NIHRDataInsights/HRCSData huggingface dataset:
Title: The role of ubiquitin in androgen receptor function in prostate cancer
Funder: Prostate Cancer UK

Abstract: Hormone therapy is the mainstay of treatment for advanced prostate cancer that has spread beyond the confines of the prostate. Unfortunately, it is only effective for a time and eventually the cancer escapes control and resumes growth. This study will examine one of the possible reasons behind the failure of hormone therapy for advanced prostate cancer by studying an important regulator of prostate cancer growth - the androgen receptor (AR) protein. Professor Robson's research team have already found evidence that the switch that turns the AR protein on and off stops working properly as prostate cancer progresses. This project will examine this switch in detail, specifically to understand whether it is the inability to turn the AR protein off that contributes to tumours becoming hormone resistant and recurring. Only by understanding this process can researchers begin to develop a new line of therapy targeted at the AR protein to extend survival for men with the most advanced stage of prostate cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: A novel chemoprotective role for vitamin D in prostate cancer
Funder: Prostate Cancer UK

Abstract: There is some scientific evidence that vitamin D may have a role in preventing prostate cancer from developing (primary prevention) or in stopping prostate tumours progressing (secondary prevention). For this reason, Dr Thompson's research team is studying the role of vitamin D in reducing the levels of testosterone hormones, key drivers of prostate cancer growth. This project will look at whether vitamin D can help prevent prostate cancer progressing to a hormone-resistant state by stopping tumours producing their own sources of testosterone when they are challenged by testosterone-reducing treatments. The team will do this using a range of technologies; studies of prostate cancer cells cultured in the laboratory, mouse models of prostate cancer, and tissue samples donated by men with prostate cancer who are taking vitamin D supplements. If these tests suggest vitamin D supplementation is effective at lowering tumour testosterone levels this would be expected to lead to clinical trials combining vitamin D supplements with hormone therapy. Delaying or preventing the onset of hormone-resistant disease would be an important step forward in improving survival for men with advanced prostate cancer.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS
Title: Exploiting defects in DNA repair for treatment of prostate cancer.
Funder: Prostate Cancer UK

Abstract: Prostate cancer growth is dependent on testosterone and can be treated with hormone therapy to reduce testosterone levels. Hormone treatment is used mostly for advanced prostate cancer that has spread beyond the confines of the prostate gland and is ther


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Development and evaluation of a guided self-help intervention to alleviate hormone treatment side effects (hot flushes and night sweats) for prostate cancer survivors.
Funder: Prostate Cancer UK

Abstract: This is a study to find out if a self-management treatment can reduce hot flushes and night sweats for men with prostate cancer. The project will develop a Self-Help intervention to help prostate cancer survivors who are living with some of the effects of prostate cancer treatments. The treatment is a 4 week programme with a self-help book and CD with information and advice and phone contacts. It has been found to be effective for women with similar symptoms from breast cancer treatment. The team will adapt the intervention for men during the pilot phase and then test whether it reduces symptoms by comparing the treatment with usual care. If effective, men will be less troubled by hot flushes and night sweats, feel better in themselves and less tired during the day, and have an overall improved quality of life. They might also feel more confident and able to deal with other symptoms and stresses in their lives.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: CANCER AND NEOPLASMS
Title: Development of tumour-selective therapeutics for advanced prostate cancer
Funder: Prostate Cancer UK

Abstract: The aim of this project is to develop new types of drugs for prostate cancer which are inactive in the body until they come into contact with the tumour. Specific proteins in tumour cells (called MMPs) will become active and cause the release of a very potent chemotherapeutic drug. This means the drug will have a better effect specifically against the tumour, and will have much lower side effects. The proposed strategy will deliver much higher amounts of the drug directly to the tumour and will avoid unwanted side effects that result from the presence of the active drug in other parts of the body. This will lead to better treatment with reduced side effects and better quality of life for men with advanced prostate cancer.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: A pilot randomized controlled trial of a nurse-led psycho-educational intervention delivered in primary care to prostate cancer survivors
Funder: Prostate Cancer UK

Abstract: Many studies (including our own) have shown that men with prostate cancer can experience a range of problems (eg physical, psychosexual, psychological) following diagnosis and treatment, and that current follow-up practices fail to meet these needs. The research team believe there is sufficient evidence to suggest a nurse-led intervention which focuses on identifying and dealing with problematic symptoms and / or psychological / psychosexual issues will lead to improvements in prostate-related quality of life. In line with current guidance on follow-up for men who are stable, our intervention is based in primary care. This study will test the effectiveness of a nurse-led intervention which will target men with prostate-related problems (physical (eg urinary, bowel, sexual functioning) or psychological/ psychosexual) when they are 12-24 months post-diagnosis, and will offer individualised advice and support. Men will be offered a nurse appointment in primary care. The nurse will identify the most important quality of life issue(s) for the man (and his partner if relevant) and offer evidence-based information, advice and support, or referral to the GP, secondary care or other support service as appropriate. A routine nurse telephone follow-up appointment will take place six months later. Additional contact will be tailored according to individual needs. This project is a pilot trial which is an essential first step required to generate the information needed to design and run a definitive, future trial to test the clinical and cost-effectiveness of the intervention.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: CANCER AND NEOPLASMS
Title: Synergistic interaction between Sprouty2 loss and PI3K/AKT activation in prostate carcinogenesis
Funder: Prostate Cancer UK

Abstract: This project will use clinical prostate cancer specimens and an animal model system to study the molecules Sprouty2 and PI3/AKT, how they work together to cause aggressive prostate cancer and its spread (metastasis), and how the cancer ultimately develops resistance to hormone treatments. Better understanding of this critical topic in prostate cancer will allow us to develop better treatment. Studying the activity levels of these molecules will be used to establish if abnormal activity levels are linked to aggressive or treatment-resistant prostate cancer. In addition, the team plan to use a mouse model to specifically test how these molecules work alone and together to cause and promote prostate cancer. This study will provide new insights into how prostate cancer develops and progresses, the team also aim to address how to better target treatments for individuals, and "group" patients according to the activity of these molecules and the aggressiveness of disease to determine the most appropriate treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The role of IKKa and IKKb in prostate cancer progression.
Funder: Prostate Cancer UK

Abstract: The research team plan to use to use prostate cancer specimens taken from men before treatment and after the men no longer respond to treatment to investigate what changes occur. Once identified, these changes will be altered and/or manipulated to see if this will stop the cancer from further growing. More specifically, the team are interested in a group of molecules in an inflammatory pathway, known as NFkB, IKKa and IKKb. This is a very well characterised inflammation pathway which is thought to be involved in prostate cancer becoming resistant to hormone treatments. Inflammatory pathways are also under investigation in other studies as potential driving factors behind the development of prostate cancer. If successful this project could provide alternative ways of treating prostate cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: A new approach to evaluating prostate cancer diagnostic markers in men with a raised PSA undergoing template mapping biopsy
Funder: Prostate Cancer UK

Abstract: This study is aimed at providing better markers to test for prostate cancer and to distinguish between aggressive and so-called 'indolent' forms of prostate cancer, also referred to as 'tigers' and pussycats'. The research team plan to collect blood and urine samples from 714 men who are due to have a prostate biopsy. Unlike all previous studies, these men will then have an extremely thorough biopsy, known as a template mapping biopsy. This type of biopsy allows us to accurately assess the presence or absence of prostate cancer, its size and grade. The next step is to test several highly promising blood and urine markers to see whether they accurately predict the presence or absence of significant prostate cancer. There is an urgent need for better markers of significant prostate cancer that could be used to tell us who should or should not have a biopsy. The team believe that it is vital to test such markers in men who have a template mapping biopsy. This is something that has never been done before.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Manipulating prohibitin: a novel therapy for prostate cancer?
Funder: Prostate Cancer UK

Abstract: Hormonal therapies are currently the best option for patients with inoperable prostate cancer that has spread outside the prostate gland. These therapies are initially successful, but after 1 to 3 years patients often relapse with life-threatening disease. At this stage, there are very limited treatment options, although chemotherapy is sometimes offered. Dr Bevan and her team aim to take the first steps in developing a novel form of therapy. This is based on their previous studies showing that a protein called prohibitin can reduce the growth of prostate cancer cells. The team will use samples obtained with permission from men with prostate cancer to determine the best targets for the new therapy. Following this, they will design and test multiple therapies in model systems that represent the conditions in men with the disease, to determine the effect on tumour growth. Ultimately, the team aim to try and offer a new therapy that could be used as an alternative to existing therapies or used in combination with hormone therapies to improve their efficacy.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Targeting the tumour-initiating population in prostate cancer
Funder: Prostate Cancer UK

Abstract: For more than six decades androgen ablative therapies have been used in the management of prostate cancer. Unfortunately this treatment is palliative, as hormone-unresponsive lesions develop. Even with the use of aggressive chemotherapy regimens a survival benefit of months is achieved. Clearly new therapies are required to target aggressive disease. There is, unfortunately, a high failure rate of novel targeted drugs in clinical trials, such that there is increasing doubt as to the suitability of traditional cell line models of preclinical studies. We have generated a series of primary xenografts that are ‘near-patient’ and can be re-derived (from frozen) with a high success rate. They are histologically heterogeneous, and importantly show differential responses to novel therapies (such as stat3 blockade) which target the clonogenic population. The aim of this proposal is firstly to determine the efficacy of these novel drugs as single agent(s) and in combination with current ‘standard of care’ therapeutics for prostate cancer and secondly to test the hypothesis that cancer stem cells are responsible for treatment failure.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Advanced prostate cancer: does targeting hypoxic cells block malignant progression and metastasis?
Funder: Prostate Cancer UK

Abstract: Treatment of advanced prostate cancer frequently involves androgen deprivation therapy. Following clinically-relevant treatment with bicalutamide (2mg/kg/day) we demonstrated profound and persistent hypoxia (lasting up to 17 days) in LNCaP prostate tumour xenografts; this was followed by a significant re-oxygenation phase. This initial (although temporary) effect of bicalutamide has not previously been identified as an opportunity for novel treatment strategies, although this effect is consistent with much of the published data in relevant animal and human studies. Recent laboratory and clinical evidence has also highlighted the critical importance of tumour hypoxia as a major cause of malignant progression and metastasis in advanced prostate cancer. In a pilot study using LNCaP tumours in vivo we used the bioreductive drug AQ4N to kill hypoxic tumour cells. AQ4N was combined with bicalutamide at day 7, when the hypoxia was greatest; this resulted in improved control of the primary tumour and reduced metastatic spread as compared to bicalutamide only. In the proposed study we aim to optimise the treatment schedule of bicalutamide in combination AQ4N for the treatment of androgen-sensitive prostate cancer. In addition we aim to investigate the efficacy of combing a bioreductive drug with chemotherapy for the treatment of castrate-resistant prostate cancer.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Therapeutic Inhibition Of The Histone Demethylase LSD1 To Attenuate Androgen Receptor Signalling In Prostate Cancer
Funder: Prostate Cancer UK

Abstract: 10,000 men die from metastatic prostate cancer in the UK per year. The treatment of this disease is critically reliant on the inhibition of androgen receptor (AR) signalling. Current approaches for achieving this are inadequate with most patients becoming resistant to initial systemic depletion of gonadal androgens. Targeting the mechanisms of persistent AR signalling is of intense interest currently. One potential means to achieve this is to target epigenetic modification of AR signalling. Lysine (K)-specific demethylase 1A (LSD1), is an epigenetic AR co-activator which modifies chromatin structure at AR responsive target genes. It’s over expression is a poor prognostic factor in prostate cancer. LSD1 inhibition is achievable with monoamine oxidase (MAO) inhibitors which exploits MAO/LSD1 sequence homology. We have synthesised novel analogues of the MAO inhibitor tranylcypromine designed as LSD1 inhibitors. Pilot data show that these analogues inhibit prostate cancer cell growth and AR signalling. We also found synergy with established AR antagonists. The similarity of these novel structures to established drugs would hopefully allow rapid translation of this approach. This project will develop our understanding of the biological consequences of LSD1 inhibition on AR signalling and how this might be incorporated into conventional therapeutic strategies for prostate cancer.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Enhancement of targeted radiotherapy for prostate cancer using PSMA-seeking agents in combination with radiosensitisers
Funder: Prostate Cancer UK

Abstract: Trofex, a glutamate-urea-lysine tripeptide, has high affinity for prostate-specific membrane antigen (PSMA) and has recently demonstrated exquisite specificity for PSMA-expressing, metastatic prostatic carcinoma. Preliminary imaging studies in patients, using [123I]Trofex, revealed tumour-selective binding and prolonged retention only in malignant sites. This indicates the therapeutic potential of this agent when labeled with Iodine-131. Our aim is to make the most effective use of [131I]Trofex for the treatment of metastatic prostate cancer by combining the [131I]-labelled radiopharmaceutical with radiosensitiser drugs. The compounds will be examined singly and in combination for their ability to sterilise clonogens derived from prostatic carcinoma cell lines using two- and three-dimensional in vitro models. Employing in vitro and in vivo systems, we will evaluate [131I]Trofex and synergising drugs (inhibitors of checkpoint kinase, PARP1, Hsp-90, Aurora kinase) for anti-tumour effect. Mechanisms of drug interaction will be determined and our clinical collaborators will evaluate the most effective schedules of therapeutic agents in patients. The study will be conducted in alliance with oncologists involved in the management of prostate cancer patients, enabling rapid translation of positive laboratory findings into improved clinical treatment.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Developing a new targeted therapy for treatment of metastatic prostate cancer: synthesis and preclinical validation of sphingosine kinase inhibitor-docetaxel combination nanoparticles.
Funder: Prostate Cancer UK

Abstract: Our lab has demonstrated the role of the oncogenic lipid kinase sphingosine kinase 1 (SK1) in prostate cancer progression and chemoresistance and shown the chemo- and radiosensitising potential of SK1 inhibition. However the absence of clinically applicable SK1 inhibitors has limited the translation of these findings into patients. Using in silico molecular field point modelling, we have recently discovered and synthesised novel specific SK1 inhibitors with low micromolar activity against human metastatic prostate cancer cells. Furthermore we have demonstrated their high-level (nanomolar) synergy with standard docetaxel anticancer therapy. The aim of this proposal is to deliver a sustained and a sequential combination of a clinically used chemotherapy (docetaxel) and novel nanomolar SK1 inhibitors by using multifunctional nano-carriers as delivery platform. We have designed a "nanoparticle within a nanoparticle" model wherein docetaxel is conjugated into a nano-particle, which is subsequently enveloped by a liposome coat containing SK1 inhibitors and conjugated to prostate-targeting peptides. This design is expected to release the selective inhibitor which primarily downregulates SK1 (suppressing chemoresistance) and the subsequent release of the chemotherapy, which induces PCa cell apoptosis. This targeted approach also esures the delivery of the drugs at the diseased site. The developed nanospheres will be tested using in vitro (2D and 3D) prostate cancer models established in our lab and their physiological role will be verified using orthotopic mouse tumour model. It is our hope that these nano-spheres combining novel SK1 inhibitors and standard docetaxel chemotherapy will offer survival benefit for patients with hormone refractory chemoresistant prostate cancer.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Evaluating synergy between deregulation of the PI3-kinase, Wnt and Ras pathways in prostate neoplasia
Funder: Prostate Cancer UK

Abstract: Several key signal transduction pathways have been implicated in the development, progression and relapse of prostate cancer, however the precise roles of these pathways and the interplay between them remain poorly understood. In this proposal we aim to use mouse models and human patient samples to define the extent and consequences of deregulation of the PI3-kinase, Wnt and Ras pathways either alone or in combination. In particular, we wish to define the influence of these pathways upon the putative cancer stem cell (CSC) population to address the hypothesis that deregulation of these pathways drives both tumour growth and progression by directly expanding the CSC population. Using cre-lox based mouse models, we will mutate Pten, Ki-Ras and -catenin alone and in combination within the prostate epithelium. We will subsequently define the effects of these mutations upon tumorigenesis, CSC expression profiles and ‘stemness’. In parallel, we will determine the extent to which these pathways are coincidently deregulated in human disease and correlate this with the CSC expression profile and disease status. Together, these studies will address the roles of three key pathways and their impact upon the stem cell/cancer stem cell populations that will ultimately permit both risk identification and stratification.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Targeting ABC transporter autocrine loop in prostate cancer
Funder: Prostate Cancer UK

Abstract: The identification of molecules and proteins involved in prostate cancer development and progression is critical in order to identify novel potential targets and to develop novel and more active drugs. ATP-Binding Cassette (ABC) transporters have been found overexpressed in several cancers including prostate cancer. This family of proteins has an established role in chemoresistance or multidrug resistance. Work in our lab has recently unraveled a novel involvement of these proteins in cancer progression. Indeed, we have demonstrated that a member of the ABC transporter family is involved in an autocrine loop by which prostate cancer cells can stimulate their own proliferation. The aim of this proposal is to test specific inhibitors of ABC transporters on prostate cancer cell proliferation in vitro and in vivo models of prostate cancer. Based on our previous work and preliminary results supporting this application we will test the effect of different compounds, inhibitors of GPR55 and the ABC transporter ABCC1, on prostate cancer growth in mice. The main goal of our research program is to improve therapeutic options, and ultimately survival, for patients diagnosed with prostate cancer. We believe that the results anticipated from this innovative proposal have the potential to provide novel therapeutic options.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS