NIHRDataInsights/HRCSData huggingface dataset:
Title: Does aspirin increase the clinical response to pre-operative chemo-radiotherapy [CRT] in rectal cancer?
Funder: Medical Research Council

Abstract: Colorectal cancer remains the second most common cause of cancer-related death in the UK. Although the success of surgical resection of rectal tumours has improved significantly with the use of pre-operative chemo-radiotherapy (CRT), the reason why some patients respond better to CRT than others remains unknown. There is an urgent need, not only to develop new treatments, but also to find ways to improve the response to existing therapies. Although evidence for the use of aspirin in colorectal cancer prevention is mounting, its use as an adjuvant to established therapies has been largely overlooked. We recently discovered that aspirin can inhibit the BCL-3 pro-survival factor, and suggest this may contribute to its chemopreventive action. In understanding the action of non-steroidal anti-inflammatory drugs (NSAIDs), the aim of these experiments is to demonstrate the importance of targeting BCL-3 function as well as COX/PGE2 for sensitizing cells to irradiation. Combining mechanistic studies in human colorectal cancer cell lines with results from an ongoing clinical cohort study, we will investigate whether NSAIDs that inhibit both COX/PGE2 and BCL-3 signalling pathways are more effective than COX-2 selective inhibitors in sensitising cells to gamma-irradiation. The role of BCL-3/beta-catenin signalling in promoting a cancer stem cell related (SCR) phenotype, and the impact of SCR protein expression on radiation sensitivity will be investigated. Results from the in-vitro study will be validated in samples from rectal cancer patients undergoing pre-operative CRT. This work aims to establish a novel use for NSAIDS as therapeutic adjuvants, increasing the tumour response to conventional therapy. In understanding the mechanism of action we will identify novel biomarkers that can be used to predict those patients that will most benefit from pre-operative radiotherapy.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: MICA: Using circulating tumour DNA to identify and predict mechanisms of resistance to targeted cancer therapies.
Funder: Medical Research Council

Abstract: Aims: To investigate circulating tumour DNA (ctDNA) as a biomarker to predict sensitivity and primary or acquired targeted therapy, focusing on advanced breast cancer treated with the CDK4/6 inhibitor palbociclib. CDK4/6 inhibitors are one of the most promising targeted therapies in clinical development with evidence of activity in multiple tumour types. Objectives: 1) Identify genetic aberrations in baseline ctDNA that predict for sensitivity to CDK4/6 inhibition, to select the most appropriate patients for therapy. 2) Assess whether change in abundance of ctDNA following 2 weeks of treatment can identify cancers that are resistant to treatment early. 3) Assess whether analysis of ctDNA can identify the emergence of resistant clones on disease progression. Methodology: The project will utilise samples collected at baseline and day 15 of treatment, then again on progression from two trials treating breast cancer patients with palbociclib, PEARL (350 samples) and PALOMA-3 (500 samples). 1) Identify genetic aberrations in baseline ctDNA that predict for sensitivity to CDK4/6 inhibition by sequencing plasma DNA using a custom targeted Ampliseq panel on the Ion Torrent Personal Genome Machine. Validation will be by using droplet digital polymerase chain reaction assays run on the BioRad QX200 platform. 2) Sequence day 15 plasma, and establish criteria for fractional change in abundance of ctDNA that predict for outcome. 3) Paired plasma DNA samples, baseline and progression, with a high proportion of ctDNA will undergo exploratory whole-exome sequencing. Acquired mutations will be validated, the function of recurrent acquired mutations investigated in vitro. Scientific and medical opportunities: This will be largest cohort of plasma sequenced for ctDNA in the literature, offering an unprecedented opportunity to link prospectively collected clinical data to ctDNA, validating it as a biomarker for targeted therapy potentially for routine clinical practice


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Investigating the use of fluorescent proteins to identify dysplasia during endoscopy and surgery
Funder: Medical Research Council

Abstract: We have identified a fluorescent protein that is able to distinguish between normal and pre- cancerous tissue, which can be applied topically and assist visualisation of dysplasia that might otherwise be missed using white light endoscopy alone. Treatment at this early stage can be achieved less invasively, often at endoscopy and is associated with higher survival rates. This technique therefore has the potential to improve patient quality of life, reduce mortality and overall costs to the NHS. The protein probe is naturally derived and can be applied topically as a spray during colonoscopy or transanal endoscopic microsurgery (TEMS). We have validated the use of this protein on simulated endoscopic examinations using freshly resected specimens. We are now in a position to undertake a "first in man" feasibility study using this tool to see if it can help identify flat lesions that might otherwise be missed by white light endoscopy and in clarifying the borders of lesions for complete resection. Suspicious lesions will be characterized with white light and compared with fluorescence after application with the protein. Signal to background ratios will be calculated. Specimens of tissue from normal and abnormal fluorescent staining will be taken and compared with subsequent histology. This will allow calculation of sensitivity and specificity, and allow sufficient data for a power calculation for a subsequent clinical trial. We will also record any complications that arise, including side effects associated with the use of this probe. This feasibility study will aim to recruit 50 patients. Inclusion criteria are patients aged over 18 undergoing endoscopic examination (colonoscopy/flexible sigmoidoscopy) or TEMS surgery. We will enrich our patient population for the presence of dysplasia by recruiting those with known flat lesions, colorectal cancer and ulcerative colitis with dysplasia. Exclusion criteria will include pregnancy and vulnerable patient groups.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Identification of in-vivo generated human autoantibodies for the screening and early detection of primary colorectal cancer (CRC)
Funder: Medical Research Council

Abstract: Colorectal cancer (CRC) is the second most common cancer in the western world: the critical survival determinant is disease stage (over 90% survival for Duke's Stage A). Randomised trials, using the faecal occult blood test (FOBt) followed by colonoscopy, have shown early detection and intervention resulting in ~16% reduced mortality. This impact is limited due to the majority of patients presenting with late disease, low patient compliance for FOBt (Uptake: UK 57%; European 34%) and the relatively low sensitivity (~50%) and specificity (~75%). Although mortality reduction for one off and repeat flexible sigmoidoscopy appears higher (22%-31%), patient acceptability remains low (45%-58%). Uptake of one-off colonoscopy is even lower (24.6%). We aim to develop a robust, non-invasive blood test with sensitivity (>65%), specificity(>85%) and a high patient acceptability rate (>90%), with the potential to significantly improve clinical outcomes by detecting early stage CRC. Immune system recognition of tumour associated antigens (TAAs) elicits autoantibody (AAb) responses during early tumour development; detection of such AAb can support early CRC detection. Microarray technologies for AAb detection offer scalability and economy of sample and reagent use, making them ideal tools for cost-effective, comprehensive CRC screening. Preliminary work, generated with an MRC CiC award, measured AAb responses to 32 TAAs: identifying that a subset of six TAAs provides >65% sensitivity & >85% specificity using CRC/control samples (262). This project will identify an optimal panel from the larger group of 32 TAAs and validate that core panel to pre-defined sensitivity and specificity using larger, clinically well-defined sample sets provided by 2 UK and 2 USA centres with known expertise in screening for CRC. An optimised AAb blood test will, in future prospective studies, be assessed against FOBt or its likely successor the quantitative Faecal Immunochemical Test (qFIT).


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Unravelling the Mechanism of the Lung Tumour Suppressor LIMD1 from Cellular Metabolism to Malignant Transformation.
Funder: Medical Research Council

Abstract: Lung cancer is the most common cancer worldwide, with in excess of 1.61 million new cases diagnosed each year, with 1 in 5 leading to death. The gene LIMD1 is lost early in the progression of non-small cell lung cancer including squamous cell carcinoma (SCC) of the lung and normally functions as a tumour suppressor. In published work we recently demonstrated that LIMD1 loss results in stabilisation of HIF1 in a number of cell lines, new preliminary data shows that this mechanism is also present in primary human bronchial epithelial cells (HBECs). We have previously shown that loss of LIMD1 leads to enhanced cellular transformation and exciting preliminary data from our groups shows that LIMD1 may also regulate metabolism, potentially driving this cellular transformation. Increased energy production is important for rapidly growing cells within tumours such as SCC and a shift towards a glycolytic Warburg-like phenotype is a common hallmark of cancer. Loss of LIMD1 leads to increased transcription of a number of genes involved in this metabolic shift. Silencing of LIMD1 also resulted in reduced pyruvate utilization and decreased mitochondrial function, suggesting an important role for LIMD1 in regulation of the mitochondrial energy production. We hypothesise that loss of LIMD1 occurs in the lung epithelium at an early stage in its transformation towards SCC of the lung. This loss of LIMD1 leads to a metabolic re-programming, that may or may not depend mechanistically on HIF1 stabilisation, which drives this transformation. We will investigate this hypothesis using an organotypic primary HBEC culture where cells are grown at an air liquid interface (ALI) to recapitulate the adult upper airways. We believe that reversal of these LIMD1 loss induced metabolic changes by chemical agents may represent a novel therapeutic avenue for the treatment of SCC. This exciting project will address the key role of LIMD1 as a master regulator of metabolism, and the Warburg-lik


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Chemical bioreductive approaches to targeted radiosensitisation and imaging of tumours
Funder: Medical Research Council

Abstract: Tumour hypoxia presents a major barrier to effective radiotherapy. We have taken a novel approach to targeting hypoxic cancer cells through the development of a molecularly targeted bioreductive drug. Our proof-of-concept compound CH-01 is a Chk1/Aurora A kinase inhibitor that only shows activity in hypoxic conditions. We have synthesised a small quantity of an improved next generation compound CH-02 and determined that it is reduced/fragmented in hypoxic conditions and also inhibits Chk1 in these situations. As a result of these positive data, we propose to scale up the synthesis of CH-02, complete the in vitro testing and progress to using it in xenograft tumour models. Our goal is to demonstrate that CH-02, in combination with radiation, is an effective was to delay tumour growth. In order to facilitate the use of this agent, and subsequent bioreductives, we have designed the compounds such that they become fluorescent in the near infrared (NIR) after bioreduction. This "switch-on" NIR fluorescence will allow us to monitor the biodistribution and activation of the prodrug during both in vitro and in vivo testing. This entirely novel approach will provide real time information on the bio-distribution of a molecularly targeted bioreductive compound for the first time. Together, our cross-disciplinary approach represents a novel strategy for the treatment of hypoxic cancers, which is likely to highly effective when combined with radiotherapy.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Contribution by NRF2 upregulation to lung carcinogenesis, and the possible therapeutic value of NRF2 inhibition by GSK-3
Funder: Medical Research Council

Abstract: Lung cancer is the most common cause of death from malignant disease worldwide. Mutations that cause constitutive upregulation of the antioxidant transcription factor NRF2 are extremely common in lung cancer, but it is not known why this is the case. Thus the objectives of this grant are to determine why NRF2 is upregulated in a large proportion of lung tumours, and to examine whether suppression of NRF2 by activating its negative regulator GSK-3 inhibits lung tumourigenesis. We will use phosphospecific antibodies to define the molecular mechanisms by which activation of GSK-3 suppresses NRF2, and will test in a human lung cancer cell line whether upregulation of NRF2 supports tumourigenesis by inhibiting apoptosis, increasing mutagenesis (arising from activating chemical carcinogens in cigarette smoke), and/or increasing production of NADPH and ATP for synthesis of macromolecules. Next we will use a lung cancer experimental model on 5 different genetic backgrounds in order to provide widely divergent and incremental increases in NRF2 activity (from null to high) in order to determine the impact of variation in NRF2 activity on lung carcinogenesis, and to identify biomarkers associated with its ability to support cancer. We will then translate these findings into man by examining the prognostic significance of NRF2 upregulation and associated biomarkers in large, clinically annotated, training and separate validation cohorts of 250 lung cancer cases collected between 2000-2006 with known outcomes. Lastly, we will examine whether suppression of NRF2, by activating GSK-3 with MK2206, decreases lung tumour burden in mice with high NRF2 levels. This project will provide new mechanistic insight into how NRF2 supports lung cancer. Further, the results will enable NRF2-based stratification of patients with lung cancer for therapy. It will also allow us to test whether the drug MK2206, which activates GSK-3, is best targeted at patients with upregulation of NRF2.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Identification of therapeutic sensitivities and pathways driving adrenocortical carcinoma
Funder: Medical Research Council

Abstract: Rare adrenocortical carcinoma (ACC) is an aggressive disease with poor 5 year prognosis. Recent sequencing studies have revealed recurrent alterations in the WNT signalling pathway to be one of the most frequent alterations in ACC. Studies in mice have shown that an adrenal cortical specific activating mutation in Ctnnb1 can give rise to tumour formation, highlighting the value of this model to study adrenal carcinogenesis. We have identified HOXB9 as a gene upregulated in adrenal mouse tumours driven by an activating Ctnnb1 mutation and in human ACC samples where high levels correlate with WNT signalling dysregulation and decreased survival frequency. The aim of this project is to investigate the cellular and molecular pathways by which HOXB9 drives tumour progression. We have generated transgenic mice with elevated Hoxb9 expression in adrenal cortical cells. Mice that contain this transgene and an activating Ctnnb1 mutation showed acceleration of tumourigenesis. We will fully analyse the adrenal tumour phenotype of these mice. We will use adrenocortical cell lines to confirm the functional role of HOXB9 in processes such as cell proliferation, survival, migration and invasion. We will also identify the molecular pathways associated with HOXB9, including its interaction with the WNT signalling pathway. An additional aim of this project is to characterise the drug sensitivities associated with the WNT signalling pathway in ACC. Using various ACC models with dysregulated WNT signalling we will investigate the effect of drugs targeting this pathway on cell survival in vivo and in vitro. Using high throughput drug library screens we will identify combination therapies that will increase the effectiveness of these targeted compounds. We will also use RNA interference screens to identify the key nodal points in the WNT pathway that when inhibited achieve a therapeutic response in ACC.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: ZMYND8-regulation of MITF as potential therapeutic target in melanoma
Funder: Medical Research Council

Abstract: In this project we will use a combination of recombinant, structural and cell biology techniques together with deep sequencing and expression profiling, aiming to understand the transcriptional control exerted over MITF, the melanoma 'master regulator', by ZMYND8, a recruiter of suppressive transcriptional complexes. The project will first examine how ZMYND8 interacts with chromatin and DNA, where it localizes genome-wide, including understanding the contribution to DNA interaction by its modular domains. We will then explore the transcriptional factors and complexes that ZMYND8 recruits and interrogate their co-localization to ZMYND8 specific loci as well as the fate of ZMYND8 localization in their absence. The attenuation of the expression of MITF and its controlled transcriptional programmes will then be examined, seeking to uncover a link to MAPK inhibitor resistance, as low levels of MITF have been linked to drug resistance in patients carrying activating BRAF mutations. The goal of this project is to describe the molecular mechanisms underpinning the attenuation of the melanoma master regulator, MITF, delineating the key factors controlling its levels and discerning the complexity of transcriptional activation/repression by epigenetic factors in melanomas, offering alternative novel targets for disease treatment in drug resistant, mutated BRAF melanomas.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Targeting the FOXM1 signature for early diagnosis and treatment in cholangiocarcinoma
Funder: Medical Research Council

Abstract: We will study the regulation and role of FOXM1 and its downstream targets in the cholagiocarcinoma (CCA) initiation, progression and drug resistance using the zebrafish, mouse and human in vivo models as well as CCA cell lines. This study will identify key FOXM1 expression signatures essential for CCA tumorigenesis, metastasis, angiogenesis and the development of drug resistance. The proposed project consists of 4 overlapping objectives (1-4). In objective 1, we will identify and characterize the putative FOXM1 signature genes in CCA cell lines using proliferation, clonogenic, Western blot and RT-qPCR analyses. We will then confirm these putative genes as FOXM1 downstream targets in CCA and in response to chemotherapy treatment using siRNA to selectively silence FOXM1 in drug sensitive and resistant CCA lines cells. We will also confirm these results and uncover novel FOXM1 targets by studying the mRNA and miRNA expression using microarrays. In objective 2, the role and regulation of FOXM1 and its targets during cholangiocarcinogenesis will be confirmed in an in vivo model of liver fluke infection by immunohistochemistry staining. The role and expression of the FOXM1 signatures in CCA angiogenesis and metastasis will be examined in in vivo systems, including a novel zebrafish embryo model. The function of the FOXM1 signature in drug resistance will also be tested in CCA cell lines. In objective 3, we will attempt to identify the components of the FOXM1 gene signature/signalling network that can be targeted to enhance cell death and senescence and to overcome drug resistance using CCA cell lines. In objective 4, the findings from the in vitro and in vivo studies will then be validated samples from CCA patients. It is anticipated these studies will identify key FOXM1 gene expression signatures that are important for CCA initiation, progression and drug resistance and help to uncover crucial early diagnostic markers and therapeutic targets for CCA.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Role of heparin binding growth factors in O.viverrini induced Cholangiocarcinoma (O-CCA) development, progression and angiogenesis
Funder: Medical Research Council

Abstract: Technical Summary. We aim to test four hypotheses. a) O-CCA tumours produce growth factor combinations that lend themselves to heparin binding mediated tumour growth. This will be done by combining tissue collection of samples and processing them into a tissue microarray for screening of tumours for expression of growth factors and their receptors. We will also generate a bank of CCA tumour cell lines from fresh tissue collected in Thailand and Nottingham. We will investigate growth factor expression by multiplex ELISA, HB-GF receptor expression and signalling by RNA expression by digital droplet PCR and western blot using phosphospecific antibodies, and by pharmacologically and molecular interference with the signalling pathways. We will develop patient derived tumour cell lines and xenografts for in vivo modelling of these tumours. We will compare NonO with O-CCA to determine differences in signalling. b) O-CCA mediated angiogenic growth factor production is a consequence of that growth factor signalling Production of angiogenic cytokines, in particular VEGF but others too will by these cells will be examined in response to pharmacological inhibition and molecular knockdown of the HN-GFs and their receptors. c) that preventing that upregulation in O-CCA cells can slow O-CCA in animal models These will then be followed up in vivo by determining cacner growth rates in heterotopic (subcutaneous, measured by calliper) and orthotopic (bile duct, measured by bioluminescent imaging) tumour growth in immunosuppressed animals with human stromal cells. d) that this can be done using sulphated galactans from G. fisherii. O-CCA and NonO-CCA cells will be treated with heparin binding inhibition with sulphated galactan and the identify of the HBGFs discovered, the mechanism of action determined, and the role of those HBGFs in mediating cell migration, proliferation and angiogenesis investigated.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS