management awaiting disease progression. Once metastatic disease is detectable with conventional imaging the outcome of first-line therapy is often poor. This study aims to improve treatment stratification for men presenting with biochemical failure following external beam radiotherapy or brachytherapy of locally advanced prostate cancer, by improved detection of aggressive (distal metastatic) disease. We hypothesize that better stratification would lead to better outcomes. The study assesses whether whole-body multi-parametric MRI improves detection of metastatic disease compared with conventional staging with CT and bone scan.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Role of phosphoinositide 3-kinase C2beta in prostate cancer
Funder: Prostate Cancer UK

Abstract: Deregulation of intracellular signalling pathways mediated by members of the family of enzymes phosphoinositide 3-kinase (PI3K) has a well established role in prostate cancer development and progression. Eight different isoforms of PI3K exist, grouped into three classes and the majority of studies have been focussed so far on members of the class I subfamily. Very little is known about the involvement of other PI3K isoforms in prostate cancer. Association of single nucleotide polymorphism in the gene encoding the class II isoform PI3K-C2? with prostate cancer risk has been reported but the specific role of this enzyme in prostate cancer is still not clear. Our preliminary data suggest that PI3K-C2? may be highly expressed in prostate cancer and they indicate that this enzyme regulates invasion of prostate cancer cells PC3. This project will perform an extensive characterisation which will define the role of PI3K-C2? in prostate cancer and it will determine whether its inhibition can inhibit prostate cancer progression and whether it accumulates in prostate cancer. These results will potentially validate PI3K-C2? as a novel therapeutic target and (possibly a marker) of advanced prostate cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Evaluating androgen action in prostate cancer progression and therapy
Funder: Prostate Cancer UK

Abstract: Androgens affect many tissues: although their effects on the male reproductive tract and genitalia are best characterised, other androgen target tissues include brain, muscles, bones, immune system and heart. Androgens signal via the androgen receptor (AR). We constructed an AR-reporter mouse for in vivo imaging of AR activity in all tissues. Prostate tumours are androgen responsive, therefore therapies repress androgen signalling. These are initially successful, but recurrence is a common problem, with tumours developing "castration resistance". Additionally, therapies elicit debilitating side-effects reflecting the range of androgen target tissues. There is a need to design targeted therapies with fewer side-effects. We aim to engineer a model in which to (i) visualise where and when AR-modulating drugs are active and (ii) assess effects of such compounds in tumours, in a model that faithfully recapitulates every stage of human prostate cancer progression. We will achieve this by introducing prostate-specific PTEN deletion into the AR reporter mouse. The study will provide a model for pre-clinical testing of new drugs and increase knowledge of androgen action in general. We will be able to monitor effects of drugs on tumour growth and spread, and determine where and when androgens are active during transition to castration resistant disease.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CHD1 Deletion: Implications to Outcome and Treatment in Prostate Cancer
Funder: Prostate Cancer UK

Abstract: Prostate cancer can be stratified as ETS gene rearranged (ETSR) and non-rearranged (ETSNR), with the latter comprising a heterogeneous group of 50-60% of all cancers. This project will characterize a subgroup of ETSNR cancers that have a CHD1 deletion (CHD1-). Recent sequencing studies have elucidated CHD1- cancers as ETSNR, and commonly PTEN and p53 wildtype and SPOP mutated, comprising up to 26% of all prostate cancers (1). ETSR cancers largely have hormone driven oncogenes that may have prognostic and predictive utility (2, 3). Less is known about ETSNRCHD1- cancers. Their lack of ETS fusions raises concern that these may not be generated through androgen receptor (AR) transcription and are not AR driven. ETSNRCHD1- cancers have a huge excess of somatic intrachromosomal rearrangements (up to 800) compared to ETSR cancers presumably due to a DNA repair defect (1). This is supported by CHD1's association with the SSRP1, part of the FACT complex, that is implicated in transcriptional regulation and DNA repair (4-9). We hypothesize that CHD1 deleted tumors are less sensitive to endocrine and taxane therapy, have a worse prognosis and need alternative treatment strategies.


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