NIHRDataInsights/HRCSData huggingface dataset:
Title: Molecular imaging biomarkers of gemcitabine resistance in advanced mouse models of pancreatic adenocarcinoma.
Funder: Pancreatic Cancer UK

Abstract: Molecular imaging, especially PET and SPECT imaging as non-invasive whole body techniques, has the potential to increase pancreatic cancer patient survival rates by aiding early detection and by early evaluation of chemotherapy efficacy. Especially those diagnosed with pancreatic adenocarcinoma (PDAC) continue to display some of the worst survival rates of any cancer patients. The main causes for poor survival are that these tumours are often difficult to diagnose at the outset, are non-resectable by the time they present with symptoms and are remarkably chemo- and radio-resistant. The role of PET imaging, e.g. using 18F-FDG, is being increasingly investigated in diagnosis of PDAC and for assessing treatment response. One of the key challenges in developing imaging trials in pancreatic cancer is the difficulty to correlate results with the gold-standard (histopathology) as repeated biopsies are difficult to obtain, especially where the tumour is confined to the pancreas. Furthermore, development of novel radiopharmaceuticals (‘contrast agents’) for PET and SPECT has thus far been performed only in xenograft-bearing athymic mice. The use of genetically engineered mouse models of pancreatic cancer (such as the well-studied KPC-model) to evaluate novel radiopharmaceuticals would allow us to image pathways/response in a mouse model which are more representative of the clinical setting. We propose to use KPC-mice to develop using PET/SPECT (1)novel methods for early detection of pancreatic cancer, (2) novel methods to determine early response to gemcitabine chemotherapy. The advantages of the KPC-mice are manifold: tumours present similar genetic mutations and sequence of tumorigenesis compared to human PDAC; many, but not all, KPC tumours are resistant to gemcitabine. The use of KPC-mice and other engineered PDAC models, will allow us to perform co-clinical trials, in parallel to those set up by our clinical trials colleagues. To explore early detection by imaging, we will use 18F-FDG, and a novel agent developed in our lab, 111In-cCPE, which targets Claudin-4, a tight junction component increasingly upregulated throughout PDAC development. We will repeatedly image KPC-mice by PET/CT (18F-FDG) or SPECT/CT (111In-cCPE) every month from weaning to death, throughout their lifetime. For our therapy efficacy studies, we will use KPC mice with existing tumours, treat them with gemcitabine, a drug regularly used for PDAC treatment. We will perform imaging before and after gemcitabine treatment using 18F-FDG and 111In-anti-gH2AX-TAT imaging. The latter, a novel compound we developed over the past years, visualizes the increasing amount of DNA double strand breaks.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Scanning of pancreatic cancer stem cells for personalised medicine
Funder: Pancreatic Cancer UK

Abstract: New hopes for more effective treatments in pancreatic ductal adenocarcinoma (PDAC) have been spurred by the recent identification of pancreatic cancer stem cells and demonstration of their pivotal role in tumour development, spread and resistance to current therapies. Thus, in order to more effectively treat PDAC we do not only have to consider intertumoural heterogeneity but also intratumoural functional hierarchy. This does not only require the identification of novel therapeutic targets against cancer stem cells, but also tailoring of these treatments to the specific functional characteristics of each individual tumour. We have identified and further exploited an inherent feature of cancer stem cells, namely autofluorescence, which provided the basis for a novel cancer stem cell-focused drug response screening platform. This early phase low-throughput screening assay analyses freshly isolated pancreatic cancer stem cells and their more differentiated progenies. Beyond its primary utilization as a centralized screening service for hospitals to provide personalized medicine for individual patients, the platform could also be used as a screening service for pharmaceutical companies to facilitate pre-clinical decision-making and as a surrogate endpoint for early phase clinical trials. Consequently, we are seeking funding to take this discovery to the next step, specifically to further develop the platform for clinical use and demonstrate its predictive power across a representative panel of PDAC patients.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Targeting the thioredoxin system in pancreatic cancer to improve radiotherapeutic response.
Funder: Pancreatic Cancer UK

Abstract: The research group led by the PI has a keen interest in regulation of redox homeostasis in cancer, with a particular focus on the Thioredoxin (Trx) system of proteins. They have shown, primarily in breast cancer (but also other tumour types, e.g. Ovarian cancer), that expression of Trx proteins in patient samples can provide prognostic information and can be predictive of response, to both chemo- and radiotherapy. They have also shown that targeting the Trx system, e.g. by siRNA, can radiosensitise breast cancer cells in vitro. A major aim of the current proposal is to determine if the Thioredoxin system also plays a similarly important role in pancreatic cancer. A new collaboration, with colleagues based in the School of Chemistry at the University of Nottingham (Prof Chris Moody), has recently commenced - Prof Moody and his team have developed a new class of agent that specifically targets the Trx system – preliminary data show that these drugs are potent in pancreatic models, in vitro and in vivo, as single modality. Our work with the Trx system suggests that targeting this system will increase radiotherapeutic response in pancreatic cancer – it is this hypothesis that is the main aim of the current proposal. We will conduct a variety of in vitro drug/radiation clonogenic survival combination experiments to assess radiosensitisation in a panel of pancreatic cell line models and will also, via a collaboration with colleagues at the University of Manchester (Prof Kaye Williams), assess enhancement of radioresponse in vivo. As indicated above, we have determined that the drug target is expressed in breast and ovarian cancers and that particular subsets of patients can be stratified into those more likely to respond to Trx inhinbitors (a personalised medicine approach) – we have tissue microarrays of pancreatic tumours available locally and will conduct such IHC target validation studies in pancreatic cancers. We are confident (from our previous track record and by the multidisciplinary collaborative approach being used) that this grant will, if funded, generate significant results that will lead to a number of publications and pave the way for further project grant submission to continue development of these novel agents for the treatment of pancreatic cancer.


Research activity codes: 5.1 PHARMACEUTICALS;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Characterization of Subtype-Specific Metabolism and Associated Therapeutic Targets in Pancreatic Ductal Adenocarcinoma
Funder: Pancreatic Cancer UK

Abstract: Background: Clinical responses to chemotherapy in patients with pancreatic ductal adenocarcinoma (PDA) are poor and, in comparison with other solid organ tumours, personalised therapeutic options are very limited. Variable therapeutic responses observed in solid tumours can be attributed to molecular heterogeneity between tumours, but a full molecular classification of PDA is lacking. Defining molecular subtypes holds the promise of discovering and defining prognostic and predictive biomarkers that can be used to stratify patients and target specific drugs to tumour subtypes based on diagnostic tests. Preliminary data: We previously classified PDA tumours and cell lines into three major gene expression subtypes with different prognostic and therapeutic characteristics, but classification is incomplete and full biological characterisation of the subtypes is lacking; this is a barrier to developing biomarkers and matching appropriate therapies. In order to overcome the relative paucity of available tissue samples and data available for PDA, and to understand the ontogeny of these subtypes, we performed cross-organ comparisons of PDA and colorectal cancer (CRC) subtypes in silico and in doing so have revealed two additional PDA subtypes of potential clinical relevance. Aims and Methods: The aims of this proposal are to: a) validate the existing and new PDA gene expression subtypes in patient samples and cell lines (microarrays and massively parallel RNA sequencing) and cross compare them with CRC subtypes (in silico); b) perform an integrated in silico analysis of the gene expression and metabolomic profiles of PDA subtypes using microarrays and targeted liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS) of cell lines; and c) identify subtype-specific targeted therapeutics using a drug repositioning approach by screening publicly available drug response data from a panel of PDA cell lines (n=30) screened with a plethora of therapeutic compounds (n100). Clinical and Future Use: This combined experimental and computational approach will lead to extended definition of PDA subtypes and fully exploit existing data using the novel cross-organ comparative approach. Subtype-specific metabolic characterisation not only characterises the underlying tumour biology but also provides leads for diagnostic/predictive biomarkers that can be validated in follow-on studies. Finally, this study could reposition a wider range of clinically available drugs (including those available for CRC) in vitro and match them to definable subtypes to guide selected future preclinical studies and clinical trials. Overall, this proposal will help to identify novel personalized diagnostic and therapeutic strategies for patients with this devastating disease.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Defining a new role for JNK signalling in acinar plasticity
Funder: Pancreatic Cancer UK

Abstract: Genetic alteration of components of the c-Jun NH2-terminal kinase (JNK) signalling pathway is frequently observed in human pancreatic cancer genomes. We have recently revealed the pathogenic significance of this observation in mice. Notably, the malignant phenotype caused by the loss of JNK activity in the exocrine pancreas harbouring KrasG12D mutation coincided with widespread acinar-to-ductal metaplasia (ADM). This process involves the de-differentiation of acinar cells towards duct-like progenitor cells that become sensitive to oncogenic transformation. Analyses of various mouse models combined with epidemiological and patient-derived observational studies have supported the idea that neoplastic lesions in the pancreas can develop from acinar cells through ADM. Therefore, we propose that the JNK pathway suppresses pancreatic tumour development by antagonising acinar de-differentiation. To test this hypothesis, the overall objective of this project is to further analyse the role of JNK signalling in the reprogramming of terminally differentiated acini. Specifically, this study will have two aims: 1) To assess JNK signalling as an essential regulator of acinar cell identity. We will develop acinar cell culture models to dissect the functional role of the JNK pathway in controlling the ability of acinar cells to de-differentiate and to acquire features of pancreatic progenitor duct-like cells with increased survival and self-renewing capabilities. 2) To identify components of the JNK pathway implicated in acinar cell fate decision. Downstream targets of JNK signalling that control acinar plasticity will be identified using a genome-wide expression analysis approach. At the end of this project, we anticipate that we will have underpinned the cellular basis of the tumour suppressive function of JNK signalling in the pancreas and advance our understanding of the mechanisms that constitute a barrier to the acquisition of acinar "stemness" at the molecular level. The next step will be to use this information to develop novel tools for early diagnosis and to rethink the possibility of exploiting acinar plasticity to manage pancreatic tumours. For example, can we mitigate tumour cell aggressive behaviour by activating JNK signalling as a mean to enforce cellular differentiation?


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Over three years to study biological mechanisms of disease relapse in childhood medulloblastoma
Funder: Action Medical Research

Abstract: Medulloblastoma (MB) is the most common malignant brain tumour of childhood affecting around 100 children each year in the UK. It is one of the largest contributors to cancer deaths in children with survivors often suffering therapy related long term health problems MB typically occurs in children under the age of ten but may occur in older children. All patients diagnosed with MB will undergo intensive treatment for 8-12 months consisting of surgery, radiotherapy and chemotherapy. None of these therapies come without side effects which are often more marked in the younger child due to the vulnerability of the developing brain. Those who survive will be left with varying degrees of learning disability, growth and development problems to name but a few. Sadly, in around 40 per cent of patients treated for MB the condition will recur. At present, the majority of patients with relapsed medulloblastoma (relapsed MB) will die from their disease, as most existing treatments for relapsed MB can only prolong life and are not a cure. This research project will investigate those patients who suffer from relapsed MB. The researchers will establish a group of up to 50 cases of patients with relapsed MB, where tumour tissue samples have been taken both at diagnosis and also when the cancer relapsed. They will then be able to anonymously review each case and look at factors such as the patient's age at diagnosis, time to relapse and types of treatment received. Also, they will be able to study the tumour samples taken from each patient at diagnosis and relapse using a variety of laboratory techniques and compare and correlate these results with the clinical information. This project will look at the clinical, pathological and genetic features of relapsed MB, which will provide essential insights into the biological mechanisms underlying disease relapse. The purpose of this study is to identify genetic patterns that detect those children who are more likely to suffer from relapsed MB. This will enable their treatment to be intensified as soon as the disease is diagnosed, with the hope of preventing relapse. It will also identify potential drug targets in relapsed disease and provide the basis for new therapeutic trials aimed at improving the response to treatment. The long term aim is to improve the lives of patients suffering from relapsed MB whilst also giving children the best opportunity of surviving their disease.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Improved initial diagnosis and localisation of prostate cancer through MRI and ultrasound data fusion
Funder: Prostate Cancer UK

Abstract: This proposal aims to test if combining MRI with ultrasound information can improve the initial diagnosis and localisation of prostate cancer. This will lead to improved cancer staging, improved localisation of biopsies and improved therapy. It is expected that these aspects will be beneficial to men affected by prostate cancer as follows: improvements in staging will lead to improved decisions about treatment; improved biopsies could reduce the number of biopsies and increase the accuracy of diagnosis from those taken; improvements in treatment could be in the form of better targeting during radiotherapy and/or a better understanding of how cancer is affected by treatment.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Targeting AMACR to treat castrate-resistant prostate cancer
Funder: Prostate Cancer UK

Abstract: The project is to study an important protein in prostate cancer, known as AMACR. High levels of the AMACR protein are found in all prostate cancers, and reducing the levels or interfering with its function stops the cancer from growing. The initial aim is to establish exactly what the protein does in the cancer, and how it works. More importantly the study plans to produce new approaches that will stop the protein from working, which can be later optimized to produce new prostate cancer treatments. Current therapies eventually fail as the cancer stops responding to hormone therapy and develops drug resistance, usually about 2 years from starting treatment. This failure results in rapid cancer progression and ultimately, death. Interfering with AMACR has been shown to stop cancers becoming drug resistant and our approach should prevent treatment failure and hence extend life-expectancy. The project will ultimately tell us what the AMACR protein does, how it does it, and will start the development of new medical treatments based on this knowledge.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Optimal radiation targeting of PTEN deficiency in castrate resistant prostate cancer in combination with modulators of DNA damage
Funder: Prostate Cancer UK

Abstract: This project will investigate a new, more effective way to treat prostate cancer by improving the effects of current radiotherapy techniques. Treatment with drugs that prevent repair of the DNA following radiation exposure will be tested to try and stop tumour resistance to radiotherapy. The study therefore aims to try and make these tumours more sensitive to radiotherapy. The first drug that will be tested stops a protein called PARP from helping in the repair of damaged DNA. The second drug that will be tested stops a protein called ATM which normally detects DNA damage at an early stage and triggers its repair. Tests will also be performed to ensure that none of these combinations of drugs and radiation damage normal cells and tissues. This will allow design of the most optimal treatment. The project could eventually lead to new treatments for advanced prostate cancer that is no longer responding to other treatments, and for which currently there is no effective cure.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: The Androgen Receptor Amino-terminal Domain: A Novel Drug Target for the Treatment of Castrate Resistant Prostate Cancer
Funder: Prostate Cancer UK

Abstract: This project aims to identify and develop new drug targets to block the activity of a protein inside the prostate called the androgen receptor. This protein interacts with testosterone and is known to drive the growth of prostate cancer in the presence of testosterone, but also in the absence of testosterone and when the cancer is no longer responding to hormone therapy. The aim is to demonstrate that the androgen receptor protein represents a novel drug target. The eventual failure of current hormone-based therapies means there are few treatment choices for men with advanced, drug resistant disease. The present proposal offers the potential of identifying new drug targets that will allow the androgen receptor to be switched off in both the presence and absence of hormones. This will block the activity of the androgen receptor in cells which are no longer responding to hormone treatment. The plans described would provide a complement or alternative to current hormone-based treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The use of a novel technology platform to create a DNA vaccine for Prostate Cancer
Funder: Prostate Cancer UK

Abstract: Despite the progress in prostate cancer vaccination, there is a ‘need’ for a more potent effect through the activation the cell-mediated immune response, primarily through cytotoxic T lymphocytes (CTLs). It has been well documented that DNA vaccination is a highly potent strategy. The ‘problem’ is that there is no effective delivery system to transport intact DNA to the nucleus of antigen presenting cells to evoke the desired immune response. The ‘solution’ to this problem is in the two-pronged approach of our system. Firstly, a peptide termed PEP has been designed to protect DNA from degradation and ensure delivery to the nucleus. Secondly, the use of dissolvable polymer microneedles in a transdermal patch will ensure that the PEP/DNA nanoparticles reach the high antigen presenting cell population in the skin to evoke maximum effect. Using DNA that codes for several tumour-associated antigens specific to prostate cancer, we will create a highly potent targeted DNA vaccine by exploiting our unique platform technology. Through a series of objectives we will demonstrate how effective this DNA vaccine is as both a therapeutic and prophylactic for those suffering from and at risk of prostate cancer.


Research activity codes: 3.4 VACCINES
Health categories: CANCER AND NEOPLASMS
Title: The FAS/AMPK axis as a determinant of Prostate Cancer Progression
Funder: Prostate Cancer UK

Abstract: Our studies at KCL along with our Dana Farber Cancer Institute and Manchester University collaborators’ studies indicate growing evidence of lipid metabolism’s role in prostate tumor development and progression. We will investigate underlying mechanisms for the associations between obesity, lipid abnormalities, and prostate cancer (PCa). Plus, this project will study fatty acid synthase (FAS) and PCa aetiology from a basic and clinical research angle using PCa cells and tissue. Our aim is to identify whether there are underlying molecular mechanisms that link FAS activity with migration and invasion of PCa cells. We aim to: (1) test whether elevated FAS increases PCa cells’ invasive potential; (2) test whether commercially available FAS inhibitors or reduced FAS expression can inhibit PCa cell migration and invasion; (3) identify novel FAS associated cytoskeletal signalling pathways that may lead to increased invasive potential. We also aim to identify how the degree of deregulation of the FAS/AMPK system affects PCa progression. In a cohort of 400 PCa patients, we will link immunohistochemical assessment of FAS over-expression and AMPK activation at time of diagnosis with progression to metastasis by conducting multivariate logistic and Cox proportional hazards regression analysis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS