NIHRDataInsights/HRCSData huggingface dataset:
Title: Validation and multiplexing on novel prostate biomarkers
Funder: Prostate Cancer UK

Abstract: Background: Prostate specific antigen (PSA) is a protein found in blood and urine and is raised in men with prostate cancer. The current test detects raised levels in blood and men with high levels go on to have further tests including prostate biopsies. However, because prostate cancer has lots of different causes, PSA isn’t very specific and can be raised with infection or benign prostate disease. As a result, as few as 1 in 4 men with an elevated PSA actually have prostate cancer and therefore many men undergo unnecessary tests and worry. Methodology: Dr Whitaker’s team’s aim is to make the test used for prostate cancer better so that it is more accurate at diagnosing prostate cancer. They hope it will also be able to differentiate between more and less aggressive prostate cancers and tell us if someone will respond well to treatment. They have already identified and validated three novel biomarkers in at least two independent groups of patients. All three of these biomarkers have shown the ability to predict which patients will have aggressive disease which is more likely to relapse following surgery. If this is known prior to surgery then patients with aggressive disease could be offered chemotherapy or radiotherapy and reduce the chances of the cancer returning. Because these biomarkers are completely new there are very few reagents available to study them and they need to be produced for us in a bespoke way. Further funding would allow us to get the reagents made so that we could develop a way of measuring these proteins in blood and urine. We already have all of the tools in place to make this test very quickly once the reagents are available. There is currently no test for how aggressive a prostate cancer is likely to be but using this ‘super test’ we hope to be able to say which patients should get more aggressive treatment sooner while those without aggressive disease will be able to avoid treatment. We would use additional funding to combine tests for MSMB, GDF-15, hK2 and the novel biomarkers into a single test that can be performed on one sample The Implications and Need for funding: This is a very important piece of research as we are yet to find accurate means of prognosis. If we can make the test for prostate cancer prognosis and diagnosis better then fewer men will need to have unnecessary biopsies and suffer the worry associated with a potential diagnosis of cancer. If their improved test can tell doctors which men have aggressive prostate cancer then they can be offered more aggressive treatment regimes, whereas men with less aggressive cancer would be able to avoid unnecessary treatments.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Proteomics of Human Prostate Cancer Stroma
Funder: Prostate Cancer UK

Abstract: Stromal tissue surrounds the glandular structures of the prostate, and is composed of smooth muscle cells, fibroblasts and vascular cells. During carcinogenesis, stroma is altered, becoming dominated by myofibroblastic cells. Such myofibroblasts likely arise from the differentiation of resident fibroblasts, and mechanisms triggering such differentiation point to a key role for TGF. Clinical data show stromal-activation as a highly significant negative prognostic indicator. Stromal-myofibroblasts drive tumour progression by secreting tumour-growth and angiogenesis promoting factors. However xenograft models reveal that not all stromal-myofibroblasts exhibit this function; suggesting differences in myofibroblast phenotype are important for disease outcome. Relevant tumour-promoting features of myofibroblasts are poorly defined, and other than a handful of markers to identify myofibroblasts, detailed data on normal vs disease stroma in human prostatic cancer are currently lacking. Mechanisms driving differentiation of normal to diseased phenotype also remain unclear. We will address this knowledge gap, using primary patient-matched cultures of normal (fibroblasts) and diseased (myofibroblasts) prostate stromal cells. We will better define phenotypic differences using a quantitative global proteomics approach. The differentially expressed proteins will be histologically validated, and their expression in low vs high risk local prostate cancer examined. Informed by our supporting data, we will examine cancer-derived nanovesicles (exosomes) that express a potent membrane form of TGF as a mechanism driving differentiation towards the diseased myofibroblastic phenotype. The study will reveal novel biomarkers of stromal aberrations that could aid in predictive assessment of disease severity. Mechanisms responsible for fibroblast differentiation will be determined, highlighting new therapeutic targets to impede tumour progression, and prolong life.


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: Investigation of the role of nuclear IGF-1R in prostate cancer
Funder: Prostate Cancer UK

Abstract: The type 1 insulin‐like growth factor receptor (IGF‐1R) undergoes activation at the cell surface to mediate proliferation and cell survival. IGF‐1R is over‐expressed in primary prostate cancer and bone metastases, and IGF‐1R targeting blocks prostate cancer growth. We have reported that IGF‐1R depletion enhances radio‐sensitivity of prostate cancer cells, and delays repair of radiation‐induced DNA damage. We hypothesise that the ability of IGF‐1R to mediate radioresistance may be associated with its ability, recently recognised by us and others, to undergo nuclear translocation. Nuclear IGF‐1R does not co‐localise with DNA damage markers, but is retained on chromatin of damaged cells, suggesting a role in the transcriptional response to damage, rather than an effector role in repair. To study IGF‐1R translocation, we generated modified IGF‐1Rs that can signal from the cell surface, but do not accumulate in the nucleus. Preliminary data indicate that cells expressing these modified IGF‐1Rs show reduced survival after ionising radiation. We will take three approaches to investigate the contribution of nuclear IGF‐1R to the DNA damage response. First, we will test whether wild‐type or modified IGF‐1Rs rescue from radio‐sensitisation and DNA repair delay induced by depletion of endogenous IGF‐1R. Secondly we will validate IGF‐1R genomic binding sites that we have identified by ChIP‐seq. Finally, we will assess IGF‐1R immunohistochemistry on prostate cancer microarrays, including cancers from patients treated with radiotherapy, to assess associations with clinical parameters including radio‐resistance. These investigations will provide new insights into IGF‐1R function, and will guide use of IGF‐1R inhibitors in prostate cancer therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Is there an aetiological role for "transformed" stem cells in human benign prostatic hyperplasia?
Funder: Prostate Cancer UK

Abstract: Benign prostatic hyperplasia is a common disease of unknown aetiology. When used as a benign control for prostate cancer studies, we unexpectedly found that only the epithelial stem cell component and their immediate (transit amplifying) daughter cells from BPH tissues expressed very high levels of telomerase, which implied that stem cell expansion may play a role in the excessive proliferation seen in BPH. In addition, knockdown of hTERT expression by siRNA induced replicative senescence in the BPH SC. We propose to investigate the ability of these expanding SC to influence stromal cell proliferation, as frequently seen in the commonest BPH type, to quantify the phenotypic effects of telomerase inhibition in the epithelial component (and the effects of this inhibition on stromal cell fate), as a prelude to the either the direct inhibition of telomerase, or the blockade of a resultant activated signalling pathway as a novel therapy. Finally we propose to develop and test the effects of telomerase inhibition in the best natural animal model of BPH, the dog, to expedite pre-clinical testing of this novel therapeutic strategy.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Over three years: Improving the scans of children with brain cancer through identifying biomarkers of survival in brain tumour tissue
Funder: Action Medical Research

Abstract: Background_x000D_ Apart from blood cancers such as leukaemia, brain cancer is the most common form of cancer affecting children. For every three children diagnosed with brain cancer, one will die - the highest rate out of all childhood cancers. Those that do survive often have neurological complications, caused by the cancer or its treatment, which will affect them for the rest of their lives. Quick and accurate diagnosis of brain tumours means that children can be given the right treatment as soon as possible to reduce the risk of disability or death. New technology, known as functional imaging, means that both diagnosis and the likely outlook for children with brain cancer can be established with a non-invasive scan without the need for surgery. _x000D_The research project_x000D_ The team have used a non-invasive scanning technique called magnetic resonance spectroscopy (MRS) to measure the chemical profiles of brain tumours in children. They have identified certain chemicals (biomarkers) which indicate how aggressive a tumour is and the likely chance of survival. The aims of this new study are to confirm these early results and find more biomarkers which indicate the chance of survival in children with brain cancer. A sophisticated laboratory technique similar to MRS will be used on brain cancer tissue samples to determine the concentrations of about 50 possible biomarkers. The team will use frozen tumour tissue samples which have been collected previously, plus any new samples obtained during the course of the study. They will then see how accurately these biomarkers can be measured without taking tissue samples, using non-invasive, highly sophisticated MRS scans in children with brain cancer. The use of biomarkers to establish diagnosis and outlook will help doctors to provide the best treatment at the earliest opportunity and could lead to increased survival in children with the most aggressive tumours. It may also help to identify children who need less intensive treatment and therefore protect them from treatment-related neurological disability. The technology developed could also have a great impact on how tumours in other parts of the body in both children and adults are diagnosed and treated.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Over three years to study 177Lu-DOTATATE combined with radiosensitisers to enhance targeted radiotherapy of neuroblastoma
Funder: Action Medical Research

Abstract: Background Neuroblastoma is a cancer that arises in nerve cells of infants and very young children. Around 100 new cases are diagnosed each year in the UK, mainly in children under the age of five years. Although neuroblastoma is frequently present from birth, it may not be diagnosed until the growth of tumours begins to affect nearby tissues, for example, a tumour in the chest may cause breathing problems Neuroblastoma often starts in the abdomen, but can spread rapidly to other parts of the body including lymph nodes, liver, skin, brain, bones and bone marrow. One way of treating this type of cancer is molecular radiotherapy, where radioactive agents bound to cancer-seeking drugs are injected into the bloodstream. Unlike conventional radiotherapy which uses high energy X-rays from a machine outside the body, molecular radiotherapy can be used to treat not only primary tumours, but also secondary tumours which may be too small to detect with cancer scans. The research project The aim of this research is to find ways to make molecular radiotherapy more effective in children with neuroblastoma. The team's strategy is to find the best way to combine a radioactive drug (177Lu-DOTATATE) with other drugs called radiosensitisers which make the cancer more susceptible to radiation-induced damage. Having established the most effective and safest combinations in cell lines, tissue models and then a mouse model, they will then collaborate with clinical colleagues to design clinical trials of 177Lu-DOTATATE combined with radiosensitisers in children with neuroblastoma. Action Medical Research and the Neuroblastoma Society are together funding this study.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Modelling Mammographic Normality - Detecting Abnormalities for Computer Aided Detection/Diagnosis Systems
Funder: Division for Social Care and Health Research (Wales)

Abstract: About 8-12% of all women will develop breast cancer in their lifetime. Early detection relies on double-reading by expert radiologists of mammograms It should be noted that cancer detected within screening programmes makes-up less than one percent of the cases (i.e. radiologists mainly observe normal cases). It has been shown that radiologists benefit from the use of computer aided detection/diagnosis (CAD) systems and unnecessary recalls are reduced. Current CAD systems rely on the detection of specific mammographic abnormalities and each type of abnormality requires a dedicated approach. To date, this has resulted in a high sensitivity/specificity for some types of abnormalities, but none of the current systems have the ability to prompt for the full range of abnormality types. The proposed research will develop a mammographic model representing the normal breast, based on mammograms containing no abnormalities. The model uses local information and will consider spatial location within the breast, and will be able to model variations in mammographic tissue. This normality model will be used for the detection of abnormalities by estimating the deviation from the model resulting in prompts for CAD systems This work has the potential therefore to benefit both patients and radiologists by improving current CAD systems


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Enhanced T Cell receptors for cancer therapy
Funder: Division for Social Care and Health Research (Wales)

Abstract: T-cells are the main immune cells responsible for recognising and eliminating foreign cells, including tumours. Cytotoxic T-lymphocytes (CTLs) have “weapons” that enable them to directly kill cells which are cancerous or infected with a pathogen. Unfortunately, natural CTLs are not optimally programmed to kill tumours because they bind to cancer protein fragments weakly, compared to CTLs that clear pathogens. We wish to improve a patient’s own CTLs to make them as effective as those that rid our bodies of viruses. This will be done by genetically modifying the T-cell receptors (TCRs) on the CTL surface responsible for recognising cancer cells. These enhanced TCRs can be introduced into patient T-cells to reprogramme them to attack the patient’s cancer cells. I will examine the effectiveness of reprogrammed T-cells using TCRs exhibiting up to >300,000-fold enhancement in their binding to several different cancer targets. I will also examine the effect of introducing these TCRs into a different T-cell type called ‘helper’ T-cells to further enhance the anti-tumor activity. These studies will establish what the optimal TCR is for subsequent TCR gene transfer therapeutic approaches and are expected to make a significant contribution to the TCR gene transfer approach in cancer immunotherapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: PET Radiotracer Chemotherapeutics -Towards Individualised Anticancer Care
Funder: Division for Social Care and Health Research (Wales)

Abstract: A major limitation of cancer chemotherapy is that it not only kills the cancer cells that are multiplying, but also damages any normal dividing cells. Sometimes, the undesirable toxicity of treatment can outweigh the intended therapeutic effects. The ability to predict, prior to treatment, which patients will fail to benefit and/or experience significant side-effects has enormous potential benefits, including the personal costs of unnecessary or unpleasant treatment and the economic benefits of more effective use of resources. PET, Positron Emission Tomography, is a non-invasive nuclear medicine imaging technique that produces a three-dimensional image of functional processes in the body. Gemcitabine is a chemotherapeutic drug extensively used to treat a wide range of cancers including pancreatic, breast, ovarian, and lung. This project seeks to manufacture the first radioactively-tagged gemcitabine for PET imaging. Visualisation of this will assist clinicians (via real time computer images) in advising individual patients on whether this treatment is likely to be of benefit. As a result, thousands of cancer sufferers will be able to receive treatment which is tailored to their individual needs much more accurately, quickly and effective in tackling their condition. This will provide a major improvement in both curative treatment and palliative chemotherapy.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: PET bio-marker imaging in response to novel targeted anti-cancer therapy in a clinically applicable mouse model of colon cancer.
Funder: Division for Social Care and Health Research (Wales)

Abstract: Thanks to the development of new drugs cancer may be increasingly viewed as a chronic illness, with patients commonly demonstrating an improved survival despite living with incurable disease. Sadly however, the prohibitive cost of novel anti-cancer agents effectively reduces patient access to potential life prolonging therapy. A means of identifying which cancer patients are most likely to benefit from a specific drug forms the basis of personalised medicine, ensuring that scarce resources are used to maximum benefit. This approach has the added benefit of protecting patients from the potential harmful effects of otherwise ineffective treatment. As a result, tests for cancer patients are being developed to help identify whether patients’ tumours will respond to drug treatments. Significant investment has been made in Wales to make PET scanning available for cancer patients. PET scanning is a technique which enables metabolic or biologic imaging of cancers. We now have a unique opportunity to bring together PET imaging and cutting edge science to apply this non-invasive test to patients in order to find out who is most likely to respond to new and expensive anti-cancer treatments. As a step towards this goal we will first be testing the usefulness of PET imaging to provide an early indication of a new anti-cancer drugs proven ability to counter growth signals responsible for tumour growth in a mouse model of colon cancer.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: CANCER AND NEOPLASMS
Title: Quantifying disease burden in patients with cancer using tumour-specific genomic rearrangements.
Funder: Department of Health (England)

Abstract: Cancer is caused by the accumulation of genetic damage (mutations) in cells within a particular organ. These mutations are only found in the cancerous cells, and therefore could be used to track the malignancy during treatment. Advances in DNA sequencing allow the high-throughput identification of these mutations from any cancer sample in a clinically relevant time-frame. As tumour cells die, they release their DNA into the bloodstream. We propose to use the new generation of genetic sequencing technologies to identify a particular class of mutations caused by the abnormal rearrangement of chromosomes in patients with breast cancer and colorectal cancer. From these rearrangements, we will develop assays to detect DNA from each patient's cancer that has been released into the bloodstream. Such assays will be highly specific (minimal risk of falsely positive results) and sensitive (capable of detecting one copy of tumour DNA in many millilitres of blood). We will measure the amount of disease using blood samples collected before surgery, after surgery, during chemotherapy and at regular time-points post-therapy. We will therefore be able to assess the ability of this approach to identify high-risk patients before treatment begins, to monitor response to treatment and to predict cancer relapse before it is clinically apparent.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Development and application of a targeted array test to diagnose and direct therapy in haematological cancers.
Funder: Department of Health (England)

Abstract: Leukaemia is a form of cancer that arises in the bone marrow or lymphoid organs. There are different types of leukaemia that reflect which blood cells are affected. Although several treatments are available, many people do not respond to treatments or experience severe side effects. It is important to understand the type of leukaemia a patient has and identify whether they are likely to respond to these before administering treatments that may be ineffective or cause adverse reactions. This is particularly the case for emerging therapies which are extremely expensive and must be used judiciously. In order to identify these different patient populations we need to use sensitive tests at the time of diagnosis. However, the genetic tests that are used currently are not precise enough. Advances made in genetic research are capable of delivering more sophisticated tests, but the techniques need to be specifically adapted for use in a clinical setting. We will develop a new technology that uses microarrays to test different regions of the genome and use this information to select appropriate treatments for patients, thereby improving their overall well-being. This will be suitable for use in hospital laboratories worldwide.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Topical tropomyosin kinase (TRK) inhibitor as a treatment for inherited CYLD defective skin tumours
Funder: Department of Health (England)

Abstract: This project aims to evaluate the ability of a new ointment to treat an inherited skin tumour condition. Patients in families with this condition carry an error in their DNA that results in the development of multiple skin tumours on the face, scalp and trunk. These tumours (collectively called CYLD defective tumours) are disfiguring, can be painful, and may ulcerate and bleed. Surgery is the only available treatment, and up to 1 in 4 female patients with this condition undergo removal of their entire scalp to manage this condition. We have recently discovered an abnormal signal in the tumour cells called TRK. This signal is recognized to give tumour cells the ability to survive, and blocking it with drugs called TRK inhibitors result in the tumour cells dying in laboratory tests. We propose a trial of an ointment formof TRK inhibitor as a means to reduce tumour growth in these patients. We havepartnered with a drug company (Creabilis) who have already produced this ointment (called CT327) for trials in skin conditions. Should this be effective, it potentially could be used by patients in the future to treat early tumours and reduce the number of operations they would otherwise undergo


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