NIHRDataInsights/HRCSData huggingface dataset:
Title: Nuffield Research Fellowship
Funder: Cancer Research UK

Abstract: Despite several advances in techniques of radiotherapy planning (intensity modulated radiotherapy (IMRT), tumour imaging (PET, MRI); radiation delivery (rotational arc therapy, flattening filter free), image guided radiotherapy (IGRT), the techniques and doses used for radiotherapy treatments of gastro-intestinal malignancies cancers have remained unchanged. The outcomes of patients with tumours such as oesophagus or pancreas; treated with chemo-radiotherapy in the radical setting have not improved over the last decades with local failure (mainly in the radiotherapy target volume) being predominant. The causes of local failure are due to several aspects: inadequate radiation dose, hypoxia, failure to target areas that have an unfavourable micro-environment. The advances in technology offer an opportunity to explore novel approaches. The aim of my research has 3 main themes with the ultimate aim of maximising clinical benefit in terms of better tumour control and reduction in toxicity. 1. Strategies of modulating radiotherapy (SMART). Radiotherapy dose escalation techniques using Simultaneous Integrated Boost (SIB) permits intensification of radiotherapy dose to predetermined volumes of the highly conformal target volume e.g. Tumour control probability/ normal tissue control probability (TCP/NTCP) models can be then used to refine the escalation further. The SIB could be derived from biological imaging such as PET or functional MRI. These techniques can incorporate imaging as a biomarker for outcome and toxicity with the aim to individualise dose and fractionation delivered. Combination with biological agents would be tested to further improve the therapeutic ratio. These techniques will be tested in oesophageal and anal cancers in the first instance. 2. Margin targeted radiotherapy concept. The use of stereotactic ablative radiotherapy to areas at risk of positive margin at surgery with the aim of achieving complete tumour resection in tumours such as pancreatic cancers. 3. Refining normal tissue toxicity modelling in thoracic malignancies. The objective of this work would be to characterise and corroborate lung, heart and oesophagus radiotherapy toxicity parameters and develop individualised RT delivery techniques to mitigate dose to susceptible cardiac and or lung substructures. Develop patient selection and specific cardiopulmonary optimisation when multimodality approach such as chemo-radiation followed by surgery is required. Novel MRI techniques would be tested to characterise changes and aid develop patient specific RT delivery.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Early diagnosis commissioned policy research programme
Funder: Cancer Research UK

Abstract: The Cancer Survival Group’s 'Cancer Policy' programme will address cancer research questions that are more specifically defined as relevant for Cancer Research UK policy needs than is usual for a research programme. It will comprise of a series of relatively short-term research projects. For example, we propose to include a comparative study on the impact of stage and treatment on net survival for the most recent possible years of diagnosis in England (or the UK) and one other jurisdiction, such as Canada. A central objective for this rapid international comparison will be to focus on a cancer for which a marked improvement in survival in England is likely to be achievable (e.g. non-small cell lung cancer, for which neither stage distribution nor stage-specific survival are optimal in the UK). As another example, we will update trends in the national cancer survival index and maintain a rolling programme of short-term survival analyses, with demographic and tumour characteristics of those who die soon after diagnosis. Other projects will be initiated as the need arise, in relation to evolving cancer policy in the UK.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Translational Cancer Research Prize 2013
Funder: Cancer Research UK

Abstract: Teams: Signal Transduction and Molecular Pharmacology and Clinical Pharmacology & Trials (including Drug Metabolism and Pharmacokenetics Group).


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: A Blood Test For Melanoma - Detection and Analysis of Tumour-Derived Circulating Free DNA by Deep Sequencing (The MELSEQ Study)
Funder: Cancer Research UK

Abstract: Background: We plan to identify mutations in circulating free DNA (cfDNA) from the plasma of melanoma patients using next generation sequencing (NGS) to simultaneously assess approx. 50 cancer genes. We will test proof of concept for the ability of cfDNA / NGS in combination to be both predictive and to detect emerging resistance in the context of BRAF inhibitor (BRAFi) therapy. Relevance to cancer: In melanoma, tumour tissue used for predictive mutation testing has often been excised years prior to development of advanced disease and may not reflect in loco tumour at the time that targeted treatment is considered. In addition, the tissue is only a sample of total tumour burden that is disseminated in space and time, so will be confounded by genetic heterogeneity. Lastly, it is rarely feasible to perform serial biopsies to monitor changing mutation status during therapy. In contrast plasma cfDNA should better reflect the total in loco tumour burden because it can be obtained contemporaneously to disease progression, it is theoretically a mixture from every tumour focus so can account for genetic heterogeneity, and it can easily be obtained sequentially as serial “liquid biopsies” during therapy to identify emerging mutations. Combining the advantages of cfDNA analysis with NGS additionally allows detection of multiple hotspot mutations across several genes, including minority mutations. Specific aims: The hypothesis is that the combination of cfDNA and NGS analysis can be both predictive of response and detect emerging genetic resistance. We will assess the validity of the NGS assay. We will also assess the value of cfDNA for assessing initial response and emerging resistance to targeted therapy in advanced melanoma using pre-treatment tissue samples and matched serial cfDNA pre and on-treatment samples. Outline plan: We recruit advanced melanoma patients who are being considered for BRAFi therapy as a proof of concept model for achieving our study aims, with premise that cfDNA/NGS can be targeted to other molecular targets and treatments as and when they emerge. NGS assay validation will be achieved by cell line DNA "spike" experiments. We will assess 100 patients being considered for BRAFi treatment and compare tissue and cfDNA mutation profiles against clinical/radiological response. Of these 100, approximately 50 will receive BRAFi treatment. We will take serial on-treatment samples from these to detect gentic changes associated with BRAFi resistance, focusing on emergence of NRAS mutation as proof of concept for detection of genetic resistance.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Stratfied Medicine Programme 2
Funder: Cancer Research UK

Abstract: Lung cancer is a devastating and very common healthcare problem. It is the most common cancer worldwide with 1.61 million new cases in 2008. There has been a revolution in the management of NSCLC over the past 10 years. The discovery of the molecular basis of response to Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) resulted in a paradigm shift in our thinking about this disease to one based on the rational selection of personalised therapy based on the determination of actionable drivers. In 2011 Cancer Research UK set up the Cancer Research UK Stratified Medicine Programme. The first part (SMP1) proving the feasibility of implementing large scale molecular testing in cancer within the NHS whilst consenting patients to use their molecular and routine clinical data for research. The National Lung Matrix Trial is aligned to the second part of the programme, SMP-2, which will focus on lung cancer. This initiative will provide large volume national molecular pre-screening integrated with a national clinical trial network to deliver a stratified trial. The National Lung Matrix Trial will provide the umbrella structure for multiple trial arms, each with treatment allocated according to molecular phenotype as determined by molecular pre-screening through SMP2. The size of each cohort will depend on the nature of the compound (cytostatic versus cytotoxic) but will be approximately 30 patients per arm in order to generate the required signal of activity. A key feature is the inclusion of repeat biopsy at disease progression to collect appropriate tissue samples prior to therapy to reveal potential positive and negative predictive biomarkers for each agent and to investigate resistance mechanisms The study will be open at all ECMCs and will be carried out under a single clinical trial protocol and regulatory submission. The objectives of the National Lung Matrix Trial are: • To detect a signal of drug activity sufficient to justify further investigation in that molecularly-defined group. • To collect tissue linked to clinical outcome data for future exploratory analysis to investigate the molecular phenotype of tumours in responding versus non-responding patients and to further develop the clinical diagnostic test necessary to support further investigation of the agent in the relevant molecularly-defined group. • To identify predictive biomarkers for activity of the various drugs used in the various molecular cohorts. • To determine the mechanisms of resistance to the target therapies utilised.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Combined ATR (AZD6738) and PARP (olaparib) inhibition as therapeutic strategy for TP53 mutated non-small cell lung cancer (NSCLC)
Funder: Cancer Research UK

Abstract: Background: Lung cancer is a devastating disease, and is the leading cause of cancer death in the UK and worldwide. Although potentially curable in its early stages, the majority of lung cancer patients present with advanced disease which has very poor long-term survival rates. TP53 is commonly mutated and inactivated in many solid tumours including in the majority of lung cancer cases. TP53 is a tumour suppressor gene where mutation leads to a loss of some, but not all, cell cycle checkpoints in response to DNA damage and genome instability. Using cell lines derived from human lung cancer, we found that combination treatment with inhibitors of Ataxia-Telangiectasia Related (ATR) protein kinase, and Poly-ADP Ribose Polymerase (PARP) selectively and potently inhibited the growth of TP53 mutated cells in both 2-D and 3-D cultures in vitro. Aims: We will examine whether a combination of an ATR inhibitor and a PARP inhibitor will selectively inhibit the growth of TP53 mutant tumours in vivo. We aim to show that the combination is not only more effective than either monotherapy, but that it is well-tolerated and can induce robust tumour regressions. We will also examine potential biomarkers of ATR and PARP inhibition in both tumour and non-tumour tissue. Methods: TP53 wild-type and mutant human NSCLC xenografts will be established (100 mm3) female nude mice. Mice will be treated with drug vehicle, each agent alone and the combination therapy for 3 days. Tumour growth will be followed for up to 6 weeks. Tumour and non-tumour tissue will be assessed during and after treatment by immuno-histochemistry to investigate potential biomarkers of drug effects. How the results of this research will be used:If the study meets its objectives we will propose a phase 1/2 trial of the combination in patients with TP53 mutated tumours. A tumour TP53 mutation assay is in place in Oxford and will be used to select patients. We aim to test the combination in an expansion cohort of TP53 mutated NSCLC to decide on performing a randomized phase 2 study using docetaxel as a comparator. In addition to an NSCLC expansion we would propose including cohorts of patients with other TP53 mutated tumours where our other ongoing preclinical work is supportive and where anti-tumour activity is evident in the escalation phase.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Advances in Cancer Drug Discovery
Funder: Cancer Research UK

Abstract: Cancer drug discovery is now firmly in the era of molecularly targeted agents. This approach builds on advances in our understanding of the molecular biology of tumours coupled with the application of modern approaches to cancer drug discovery. One of the key features, which is clearly apparent as this approach matures is the importance of a holistic understanding with biologists, medicinal chemists and clinicians collaborating closely and providing feedback to enable the challenges of cancer drug discovery to be overcome. This complete picture of the cancer drug discovery effort is a key feature of the Advances in Cancer Drug Discovery conference.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: First-in-class selective IKKalpha inhibitors for evaluation in pancreatic cancer
Funder: Cancer Research UK

Abstract: Pancreatic cancer is one of the most intractable and untreatable cancers in the UK. Death rates are unacceptably high and despite considerable research, the survival rate for both men and women over five years remains less than 4%. New therapies are desperately needed. Recent studies implicate the involvement of the Nuclear Factor Kappa B (NF?B) pathway in the development of pancreatic cancer and key roles for the upstream regulatory kinases, the inhibitory kappa B kinases (IKKs). Whilst the majority of work has focussed on the IKKß component of the pathway, more recent studies strongly implicate a role for IKKa. Over the last five years, the SMDD group at Strathclyde has successfully prosecuted a program to establish the first ever series of selective IKKa inhibitors, generating novel compounds with promising pharmacodynamic properties and considerable clinical potential. Indeed, our preliminary studies demonstrate for the first time that one these compounds, SU1261, not only inhibits proliferation of a number of pancreatic cells lines but significantly, inhibits acinar-to-ductal metaplasia, a key transition stage in pancreatic cancer development. Therefore the aim of this one year, proof-of-concept project is to establish the potential of selective IKKa inhibitors as a new class of therapy for the treatment of pancreatic cancer. In this project we will: 1) Establish that our novel series of compounds are able to selectively block the IKKa pathway in pancreatic cell lines and as a consequence inhibit tumour growth and proliferation. This will be achieved by assay of p100 phosphorylation, formation of p52 and RelB, analysis of secondary downstream transcription factors and measures of proliferation, cell cycle progression, clonogenic expansion and apoptosis. 2) Utilise gene array approaches to establish a composite set of IKKa-dependent genes unique to pancreatic cancer which are selectively inhibited by treatment with our lead compounds. This marker profile will link pharmacological inhibition of IKKa to cellular outcomes relevant to pancreatic tumour development, will enable the efficacy of the inhibitor series to be tested in vivo and will facilitate the future interrogation of patient cohorts and their stratification. 3) Improve the physiochemical properties of our lead series to enable future use in vivo and address any significant off-target effects, specifically CDK2 and CDK9 activity. Compounds will be progressed through our established assay cascade, incorporating parameters outlined in (1) and (2), towards downstream in vivo assessment.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Development of the RALA-hOC/iNOS gene therapy for metastatic breast and prostate cancer
Funder: Cancer Research UK

Abstract: This proposal is designed to develop our novel nanoparticles to a stage that they can be taken forward into a clinical trial for patients with breast and prostate cancer bone metastases. For patients in this position the treatment options are limited. Tumours that have metastasized to bone have higher levels RUNX2, the main transcription factor involved in activating the human osteocalcin (hOC) promoter. We have developed a transgene construct utilizing the cytotoxic and chemo/radio sensitising inducible nitric oxide synthase gene (iNOS) and have previously compiled evidence for a significant anti-tumour effect in vivo. The drawback to many gene therapies has been an effective non-toxic delivery system. To that end, we have designed a novel 30 amino acid peptide sequence, RALA which is able to condense DNA, form stable nanoparticles, enter cells, disrupt endosomes and transport its cargo to the nucleus. With previous funding from Cancer Research UK Discovery Committee (Feb 2012-Jan 2014) we have compiled further evidence to support RALA/hOC-iNOS as a viable therapeutic following systemic administration. More specifically we have shown that the RALA can overcome the biological barriers and deliver the cargo DNA to the nucleus and that there is no vector neutralization after repeated delivery of the nanoparticles and no evidence of anti-RALA/DNA antibodies. Most crucially though whenever we create highly aggressive metastatic models for both breast and prostate cancer, there is a significant therapeutic effect with a delayed initiation of tumours, reduction in tumour burden coupled with increased survival. Initial freeze-drying studies have indicated that the nanoparticles do not lose their efficacy. Based upon this evidence Cancer Research Technology are now in discussions with QUB to license the RALA/hOC-iNOS technology. In this proposal we are seeking funding to further optimize the RALA/hOC-iNOS nanoparticles with respect to dose, frequency of delivery, duration of treatment and as an add-on therapy to chemotherapies in xenograft models. Most importantly we want to show the effects of RALA/hOC-iNOS in clinically relevant patient derived xenograft models. In addition we want to gather data on RUNX2 expression in tumour samples to validate it as a companion biomarker to pre-select patients most likely to respond to our hOC-iNOS therapy. Finally we will also acquire the necessary pre-clinical regulatory data with respect to storage and sterility. The over-riding focus of this proposal is to provide translational evidence for regulators, attract commercialization together with Cancer Research Technology in order to facilitate RALA/hOC-iNOS clinical development.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Advancing Genotype Guided Stratified Therapy for Pancreatic Cancer.
Funder: Cancer Research UK

Abstract: Pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer (90%), is the 5th commonest cause of cancer death in the UK. Surgery is the only chance of cure, however, the vast majority of patients have advanced disease and are inoperable at the time of diagnosis. Over 80% of the 10 – 20% who undergo resection for small, localised lesions still succumb to the disease1. Post-operative chemotherapy can improve survival despite the modest anti-tumour efficacy of these agents, nevertheless, overall outcomes remain disappointing2, 3 with a 5 year survival rate that has remained below 5% for over 45 years. Consequently there is an urgent need to develop early detection and novel therapeutic approaches. The overall aim of this proposal is to build on our large-scale efforts in cancer genomics 4-6 and define actionable molecular phenotypes for early translation into stratified therapeutic strategies, uncover and validate mutational signatures in genetically engineered mouse models of PDAC, and identify novel candidate molecular mechanisms that are important in the development and progression of pancreatic cancer. We aim to: 1. Define candidate molecular phenotypes that confer sensitivity to existing therapies (including rescuing, repurposing, and emerging therapeutics), using extensive genomic data from the Australian Pancreatic Cancer Genome Initiative (APGI), which used a prospective, non-interventional cohort study design. Then test the therapeutic responsiveness of these molecular phenotypes in unique, comprehensively genomically characterised patient-derived xenografts (PDX). 2. Characterise the genomic events that are present in specific genetically engineered mouse models of PDAC to uncover and validate mutational signatures in the human disease, and inform driver discovery in human PDAC. 3. Integrate genomic data from human and murine PDAC with other “-omic” datasets to define novel candidate driver mutations and mechanisms that contribute to pancreatic carcinogenesis that may constitute therapeutic targets.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS